Sample records for a-t-il une place

  1. Appendicite aigue non compliquée: y a-t- il une place pour le traitement conservateur

    PubMed Central

    El Khader, Ahmed; Lahkim, Mohamed; El Barni, Rachid; Achour, Abdessamad

    2015-01-01

    Le but de cette étude a été d’évaluer l'efficacité de l'antibiothérapie seule dans le traitement des appendicites aigues non compliquées. C'est une étude prospective, intéressant 68 patients ayant eu une appendicite aigue simple, de confirmation radiologique, traités par l'amoxicilline associée à l'acide clavulanique pendant 10 jours. L'appendicectomie a été réalisée en cas d'aggravation ou en cas de non amélioration au bout de 48heures de traitement. Le traitement conservateur a été efficace dans 82,35% avec une résolution complète des symptômes chez 56 patients. Les 12 cas restants (17,65%) ont subit une appendicectomie. l'appendicite a été gangréneuse dans 8 cas et phlegmoneuse dans 4 cas. Cinq des 56 patients, qui ont bien évolué sous traitement conservateur, ont été réadmis et opérés pour récidive, soit 8,9%. Deux cas ont eu une appendicite compliquée. L'appendicectomie reste le traitement de référence pour l'appendicite aigue, mais le traitement antibiotique peut être proposé en première intension à des patients présentant une appendicite aigue non compliquée. PMID:26327981

  2. Les infestations par les poux de tête : une mise à jour clinique.

    PubMed

    Cummings, Carl; Finlay, Jane C; MacDonald, Noni E

    2018-02-01

    Les infestations par les poux de tête ( Pediculus humanus capitis ) ne constituent ni un risque sanitaire primaire ni un vecteur de maladie, mais représentent plutôt un problème de société au coût impor- tant. Pour diagnostiquer une infestation, il faut déceler un pou vivant. Même si les pyréthines et la perméthrine demeurent les traitements de première intention au Canada, la solution de myristate d'isopropyle et de ST-cyclométhicone et la diméticone peuvent être envisagées en deuxième intention après un échec thérapeutique démontré.

  3. L’alimentation des enfants ayant une déficience neurologique

    PubMed Central

    2009-01-01

    La malnutrition, qu’il s’agisse de sous-alimentation ou de suralimentation, est courante chez les enfants ayant une déficience neurologique. Les besoins en énergie sont difficiles à définir au sein de cette population hétérogène. De plus, on manque d’information sur ce qui constitue la croissance normale chez ces enfants. Des facteurs non nutritionnels peuvent influer sur la croissance, mais des facteurs nutritionnels, tels qu’un apport calorique insuffisant, des pertes excessives d’éléments nutritifs et un métabolisme énergétique anormal, contribuent également au retard de croissance de ces enfants. La malnutrition est liée à une importante morbidité, tandis que la réadaptation nutritionnelle améliore l’état de santé global. Le soutien nutritionnel doit faire partie intégrante de la prise en charge des enfants ayant une déficience nutritionnelle et viser non seulement à améliorer l’état nutritionnel, mais également la qualité de vie des patients et de leur famille. Au moment d’envisager une intervention nutritionnelle, il faut tenir compte du dysfonctionnement oromoteur, du reflux gastro-œsophagien et de l’aspiration pulmonaire, et une équipe multidisciplinaire doit se concerter. Il faut repérer rapidement les enfants vulnérables à des troubles nutritionnels et procéder à une évaluation de leur état nutritionnel au moins une fois par année, et plus souvent chez les nourrissons et les jeunes enfants ou chez les enfants qui risquent de souffrir de malnutrition. Il faut optimiser l’apport oral s’il est sécuritaire, mais entreprendre une alimentation entérale chez les enfants ayant un dysfonctionnement oromoteur qui provoque une aspiration marquée ou chez ceux qui sont incapables de maintenir un état nutritionnel suffisant au moyen de l’apport oral. Il faut réserver l’alimentation par sonde nasogastrique aux interventions à court terme, mais si une intervention nutritionnelle prolongée s

  4. A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells.

    PubMed

    Mao, Yujia; Yin, Shanshan; Zhang, Jianmin; Hu, Yu; Huang, Bo; Cui, Lianxian; Kang, Ning; He, Wei

    2016-03-01

    Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (γδ) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of γδ T cells and the balance between variable delta 1 (Vδ1) and Vδ2 T cells in humans. The results show that IL-4 inhibits the activation of γδ T cells in the presence of γδ T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated γδ T cells and increased the levels of Vδ1 T cells, which in turn inhibited Vδ2 T-cell growth via significant IL-10 secretion. Vδ1 T cells secreted significantly less interferon gamma (IFNγ) and more IL-10 relative to Vδ2. Furthermore, Vδ1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vδ1 T cells weaken the γδ T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in γδ T cell-mediated anti-tumor immunity.

  5. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9.

    PubMed

    Dumoutier, L; Louahed, J; Renauld, J C

    2000-02-15

    IL-9 is a Th2 cytokine active on various cell types such as T and B lymphocytes, mast cells, and eosinophils, and potentially involved in allergy and asthma. To understand better the molecular mechanisms underlying the activity of this cytokine, we used a cDNA subtraction method to identify genes specifically induced by IL-9 in mouse T cells. One of the IL-9-regulated genes isolated by this approach turned out to encode a 180-amino acid long protein, including a potential signal peptide, and showing 22% amino acid identity with IL-10. This protein, designated IL-10-related T cell-derived inducible factor (IL-TIF), is induced by IL-9 in thymic lymphomas, T cells, and mast cells, and by lectins in freshly isolated splenocytes. Experiments concerning the mechanism regulating IL-TIF expression in T cells indicate that IL-9 induction is rapid (within 1 h), does not require protein synthesis, and depends on the activation of the Janus kinase (JAK)-STAT pathway. In vivo, constitutive expression of IL-TIF was detected by RT-PCR in thymus and brain, suggesting that the role of this new factor is not restricted to the immune system. Transfection of HEK293 cells with the IL-TIF cDNA resulted in the production of a glycosylated protein of about 25 kDa that was found to induce STAT activation in mesangial and neuronal cell lines. Further studies will have to address the possibility that some of the IL-9 activities may be mediated by IL-TIF.

  6. IL-21 sustains CD28 expression on IL-15-activated human naive CD8+ T cells.

    PubMed

    Alves, Nuno L; Arosa, Fernando A; van Lier, René A W

    2005-07-15

    Human naive CD8+ T cells are able to respond in an Ag-independent manner to IL-7 and IL-15. Whereas IL-7 largely maintains CD8+ T cells in a naive phenotype, IL-15 drives these cells to an effector phenotype characterized, among other features, by down-regulation of the costimulatory molecule CD28. We evaluated the influence of the CD4+ Th cell-derived common gamma-chain cytokine IL-21 on cytokine-induced naive CD8+ T cell activation. Stimulation with IL-21 did not induce division and only slightly increased IL-15-induced proliferation of naive CD8+ T cells. Strikingly, however, IL-15-induced down-modulation of CD28 was completely prevented by IL-21 at the protein and transcriptional level. Subsequent stimulation via combined TCR/CD3 and CD28 triggering led to a markedly higher production of IL-2 and IFN-gamma in IL-15/IL-21-stimulated cells compared with IL-15-stimulated T cells. Our data show that IL-21 modulates the phenotype of naive CD8+ T cells that have undergone IL-15 induced homeostatic proliferation and preserves their responsiveness to CD28 ligands.

  7. Variabilite temporelle des naines T et construction d'une camera infrarouge a grand champ

    NASA Astrophysics Data System (ADS)

    Artigau, Etienne

    Le travail de thèse décrit ici se divise en deux sections distinctes: la première porte sur une étude de la variabilité temporelle des naines T et la seconde sur la construction et les performances de la Caméra PAnoramique Proche InfraRouge (CPAPIR). Les naines brunes sont des objets qui se forment comme les étoiles, lors de l'effondrement gravitationnel d'un nuage de gaz moléculaire, mais dont la masse est trop faible pour leur permettre d'entretenir des réactions de fusion nucléaire. Environ 70% des naines brunes de type L, qui ont des températures comprises entre 2200 K et 1500 K, présentent une variabilité temporelle dont les mécanismes exacts font toujours l'objet de débats. Nous avons étendu la recherche de variabilité temporelle aux naines brunes ayant des températures inférieures à ~1500 K et qui présentent les signatures du méthane, soit les naines T. Nos observations menées à l'Observatoire du mont Mégantic montrent qu'une fraction importante des naines T sont variables à 1.2 mm et 1.6 mm à des niveaux allant de 17 mmag à 53 mmag RMS. Les propriétés photométriques de cette variabilité sont consistantes avec une évolution de la couverture de nuages de poussière à la surface de plusieurs naines T. Des observations complémentaires menées en spectroscopie au télescope Canada-France-Hawaii montrent, pour une naine T, une variabilité spectroscopique dans le proche infrarouge qui est aussi consistante avec l'évolution de tels nuages de poussière. CPAPIR est une caméra infrarouge con=E7ue pour être utilisée à l'Observatoire du mont Mégantic. Elle possède un champ de 30' × 30', soit le plus grand champ de vue parmi les caméras infrarouges astronomiques actuellement en service. CPAPIR est équipé d'un détecteur de type Hawaii-II sensible de 0.8 mm à 2.4 mm avec 2048×2048 pixels. L'optique cryogénique de CPAPIR comprend 8 lentilles cryogéniques et 10 filtres disposés dans deux roues à filtres. Les observations

  8. IL-23 Activated γδ T Cells Affect Th17 Cells and Regulatory T Cells by Secreting IL-21 in Children with Primary Nephrotic Syndrome.

    PubMed

    Zhang, L; Yan, J; Yang, B; Zhang, G; Wang, M; Dong, S; Liu, W; Yang, H; Li, Q

    2018-01-01

    This study (1) analysed the percentage of γδ T cells, γδ T cell subsets, Th17 cells and regulatory T cells (Treg cells) and (2) determined the role of IL-23 in primary nephrotic syndrome (PNS) patients with active disease and in remission. Eighty-four patients with PNS and 51 healthy age-matched controls were included in this study. The percentage of γδ T cells, γδ T cell subsets, Th17 cells and Treg cells in peripheral blood mononuclear cells (PBMCs) were analysed by fluorescence-activated cell sorting. PMBCs from PNS patients with active disease were cultured in the presence of IL-23, IL-23 and an IL-23 antagonist, or IL23 and an anti-IL-21 monoclonal antibody (mAb). The percentage of γδ T cells, IL-23R + γδ T cells and IL-17 + γδ T cells were significantly increased in PNS patients with active disease. There was a positive correlation between the percentage of γδ T cells, IL-23R + γδ T cells, IL-17 + γδ T cells and the Th17/Treg ratio. IL-23 increased the percentage of γδ T cells and Th17 cells and decreased the percentage of Treg cells in PBMCs isolated from PNS patients with active disease. Anti-IL-21 mAb reduced the percentage of γδ T cells and Th17 cells, but increased the percentage of Treg cells. γδ T cells, IL-17 + γδ T cells and IL-23R + γδ T cells may be involved in the pathogenesis of paediatric PNS by modulating the balance of Th17/Treg cells. γδ T cells may cause an imbalance in Th17/Treg cells by secreting IL-21 in the presence of IL-23. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  9. Le kyste hydatique du cordon spermatique: une localisation exceptionnelle

    PubMed Central

    Hamdane, Mohamed Moncef; Bougrine, Fethi; Msakni, Issam; Dhaoui-Ghozzi, Amen; Bouziani, Ammar

    2011-01-01

    L’ hydatidose est une anthropo-zoonose due au développement chez l'homme de la forme larvaire du taenia Echinococcus granulosis. La plupart des kystes hydatiques se localisent dans le foie et les poumons. Le kyste hydatique du cordon spermatique est extrêmement rare avec seulement 4 cas rapportés dans la littérature. Les auteurs rapportent dans cet article un nouveau cas d'hydatidose du cordon spermatique. Il s'agissait d'un homme de 40 ans qui consultait pour des douleurs scrotales évoluant depuis huit mois. L'examen clinique a mis en évidence une tuméfaction mobile, inguino-scrotale, droite. L’échographie testiculaire a objectivé une hernie inguinale droite associée à deux kystes épididymaires bilatéraux. Le patient a été opéré pour cure de son hernie avec découverte en per-opératoire d'un kyste du cordon spermatique qui a été réséqué. L'examen anatomopathologique a conclu à une hydatidose du cordon spermatique. PMID:22384304

  10. Une complication exceptionnelle du tétanos généralisé: l’embolie pulmonaire

    PubMed Central

    Regaieg, Kais; Bahloul, Mabrouk; Gargouri, Rahma; Bouattour, Abir; Chelly, Hèdi; Bouaziz, Mounir

    2016-01-01

    Le tétanos est une maladie caractérisée par une paralysie spastique et des spasmes. C’est une pathologie grave. Elle nécessite une prise en charge en milieu de réanimation. La mortalité est essentiellement liée aux complications neurovégétatives et infectieuses. Les complications thromboemboliques sont exceptionnelles au cours de cette maladie. A notre connaissance, l’embolie pulmonaire n’a jamais été rapportée et confirmée au cours du tétanos généralisé. Nous présentons à travers cette observation un cas de tétanos généralisé compliqué d’une embolie pulmonaire fibrino cruorique. PMID:28292134

  11. Maladie de Horton révélée par une dyspnée

    PubMed Central

    Mahfoudhi, Madiha; Mamlouk, Habiba; Turki, Sami; Kheder, Adel

    2015-01-01

    Les manifestations pleuro-pulmonaires de la maladie de Horton sont rares et peu connues. Elles peuvent être inaugurales, à l'origine d'un retard à la prise en charge si elles sont méconnues. Il s'agissait d'un patient âgé de 75 ans, admis pour une dyspnée, une toux chronique et une fièvre. Il a reçu une antibiothérapie et a bénéficié d'une fibroscopie bronchique avec lavage broncho-alvéolaire à la recherche d'un germe, qui a révélé plutôt, une alvéolite lymphocytaire. L’évolution était marquée par la persistance des signes cliniques et du syndrome inflammatoire biologique. Un angio-scanner thoracique et une échographie cardiaque étaient sans anomalies. Une origine cardiaque, musculaire, hématologique, néoplasique, vasculaire ou métabolique de la dyspnée a été éliminée. Une maladie de Horton a été évoquée. La biopsie de l'artère temporale a confirmé le diagnostic d'une maladie de Horton. L’évolution sous corticothérapie était marquée par la disparition des signes cliniques et biologiques. Les manifestations pleuro-pulmonaires au cours de la maladie de Horton sont rares, et classiquement, rarement révélatrices de la maladie. La dyspnée peut initialement égarer le diagnostic vers d'autres étiologies notamment infectieuses. Le but de ce travail est d'insister sur le fait que la connaissance de ces différentes manifestations respiratoires au cours de la maladie de Horton (toux persistante, dyspnée, épanchement pleural) est utile au clinicien afin de prescrire une corticothérapie, chez un sujet le plus souvent âgé ayant un état fébrile et inflammatoire prolongé, permettant ainsi d’éviter l'apparition de complications. PMID:26161171

  12. Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα

    PubMed Central

    Choi, I-K; Lee, J-S; Zhang, S-N; Park, J; Lee, K-M; Sonn, C H; Yun, C-O

    2011-01-01

    The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte–macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4+ and CD8+ T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12Rβ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity. PMID:21451575

  13. Failure of FIV-infected cats to control Toxoplasma gondii correlates with reduced IL2, IL6, and IL12 and elevated IL10 expression by lymph node T cells.

    PubMed

    Levy, Julie K; Liang, Yinghua; Ritchey, Jerry W; Davidson, Michael G; Tompkins, Wayne A; Tompkins, Mary B

    2004-03-01

    Increased susceptibility to intracellular pathogens in HIV-infected individuals and FIV-infected cats is attributed to a defective T-helper 1 (Th1) immune response. However, little is known about specific cytokine responses to secondary pathogens. To address this question, control and FIV-infected cats were challenged with Toxoplasma gondii, and lymph node cells analyzed for cytokine mRNA expression. Twenty-four weeks post-FIV infection, prior to T. gondii challenge, IL2 and IL12 mRNAs were depressed, whereas IL10 and IFNgamma mRNAs were increased in CD4+ and CD8+ subsets. Following T. gondii challenge, control cats showed increased expression of IL2, IFNgamma, IL10, IL12, and IL6 mRNAs. In contrast, IL2, IL6, IFNgamma, and IL12 mRNAs were suppressed in FIV-T. gondii co-infected cats, whereas IL10 remained at the high prechallenge levels. IFNgamma and IL10 mRNAs were produced by both CD4+ and CD8+ cells in FIV-T. gondii cats. Elevated IL10 may suppress a Th1 cytokine response to T. gondii challenge.

  14. Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP

    PubMed Central

    Mazzucchelli, Renata; Hixon, Julie A.; Spolski, Rosanne; Chen, Xin; Li, Wen Qing; Hall, Veronica L.; Willette-Brown, Jami; Hurwitz, Arthur A.; Leonard, Warren J.

    2008-01-01

    Interleukin-7 (IL-7), a cytokine produced by stromal cells, is required for thymic development and peripheral homeostasis of most major subsets of T cells. We examined whether regulatory T (Treg) cells also required the IL-7 pathway by analyzing IL-7Rα−/− mice. We observed a striking reduction in cells with the Treg surface phenotype (CD4, CD25, GITR (glucocorticoid-induced tumor necrosis factor [TNF]-like receptor), CD45RB, CD62L, CD103) or intracellular markers (cytotoxic T-lymphocyte–associated antigen-4, CTLA-4, and forkhead box transcription factor 3, Foxp3). Foxp3 transcripts were virtually absent in IL-7Rα−/− lymphoid tissues, and no Treg cell suppressive activity could be detected. There are 2 known ligands for IL-7Rα: IL-7 itself and thymic stromal lymphopoietin (TSLP). Surprisingly, mice deficient in IL-7 or the other chain of the TSLP receptor (TSLPR) developed relatively normal numbers of Treg cells. Combined deletion of IL-7 and TSLP receptor greatly reduced Treg cell development in the thymus but was not required for survival of mature peripheral Treg cells. We conclude that Treg cells, like other T cells, require signals from the IL-7 receptor, but unlike other T cells, do not require IL-7 itself because of at least partially overlapping actions of IL-7 and TSLP for development of Treg cells. PMID:18664628

  15. Anévrisme de l'artère fémorale superficielle lié à une infection à salmonelle

    PubMed Central

    Mrad, Melek Ben; Hammamia, Mohammed Ben; Miri, Rim; Derbel, Bilel; Koubaa, Mohammed Ali; Ziadi, Jalel; Khayati, Adel

    2015-01-01

    Les anévrismes infectieux de l'axe fémoro-poplité sont rares et d’évolution silencieuse. Ils surviennent surtout chez les sujets immunodéprimés. Leur traitement fait appel souvent à l'exclusion chirurgicale associée ou non à un geste de revascularisation. Nous rapportons le cas d'un patient opéré pour un anévrisme de l'artère fémorale superficielle, lié à une infection à salmonelle, il a eu une résection de l'anévrysme et une revascularisation par greffe veineuse. Ce patient a été repris par la suite à deux reprise pour rupture du greffon veineux. Pour cette raison, nous étions contraints à une explantation du pontage et une ligature des 2 bouts de l'artère sans revascularisation. Malgré l'absence de revascularisation, l’évolution a été favorable sous couverture d'une une antibiothérapie adaptée. En cas d'anévrysme infectieux de l'axe fémoro-poplité par infection à salmonelle, le rétablissement de la continuité artérielle, même avec un greffon veineux, peut exposer au risque de rupture artérielle. PMID:26955409

  16. IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

    PubMed Central

    2017-01-01

    γδT17 cells are a subset of γδ T cells committed to IL-17 production and are characterized by the expression of IL-23R and CCR6 and lack of CD27 expression. γδT17 cells are believed to arise within a narrow time window during prenatal thymic development. In agreement with this concept, we show in this study that adult Rag1−/− recipient mice of Il23rgfp/+ (IL-23R reporter) bone marrow selectively lack IL-23R+ γδT17 cells. Despite their absence in secondary lymphoid tissues during homeostasis, γδT17 cells emerge in bone marrow chimeric mice upon induction of skin inflammation by topical treatment with imiquimod cream (Aldara). We demonstrate that IL-1β and IL-23 together are able to promote the development of bona fide γδT17 cells from peripheral CD122−IL-23R− γδ T cells, whereas CD122+ γδ T cells fail to convert into γδT17 cells and remain stable IFN-γ producers (γδT1 cells). IL-23 is instrumental in expanding extrathymically generated γδT17 cells. In particular, TCR-Vγ4+ chain–expressing CD122−IL-23R− γδ T cells are induced to express IL-23R and IL-17 outside the thymus during skin inflammation. In contrast, TCR-Vγ1+ γδ T cells largely resist this process because prior TCR engagement in the thymus has initiated their commitment to the γδT1 lineage. In summary, our data reveal that the peripheral pool of γδ T cells retains a considerable degree of plasticity because it harbors “naive” precursors, which can be induced to produce IL-17 and replenish peripheral niches that are usually occupied by thymus-derived γδT17 cells. PMID:28855314

  17. Tumeur d'Abrikossoff juxta axillaire: une localisation rare d'une tumeur très rare, à propos d'un cas

    PubMed Central

    Amourak, Sarah; Bouzoubaa, Wael; Jayi, Sofia; Alaoui, Fatimazahra Fdili; Chaara, Hikmat; Melhouf, Moulay Abdelilah

    2015-01-01

    Décrite pour la première fois en 1926 par Abrikossoff, les tumeurs à cellules granuleuses (TCG) sont bénignes et uniques dans la grande majorité des cas. Les principales localisations sont la cavité orale, puis les tissus sous-cutanés de la tête et du cou et les seins. La pathogenèse a été longtemps débattue, après avoir proposé initialement une origine musculaire striée les études récentes sont en faveur d'une origine neurogène schwannienne confirmées par une étude immunohistochimique. Le traitement de la tumeur à cellules granuleuses est un traitement chirurgical, il permet un diagnostic de certitude par l'examen anatomo-pathologique de la pièce d'exérèse qui doit rechercher les limites d'exérèse et la présence de critères de malignité. Leur évolution est souvent favorable si la résection chirurgicale est complète. Nous rapportons ici le cas d'une tumeur d'Abrikossoff à localisation juxta axillaire et nous profitons de faire une revue de la littérature afin de mettre le point sur cette entité rare. PMID:26328001

  18. IL-8 -251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population.

    PubMed

    Liu, S; Yin, C; Chu, N; Han, L; Li, C

    2013-01-01

    Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate NALP3 and mediate interleukin (IL)-1β generation from its inactive pro-form, resulting in cellular activation and an IL-8-mediated neutrophil influx into the joint. IL-8 and IL-12 are important chemokines related to the initiation and amplification of acute and chronic inflammatory processes. In this study, we investigated whether the IL-8 -251T/A and IL-12 1188A/C polymorphisms are associated with susceptibility to gout in a Chinese Han male population. Overall, 387 patients with gout and 576 controls were included in this study. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). An association analysis was carried out using the χ2 test. A genotype-phenotype analysis was also conducted. The T allele of IL-8 -251 was associated with risk of gout [p = 0.031 (odds ratio (OR) 1.229, 95% confidence interval (CI) 1.019-1.483]. There was a clear link between the IL-12 1188 AA and AC genotypic and A allelic frequencies between gout cases and controls (p < 0.001, df = 2 by genotype; p < 0.001, OR 1.404, 95% CI 1.165-1.691 by allele). Our results suggest that the IL-8 -251T/A and IL-12B 1188A/C polymorphisms may be relevant host susceptibility factors for the development of gout.

  19. Tumeur stromale du mésentère: une cause inhabituelle d'une masse abdominale

    PubMed Central

    Tarchouli, Mohamed; Bounaim, Ahmed; Boudhas, Adil; Ratbi, Moulay Brahim; Ndjota, Bobby Nguele; Ali, Abdelmounaim Ait; Sair, Khalid

    2015-01-01

    Les tumeurs stromales gastro-intestinales (GIST) sont les tumeurs mésenchymateuses les plus fréquentes du tractus digestif. Elles représentent une entité nosologique individualisée depuis la découverte de l'expression quasi-constante de la protéine c-Kit détectée par la coloration immunohistochimique de l'antigène CD117. Des tumeurs avec les mêmes caractéristiques morphologiques et immuno-phénotypiques peuvent rarement apparaître en dehors du tractus gastro-intestinal. Nous rapportons le cas d'une jeune patiente de 34 ans présentant une masse tumorale mésentérique se révélant être de nature stromale sans aucun contact avec la paroi intestinale. Il s'agit d'une localisation très rare des tumeurs stromales à laquelle il faut penser en préopératoire afin d'avoir une conduite thérapeutique adaptée et efficace. PMID:26327998

  20. IL-2 activation of STAT5 enhances production of IL-10 from human cytotoxic regulatory T cells, HOZOT.

    PubMed

    Tsuji-Takayama, Kazue; Suzuki, Motoyuki; Yamamoto, Mayuko; Harashima, Akira; Okochi, Ayumi; Otani, Takeshi; Inoue, Toshiya; Sugimoto, Akira; Motoda, Ryuichi; Yamasaki, Fumiyuki; Nakamura, Shuji; Kibata, Masayoshi

    2008-02-01

    Interleukin (IL)-10 is an immunosuppressive cytokine produced by many cell types, including T cells. We previously reported that a novel type of regulatory T (Treg) cells, termed HOZOT, which possesses a FOXP3+CD4+CD8+CD25+ phenotype and dual suppressor/cytotoxic activities, produced high levels of IL-10. In this study, we examined the mechanisms of high IL-10 production by HOZOT, focusing on Janus activating kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway. We prepared five different types of T cells, including HOZOT from human umbilical cord blood. Cytokine productions of IL-10, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were compared among these T cells after anti-CD3/CD28 antibody stimulation in the presence or absence of IL-2. Specific inhibitors for JAK/STAT, nuclear factor-kappaB (NF-kappaB), and nuclear factor for activated T cell (NFAT) were used to analyze signal transduction mechanisms. IL-10 production by HOZOTs was greatly enhanced by the addition of IL-2. Little or no enhancement of IFN-gamma and TNF-alpha production was observed under the same conditions. The enhancing effect of IL-2 was specific for both HOZOT and IL-10-secreting Treg cells. T helper type 2 cells, whose IL-10 production mechanisms involve GATA-3, failed to show IL-2-mediated enhancement of IL-10. Similar enhancing effects of IL-15 and IFN-alpha suggested a major role of JAK/STAT activation pathway for high IL-10 production. Further inhibitor experiments demonstrated that STAT5 rather than STAT3 was critically involved in this mechanism. Our results demonstrated that IL-2 selectively enhanced production of IL-10 in HOZOT primarily through activation of STAT5, which synergistically acts with NF-kappaB/NFAT activation, implying a novel regulatory mechanism of IL-10 production in Treg cells.

  1. TNF-α blockade induces IL-10 expression in human CD4+ T cells

    NASA Astrophysics Data System (ADS)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.

    2014-02-01

    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.

  2. IL-10 and IL-27 producing dendritic cells capable of enhancing IL-10 production of T cells are induced in oral tolerance.

    PubMed

    Shiokawa, Aya; Tanabe, Kosuke; Tsuji, Noriko M; Sato, Ryuichiro; Hachimura, Satoshi

    2009-06-30

    Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to ingested antigens (Ag). Dendritic cells (DC) have been revealed as important immune regulators, however, the precise role of DC in oral tolerance induction remains unclear. We investigated the characteristics of DC in spleen, mesenteric lymph node (MLN), and Peyer's patch (PP) after oral Ag administration in a TCR-transgenic mouse model. DC from PP and MLN of tolerized mice induced IL-10 production but not Foxp3 expression in cocultured T cells. IL-10 production was markedly increased after 5-7-day Ag administration especially in PP DC. On the other hand, IL-27 production was increased after 2-5-day Ag administration. CD11b(+) DC, which increased after ingestion of Ag, prominently expressed IL-10 and IL-27 compared with CD11b(-) DC. These results suggest that IL-10 and IL-27 producing DC are increased by interaction with antigen specific T cells in PP, and these DC act as an inducer of IL-10 producing T cells in oral tolerance.

  3. Casein-specific IL-4- and IL-13-secreting T cells: a tool to implement diagnosis of cow's milk allergy.

    PubMed

    Michaud, B; Aroulandom, J; Baiz, N; Amat, F; Gouvis-Echraghi, R; Candon, S; Foray, A-P; Couderc, R; Bach, J-F; Chatenoud, L; Just, J

    2014-11-01

    Cow's milk allergy (CMA) is a frequent food allergy in young children. The oral food challenge is the gold standard for diagnosis, and there is currently no reliable biological test. Our aim was to evaluate the diagnostic potential of a functional assay quantifying allergen-specific Th2 cells in CMA children. A total of 29 children aged 2.8-10.5 years underwent a double-blind, placebo-controlled food challenge (DBPCFC) to cow's milk. Blood was collected before performing the DBPCFC, and peripheral mononuclear cells were cultured in an 18-h ELISpot assay with casein, α-lactalbumin, or β-lactoglobulin. Numbers of antigen-specific IL-4- and IL-13-secreting lymphocytes and serum-specific IgE, IgG4, and total IgE levels were assessed. Receiver operating characteristic (ROC) curves were generated. A total of 17 (59%) children reacted to cow's milk and were therefore considered as allergic to cow's milk (CMA). The mean number of casein-specific IL-4- and IL-13-secreting T cells was higher in CMA than in non-CMA children (P = 0.009, 0.004, respectively). Moreover, it was inversely correlated with the cumulative dose of cow's milk tolerated (P = 0.003, 0.0009, respectively). ROC curve of combined IL-4 and IL-13 analysis showed an area under the curve of 0.98 (95% CI 0.90-1.06). For a cutoff of 10 IL-4- and 12 IL-13-secreting T cells, sensitivity and negative predictive value were 100%. Enumeration of casein-specific IL-4- and IL-13-secreting T cells appears a promising tool to improve diagnosis and, if confirmed in larger studies, could permit less frequent use of the oral food challenge. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo.

    PubMed Central

    Taub, D D; Anver, M; Oppenheim, J J; Longo, D L; Murphy, W J

    1996-01-01

    IL-8 has been shown to be a human neutrophil and T cell chemoattractant in vitro. In an effort to assess the in vivo effects of IL-8 on human leukocyte migration, we examined the ability of rhIL-8 to induce human T cell infiltration using a human/mouse model in which SCID mice were administered human peripheral blood lymphocytes intraperitoneally, followed by subcutaneous injections of rhIL-8. rhIL-8 induced predominantly murine neutrophil accumulation by 4 h after administration while recombinant human macrophage inflammatory protein-1beta (rhMIP-1beta) induced both murine monocytes and human T cell infiltration during the same time period as determined by immunohistology. Interestingly, 72 h after chemokine administration, a marked human T cell infiltrate was observed in the IL-8 injection site suggesting that rhIL-8 may be acting indirectly possibly through a murine neutrophil-derived T cell chemoattractant. This hypothesis was confirmed using granulocyte-depleted SCID mice. Moreover, human neutrophils stimulated in vitro with IL-8 were found to release granule-derived factor(s) that induce in vitro T cell and monocyte chemotaxis and chemokinesis. This T cell and monocyte chemotactic activity was detected in extracts of both azurophilic and specific granules. Together, these results demonstrate that neutrophils store and release, upon stimulation with IL-8 or other neutrophil activators, chemoattractants that mediate T cell and monocyte accumulation at sites of inflammation. PMID:8621778

  5. Hepatocytes and IL-15: a favorable microenvironment for T cell survival and CD8+ T cell differentiation.

    PubMed

    Correia, Margareta P; Cardoso, Elsa M; Pereira, Carlos F; Neves, Rui; Uhrberg, Markus; Arosa, Fernando A

    2009-05-15

    Human intrahepatic lymphocytes are enriched in CD1d-unrestricted T cells coexpressing NKR. Although the origin of this population remains controversial, it is possible to speculate that the hepatic microenvironment, namely epithelial cells or the cytokine milieu, may play a role in its shaping. IL-15 is constitutively expressed in the liver and has a key role in activation and survival of innate and tissue-associated immune cells. In this in vitro study, we examined whether hepatocyte cell lines and/or IL-15 could play a role in the generation of NK-like T cells. The results show that both HepG2 cells and a human immortalized hepatocyte cell line increase survival and drive basal proliferation of T cells. In addition, IL-15 was capable of inducing Ag-independent up-regulation of NKR, including NKG2A, Ig-like receptors, and de novo expression of CD56 and NKp46 in CD8(+)CD56(-) T cells. In conclusion, our study suggests that hepatocytes and IL-15 create a favorable microenvironment for T cells to growth and survive. It can be proposed that the increased percentage of intrahepatic nonclassical NKT cells could be in part due to a local CD8(+) T cell differentiation.

  6. Whodunit? The Contribution of Interleukin (IL)-17/IL-22-Producing γδ T Cells, αβ T Cells, and Innate Lymphoid Cells to the Pathogenesis of Spondyloarthritis

    PubMed Central

    Reinhardt, Annika; Prinz, Immo

    2018-01-01

    γδ T cells, αβ T cells, and innate lymphoid cells (ILCs) are capable of producing interleukin (IL)-17A, IL-17F, and IL-22. Among these three families of lymphocytes, it is emerging that γδ T cells are, at least in rodents, the main source of these key pro-inflammatory cytokines. γδ T cells were implicated in multiple inflammatory and autoimmune diseases, including psoriasis, experimental autoimmune encephalomyelitis and uveitis, colitis, and rheumatoid arthritis. Recent findings pointed toward a central role of γδ T cells in the pathogenesis of spondyloarthritis (SpA), a group of inflammatory rheumatic diseases affecting the axial skeleton. SpA primarily manifests as inflammation and new bone formation at the entheses, which are connecting tendons or ligaments with bone. In SpA patients, joint inflammation is frequently accompanied by extra-articular manifestations, such as inflammatory bowel disease or psoriasis. In humans, genome-wide association studies could link the IL-23/IL-17 cytokine axis to SpA. Accordingly, antibodies targeting IL-23/IL-17 for SpA treatment already showed promising results in clinical studies. However, the contribution of IL-17-producing γδ T cells to SpA pathogenesis is certainly not an open-and-shut case. Indeed, the cell types that are chiefly involved in local inflammation in human SpA still remain largely unclear. Some studies focusing on blood or synovium from SpA patients reported augmented IL-17-producing and IL-23 receptor-expressing γδ T cells, but other cell types might contribute as well. Here, we summarize the current understanding of how γδ T cells, αβ T cells, and ILCs contribute to the pathogenesis of human and experimental SpA. PMID:29922283

  7. IL13Rα2 expression identifies tissue-resident IL-22 producing PLZF+ innate T cells in the human liver.

    PubMed

    Paquin-Proulx, Dominic; Greenspun, Benjamin C; Pasquet, Lise; Strunz, Benedikt; Aleman, Soo; Falconer, Karolin; Terabe, Masaki; Berzofsky, Jay A; Sandberg, Johan K; Melum, Espen; Nixon, Douglas F; Björkström, Niklas K

    2018-04-20

    Innate lymphocytes are selectively enriched in the liver where they have important roles in liver immunology. Murine studies have shown that type I NKT cells can promote liver inflammation whereas type II NKT cells have an anti-inflammatory role. In humans, type II NKT cells were found to accumulate in the gut during inflammation and IL13Rα2 was proposed as a marker for these cells. In the human liver, less is known about type I and II NKT cells. Here, we studied the phenotype and function of human liver T cells expressing IL13Rα2. We found that IL13Rα2 was expressed by around 1% of liver resident memory T cells but not on circulating T cells. In support of their innate-like T cell character, the IL13Rα2 + T cells had higher expression of PLZF compared to IL13Rα2 - T cells and possessed the capacity to produce IL-22. However, only a minority of human liver sulfatide-reactive type II NKT cells expressed IL13Rα2. Collectively, these findings suggest that IL13Rα2 identifies tissue-resident intrahepatic T cells with innate characteristics and the capacity to produce IL-22. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  8. Une masse palpébrale révélant une fistule carotidocaverneuse

    PubMed Central

    Oulali, Noureddine; Moufid, Fayçal; Khoulali, Mohammed; Sekhsoukh, Rachid; Housni, Brahim; Ghailan, Mohamed Rachid

    2012-01-01

    Les auteurs rapportent une observation particulière, chez un homme de 48 ans ayant dans ces antécédents un traumatisme crânio-faciale grave il y'a dix ans, qui présente depuis huit mois une masse palpébrale droite, avec une discrète exophtalmie et hémorragie sous conjonctivale, l'angio IRM a permis de confirmer le diagnostique d'une fistule carotidocaverneuse à haut débit, qui est responsable de cette symptomatologie. L'objectif de cet article est de mettre la lumière sur cette pathologie rare, en insistant sur les particularités cliniques de présentation d'une part, et sur le plan thérapeutique d'autre part, en exposant l'intérêt de la radiologie interventionnelle. PMID:23330040

  9. The distribution of IL-13 receptor alpha1 expression on B cells, T cells and monocytes and its regulation by IL-13 and IL-4.

    PubMed

    Graber, P; Gretener, D; Herren, S; Aubry, J P; Elson, G; Poudrier, J; Lecoanet-Henchoz, S; Alouani, S; Losberger, C; Bonnefoy, J Y; Kosco-Vilbois, M H; Gauchat, J F

    1998-12-01

    To study the expression of IL-13 receptor alpha1 (IL-13Ralpha1), specific monoclonal antibodies (mAb) were generated. Surface expression of the IL-13Ralpha1 on B cells, monocytes and T cells was assessed by flow cytometry using these specific mAb. Among tonsillar B cells, the expression was the highest on the IgD+ CD38- B cell subpopulation which is believed to represent naive B cells. Expression was also detectable on a large fraction of the IgD-CD38- B cells but not on CD38+ B cells. Activation under conditions which promote B cell Ig class switching up-regulated the expression of the receptor. However, the same stimuli had an opposite effect for IL-13Ralpha1 expression levels on monocytes. While IL-13Ralpha1 mRNA was clearly detectable in T cell preparations, no surface expression was detected. However, permeabilization of the T cells showed a clear intracellular expression of the receptor. A soluble form of the receptor was immunoprecipitated from the supernatant of activated peripheral T cells, suggesting that T cell IL-13Ralpha1 might have functions unrelated to the capacity to form a type II IL-4/IL-13R with IL-4Ralpha.

  10. The effect of IL-18 on IL-12-induced CD30 expression and IL-4 and IFN-γ production by allergen and PPD specific T cells

    PubMed Central

    Tarkowski, M; Chrul, S; Bodalski, J

    2002-01-01

    CD30 is expressed on activated T cells that, as has been suggested, preferentially produce IFN-γ. Interleukin 12 increases antigen-induced CD30 expression on T cells and IFN-γ production. Synthesis of IFN-γ can be augmented further by IL-18. The aim of our study was to investigate whether IL-18 affects the IL-12 induced CD30 expression and cytokine production by allergen or PPD specific T cells. Mononuclear cells of healthy or atopic volunteers were stimulated with PPD or allergen, respectively, to obtain specific T cell lines. T cells were restimulated with appropriate antigen and antigen-presenting cells in the presence of IL-12, IL-18 or a combination of these cytokines. After 3 days, expression of CD30 was investigated on CD4 and CD8 T cells and IFN-γ and IL-4 cytokine production was estimated in the culture supernatants. Flow cytometric analyses showed no effect of IL-18 on CD30 expression during IL-12 co-stimulation. At the same time after the optimal stimulation for CD30 expression, the levels of IFN-γ were high in PPD-stimulated cell lines but have not been up-regulated by IL-18. IFN-γ levels were much lower in allergen-stimulated T cells and although they were up-regulated by IL-12 there was no additional or synergistic effect from IL-18. IL-18, however, increased production of IL-4 in allergen-stimulated cell lines. Our studies provide new information about IL-18 activity on human cells and question its exclusive role in Th1 mediated responses. PMID:11882036

  11. Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

    PubMed Central

    de Beaucoudrey, Ludovic; Puel, Anne; Filipe-Santos, Orchidée; Cobat, Aurélie; Ghandil, Pegah; Chrabieh, Maya; Feinberg, Jacqueline; von Bernuth, Horst; Samarina, Arina; Jannière, Lucile; Fieschi, Claire; Stéphan, Jean-Louis; Boileau, Catherine; Lyonnet, Stanislas; Jondeau, Guillaume; Cormier-Daire, Valérie; Le Merrer, Martine; Hoarau, Cyrille; Lebranchu, Yvon; Lortholary, Olivier; Chandesris, Marie-Olivia; Tron, François; Gambineri, Eleonora; Bianchi, Lucia; Rodriguez-Gallego, Carlos; Zitnik, Simona E.; Vasconcelos, Julia; Guedes, Margarida; Vitor, Artur Bonito; Marodi, Laszlo; Chapel, Helen; Reid, Brenda; Roifman, Chaim; Nadal, David; Reichenbach, Janine; Caragol, Isabel; Garty, Ben-Zion; Dogu, Figen; Camcioglu, Yildiz; Gülle, Sanyie; Sanal, Ozden; Fischer, Alain; Abel, Laurent; Stockinger, Birgitta; Picard, Capucine; Casanova, Jean-Laurent

    2008-01-01

    The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo. PMID:18591412

  12. Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants.

    PubMed

    Krenciute, Giedre; Prinzing, Brooke L; Yi, Zhongzhen; Wu, Meng-Fen; Liu, Hao; Dotti, Gianpietro; Balyasnikova, Irina V; Gottschalk, Stephen

    2017-07-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo , IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens. Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen

  13. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells

    PubMed Central

    Dienz, Oliver; Eaton, Sheri M.; Bond, Jeffrey P.; Neveu, Wendy; Moquin, David; Noubade, Rajkumar; Briso, Eva M.; Charland, Colette; Leonard, Warren J.; Ciliberto, Gennaro; Teuscher, Cory; Haynes, Laura; Rincon, Mercedes

    2009-01-01

    Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4+ T cells upon T cell receptor stimulation. IL-21 production by CD4+ T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4+ T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity. PMID:19139170

  14. Vγ4 T Cells Inhibit the Pro-healing Functions of Dendritic Epidermal T Cells to Delay Skin Wound Closure Through IL-17A

    PubMed Central

    Li, Yashu; Wang, Yangping; Zhou, Lina; Liu, Meixi; Liang, Guangping; Yan, Rongshuai; Jiang, Yufeng; Hao, Jianlei; Zhang, Xiaorong; Hu, Xiaohong; Huang, Yong; Wang, Rupeng; Yin, Zhinan; Wu, Jun; Luo, Gaoxing; He, Weifeng

    2018-01-01

    Dendritic epidermal T cells (DETCs) and dermal Vγ4 T cells engage in wound re-epithelialization and skin inflammation. However, it remains unknown whether a functional link between Vγ4 T cell pro-inflammation and DETC pro-healing exists to affect the outcome of skin wound closure. Here, we revealed that Vγ4 T cell-derived IL-17A inhibited IGF-1 production by DETCs to delay skin wound healing. Epidermal IL-1β and IL-23 were required for Vγ4 T cells to suppress IGF-1 production by DETCs after skin injury. Moreover, we clarified that IL-1β rather than IL-23 played a more important role in inhibiting IGF-1 production by DETCs in an NF-κB-dependent manner. Together, these findings suggested a mechanistic link between Vγ4 T cell-derived IL-17A, epidermal IL-1β/IL-23, DETC-derived IGF-1, and wound-healing responses in the skin. PMID:29483920

  15. An essential role for IL-2 receptor in regulatory T cell function

    PubMed Central

    Levine, Andrew G; Fan, Xiying; Klein, Ulf; Zheng, Ye; Gasteiger, Georg; Feng, Yongqiang; Fontenot, Jason D.; Rudensky, Alexander Y.

    2016-01-01

    Regulatory T (Treg) cells, expressing abundant amounts of the IL-2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature implied a key role for a simple network based on IL-2 consumption by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage specification factor Foxp3, confounding experimental efforts to understand the role of IL-2R expression and signaling in Treg suppressor function. Using genetic gain and loss of function approaches, we demonstrate that IL-2 capture is dispensable for control of CD4+ T cells, but is important for limiting CD8+ T cell activation, and that IL-2R dependent STAT5 transcription factor activation plays an essential role in Treg cell suppressor function separable from T cell receptor signaling. PMID:27595233

  16. Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients

    PubMed Central

    Bhat, Shreyas; Gardi, Nilesh; Hake, Sujata; Kotian, Nirupama; Sawant, Sharada; Kannan, Sadhana; Parmar, Vani; Desai, Sangeeta; Dutt, Amit

    2018-01-01

    Purpose Pro-inflammatory cytokines such as Interleukin-17A (IL17A) and Interleukin-32 (IL32), known to enhance natural killer and T cell responses, are also elevated in human malignancies and linked to poor clinical outcomes. To address this paradox, we evaluated relation between IL17A and IL32 expression and other inflammation- and T cell response-associated genes in breast tumors. Methods TaqMan-based gene expression analysis was carried out in seventy-eight breast tumors. The association between IL17A and IL32 transcript levels and T cell response genes, ER status as well as lymph node status was also examined in breast tumors from TCGA dataset. Results IL17A expression was detected in 32.7% ER-positive and 84.6% ER-negative tumors, with higher expression in the latter group (26.2 vs 7.1-fold, p < 0.01). ER-negative tumors also showed higher expression of IL32 as opposed to ER-positive tumors (8.7 vs 2.5-fold, p < 0.01). Expression of both IL17A and IL32 genes positively correlated with CCL5, GNLY, TBX21, IL21 and IL23 transcript levels (p < 0.01). Amongst ER-positive tumors, higher IL32 expression significantly correlated with lymph node metastases (p < 0.05). Conversely, in ER-negative subtype, high IL17A and IL32 expression was seen in patients with negative lymph node status (p < 0.05). Tumors with high IL32 and IL17A expression showed higher expression of TH1 response genes studied, an observation validated by similar analysis in the TCGA breast tumors (n=1041). Of note, these tumors were characterized by low expression of a potentially immunosuppressive isoform of IL32 (IL32γ). Conclusion These results suggest that high expression of both IL17A and IL32 leads to enhancement of T cell responses. Our study, thus, provides basis for the emergence of strong T cell responses in an inflammatory milieu that have been shown to be associated with better prognosis in ER-negative breast cancer. PMID:28470472

  17. Sidération myocardique au cours d'une intoxication au monoxyde de carbone (CO) chez une femme enceinte

    PubMed Central

    Coulibaly, Mahamadoun; Berdai, Mohamed Adnane; Labib, Smael; Harandou, Mustapha

    2015-01-01

    L'intoxication au monoxyde de carbone (CO) est la première cause de décès par intoxication en France. La littérature est ancienne et peu connue. Les signes les plus fréquents de l'intoxication sont la triade: Céphalées; asthénie, faiblesse musculaire surtout des membres inférieurs. Ses conséquences sont potentiellement graves pour le fœtus quand elle survient chez la femme enceinte, il est particulièrement exposé au risque d'hypoxie en raison de la forte affinité de son hémoglobine pour le CO qui traverse aisément le placenta. Les événements cardiovasculaires ne sont pas rares et peuvent être responsable d'une morbi-mortalité assez importante qui peuvent être d'apparition rapide ou secondaire mais régressent habituellement en quelques jours. Des SCA peuvent survenir lors d'une une intoxication au CO avec à l'extrême infarctus myocardique avec surélévation du segment ST. Il paraît légitime de proposer pour toutes les patientes: l’éloignement maternel de la source de CO; l'oxygénothérapie à 100% au masque facial par les services de secours et pendant le transfert; le traitement par oxygénothérapie hyperbare pour toutes les femmes enceintes, le plus rapidement possible et quelque soit l’âge gestationnel. PMID:26405502

  18. IL-12 and IL-23 Production in Toxoplasma gondii- or LPS-Treated Jurkat T Cells via PI3K and MAPK Signaling Pathways.

    PubMed

    Ismail, Hassan Ahmed Hassan Ahmed; Kang, Byung-Hun; Kim, Jae-Su; Lee, Jae-Hyung; Choi, In-Wook; Cha, Guang-Ho; Yuk, Jae-Min; Lee, Young-Ha

    2017-12-01

    IL-12 and IL-23 are closely related in structure, and have been shown to play crucial roles in regulation of immune responses. However, little is known about the regulation of these cytokines in T cells. Here, we investigated the roles of PI3K and MAPK pathways in IL-12 and IL-23 production in human Jurkat T cells in response to Toxoplasma gondii and LPS. IL-12 and IL-23 production was significantly increased in T cells after stimulation with T. gondii or LPS. T. gondii and LPS increased the phosphorylation of AKT, ERK1/2, p38 MAPK, and JNK1/2 in T cells from 10 min post-stimulation, and peaked at 30-60 min. Inhibition of the PI3K pathway reduced IL-12 and IL-23 production in T. gondii-infected cells, but increased in LPS-stimulated cells. IL-12 and IL-23 production was significantly reduced by ERK1/2 and p38 MAPK inhibitors in T. gondii- and LPS-stimulated cells, but not in cells treated with a JNK1/2 inhibitor. Collectively, IL-12 and IL-23 production was positively regulated by PI3K and JNK1/2 in T. gondii-infected Jurkat cells, but negatively regulated in LPS-stimulated cells. And ERK1/2 and p38 MAPK positively regulated IL-12 and IL-23 production in Jurkat T cells. These data indicate that T. gondii and LPS induced IL-12 and IL-23 production in Jurkat T cells through the regulation of the PI3K and MAPK pathways; however, the mechanism underlying the stimulation of IL-12 and IL-23 production by T. gondii in Jurkat T cells is different from that of LPS.

  19. Leishmania-infected MHC class IIhigh dendritic cells polarize CD4+ T cells toward a nonprotective T-bet+ IFN-γ+ IL-10+ phenotype.

    PubMed

    Resende, Mariana; Moreira, Diana; Augusto, Jorge; Cunha, Joana; Neves, Bruno; Cruz, Maria Teresa; Estaquier, Jérôme; Cordeiro-da-Silva, Anabela; Silvestre, Ricardo

    2013-07-01

    A differential behavior among infected and bystander dendritic cells (DCs) has been explored in different infection models. We have analyzed both populations sorted on contact with visceral Leishmania infantum on a susceptible mice model evaluating the subsequent repercussions on adaptive immune response. Our results demonstrate a clear dichotomy between the immunomodulatory abilities of bystander and infected DCs. The bystander population presents increased levels of IL-12p40 and costimulatory molecules being capable to induce CD4(+) T cell activation with immune protective capabilities. In contrast, infected DCs, which express lower costimulatory molecules and higher levels of IL-10, promote the development of Leishmania Ag-specific, nonprotective T-bet(+)IFN-γ(+)IL-10(+) CD4(+) T cells with an effector phenotype. This specific polarization was found to be dependent on IL-12p70. Splenic infected DCs recovered from chronic infected animals are similarly capable to polarize ex vivo syngeneic naive CD4(+) T cells toward a T-bet(+)IFN-γ(+)IL-10(+) phenotype. Further analysis revealed that only MHC class II(high)-infected DCs were responsible for this polarization. The adoptive transfer of such polarized CD4(+) T cells facilitates visceral leishmaniasis in BALB/c mice in a clear contrast with their counterpart generated with bystander DCs that significantly potentiate protection. Further, we demonstrated that CD4(+) T cells primed by infected DCs in an IL-10 free system, thus deprived of T-bet(+)IFN-γ(+)IL-10(+) population, restore the immune response and reduce parasite load, supporting a deleterious role of IFN-γ(+)IL-10(+) T cells in the maintenance of infection. Overall, our results highlight novel subversion mechanisms by which nonprotective T-bet(+)IFN-γ(+)IL-10(+) T cells are associated with chronicity and prolonged parasite persistence.

  20. Overexpression of IL-7R alpha provides a competitive advantage during early T-cell development.

    PubMed

    Laouar, Yasmina; Crispe, I Nicholas; Flavell, Richard A

    2004-03-15

    Critical checkpoints controlling early thymic T-cell development and homeostasis are set by the proper signaling function of the interleukin 7 receptor (IL-7R) and the pre-T-cell antigen receptor. Although alpha beta T-cell development is observed in IL-7- and IL-7R alpha-deficient mice, the number of thymocytes is significantly reduced, implying a role for the IL-7R in controlling the size of the thymic T-cell compartment. Here, we report the overexpression of IL-7R alpha that occurs in the early T-cell compartment from AKR/J mice, animals that are highly susceptible to the spontaneous development of thymoma. Increased IL-7R alpha was revealed by surface staining, and increased IL-7R alpha mRNA was documented by using reverse transcriptase-polymerase chain reaction (RT-PCR). This resulted in increased survival of AKR/J early thymocytes, shown by the decreased frequency of TUNEL(+) (terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate [dUTP]-fluorescein nick end labeling) cells. In an in vivo thymocyte repopulation model, AKR/J thymocytes had a selective advantage over healthy thymocytes. This advantage occurred at early stages of T-cell development. Our findings support the model that overexpression of growth factor receptors can contribute to proliferation and malignancy.

  1. IL-7 receptor blockade following T cell depletion promotes long-term allograft survival

    PubMed Central

    Mai, Hoa-Le; Boeffard, Françoise; Longis, Julie; Danger, Richard; Martinet, Bernard; Haspot, Fabienne; Vanhove, Bernard; Brouard, Sophie; Soulillou, Jean-Paul

    2014-01-01

    T cell depletion is commonly used in organ transplantation for immunosuppression; however, a restoration of T cell homeostasis following depletion leads to increased memory T cells, which may promote transplant rejection. The cytokine IL-7 is important for controlling lymphopoiesis under both normal and lymphopenic conditions. Here, we investigated whether blocking IL-7 signaling with a mAb that targets IL-7 receptor α (IL-7Rα) alone or following T cell depletion confers an advantage for allograft survival in murine transplant models. We found that IL-7R blockade alone induced indefinite pancreatic islet allograft survival if anti–IL-7R treatment was started 3 weeks before graft. IL-7R blockade following anti-CD4– and anti-CD8–mediated T cell depletion markedly prolonged skin allograft survival. Furthermore, IL-7 inhibition in combination with T cell depletion synergized with either CTLA-4Ig administration or suboptimal doses of tacrolimus to induce long-term skin graft acceptance in this stringent transplant model. Together, these therapies inhibited T cell reconstitution, decreased memory T cell numbers, increased the relative frequency of Tregs, and abrogated both cellular and humoral alloimmune responses. Our data suggest that IL-7R blockade following T cell depletion has potential as a robust, immunosuppressive therapy in transplantation. PMID:24569454

  2. CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas

    PubMed Central

    Butcher, Matthew J.; Wu, Chih-I; Waseem, Tayab

    2016-01-01

    The adaptive immune response is involved in the development and progression of atherosclerosis and IL-17A+ cells play a role in this disease. Although elevated number of CD4+ IL-17A+ (Th17) and IL-17A+TCRγδ+ T cells are found within murine atherosclerotic aortas and human plaques, the mechanisms governing IL-17A+ T-cell migration to atherosclerotic lesions are unclear. The chemokine receptor CXCR6 is expressed on several T-cell subsets and plays a pro-atherogenic role in atherosclerosis. Here, we used CXCR6-deficient (Cxcr6 GFP/GFP) apolipoprotein E-deficient (Apoe −/−) mice to investigate the involvement of CXCR6 in the recruitment IL-17A+ T cells to atherosclerotic aortas. Flow cytometric analyses revealed reductions in Th17 and IL-17A+TCRγδ+ T cells within aged Cxcr6 GFP/GFP Apoe −/− aortas, in comparison with age-matched Cxcr6 GFP/+ Apoe −/− aortas. Although CXCR6-sufficient IL-17A+ T cells efficiently migrated toward CXCL16, the migration of CXCR6-deficient IL-17A+ T cells was abolished in transwell assays. Importantly, the recruitment of Cxcr6 GFP/GFP Apoe −/− IL-17A+ T cells into the aortas of Apoe −/− recipients was markedly reduced in short-term adoptive transfer experiments. Altogether these results demonstrate an important role of CXCR6 in the regulation of pathological Th17 and IL-17A+TCRγδ+ T-cell recruitment into atherosclerotic lesions. PMID:26614640

  3. CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas.

    PubMed

    Butcher, Matthew J; Wu, Chih-I; Waseem, Tayab; Galkina, Elena V

    2016-05-01

    The adaptive immune response is involved in the development and progression of atherosclerosis and IL-17A(+) cells play a role in this disease. Although elevated number of CD4(+) IL-17A(+) (Th17) and IL-17A(+)TCRγδ(+) T cells are found within murine atherosclerotic aortas and human plaques, the mechanisms governing IL-17A(+) T-cell migration to atherosclerotic lesions are unclear. The chemokine receptor CXCR6 is expressed on several T-cell subsets and plays a pro-atherogenic role in atherosclerosis. Here, we used CXCR6-deficient (Cxcr6 (GFP/GFP) ) apolipoprotein E-deficient (Apoe (-/-) ) mice to investigate the involvement of CXCR6 in the recruitment IL-17A(+) T cells to atherosclerotic aortas. Flow cytometric analyses revealed reductions in Th17 and IL-17A(+)TCRγδ(+) T cells within aged Cxcr6 (GFP/GFP) Apoe (-/-) aortas, in comparison with age-matched Cxcr6 (GFP/+) Apoe (-/-) aortas. Although CXCR6-sufficient IL-17A(+) T cells efficiently migrated toward CXCL16, the migration of CXCR6-deficient IL-17A(+) T cells was abolished in transwell assays. Importantly, the recruitment of Cxcr6 (GFP/GFP) Apoe (-/-) IL-17A(+) T cells into the aortas of Apoe (-/-) recipients was markedly reduced in short-term adoptive transfer experiments. Altogether these results demonstrate an important role of CXCR6 in the regulation of pathological Th17 and IL-17A(+)TCRγδ(+) T-cell recruitment into atherosclerotic lesions. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Tumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene therapy with single-chain IL-12

    PubMed Central

    Lode, Holger N.; Xiang, Rong; Duncan, Steven R.; Theofilopoulos, Argyrios N.; Gillies, Stephen D.; Reisfeld, Ralph A.

    1999-01-01

    Induction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD2 antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8+ T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vβ11 and -13 in mouse CD8+ T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8+ T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials. PMID:10411920

  5. IL-17+ γδ T cells as kick-starters of inflammation.

    PubMed

    Papotto, Pedro H; Ribot, Julie C; Silva-Santos, Bruno

    2017-05-18

    Shortly after the discovery of interleukin 17 (IL-17)-producing CD4 + helper T cells (T H 17 cells), it was found that γδ T cells can also secrete large amounts of this pro-inflammatory cytokine. A decade later, it is now known that IL-17 + γδ T cells (γδ17 T cells) are often the main providers of IL-17A in various models of inflammatory diseases, while they also contribute to protective immune responses to infectious organisms. Due to an intricate thymic program of differentiation, γδ17 T cells are able to respond faster than T H 17 cells do and thus predominate in the early stages of inflammatory responses. Here we review the current knowledge of the development, activation and pathophysiological functions of γδ17 T cells, aiming to increase the awareness in the community of the therapeutic potential of this 'other side' of IL-17-mediated immune responses.

  6. CD4 T cells play important roles in maintaining IL-17-producing γδ T-cell subsets in naive animals.

    PubMed

    Do, Jeong-Su; Visperas, Anabelle; O'Brien, Rebecca L; Min, Booki

    2012-04-01

    A proportional balance between αβ and γδ T-cell subsets in the periphery is exceedingly well maintained by a homeostatic mechanism. However, a cellular mechanism underlying the regulation remains undefined. We recently reported that a subset of developing γδ T cells spontaneously acquires interleukin (IL)-17-producing capacity even within naive animals through a transforming growth factor (TGF)β1-dependent mechanism, thus considered 'innate' IL-17-producing cells. Here, we report that γδ T cells generated within αβ T cell (or CD4 T cell)-deficient environments displayed altered cytokine profiles; particularly, 'innate' IL-17 expression was significantly impaired compared with those in wild-type mice. Impaired IL-17 production in γδ T cells was directly related to CD4 T-cell deficiency, because depletion of CD4 T cells in wild-type mice diminished and adoptive CD4 T-cell transfer into T-cell receptor β-/- mice restored IL-17 expression in γδ T cells. CD4 T cell-mediated IL-17 expression required TGFβ1. Moreover, Th17 but not Th1 or Th2 effector CD4 T cells were highly efficient in enhancing γδ T-cell IL-17 expression. Taken together, our results highlight a novel CD4 T cell-dependent mechanism that shapes the generation of IL-17+ γδ T cells in naive settings.

  7. γδ T cells affect IL-4 production and B-cell tolerance

    PubMed Central

    Huang, Yafei; Heiser, Ryan A.; Detanico, Thiago O.; Getahun, Andrew; Kirchenbaum, Greg A.; Casper, Tamara L.; Aydintug, M. Kemal; Carding, Simon R.; Ikuta, Koichi; Huang, Hua; Cambier, John C.; Wysocki, Lawrence J.; O’Brien, Rebecca L.; Born, Willi K.

    2015-01-01

    γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αβ T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4–producing T cells (both residual γδ T cells and αβ T cells) and in systemic IL-4 levels. Its B cells expressed IL-4–regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4–inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance. PMID:25535377

  8. γδ T cells affect IL-4 production and B-cell tolerance.

    PubMed

    Huang, Yafei; Heiser, Ryan A; Detanico, Thiago O; Getahun, Andrew; Kirchenbaum, Greg A; Casper, Tamara L; Aydintug, M Kemal; Carding, Simon R; Ikuta, Koichi; Huang, Hua; Cambier, John C; Wysocki, Lawrence J; O'Brien, Rebecca L; Born, Willi K

    2015-01-06

    γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αβ T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4-producing T cells (both residual γδ T cells and αβ T cells) and in systemic IL-4 levels. Its B cells expressed IL-4-regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4-inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance.

  9. A response to U. T. Place

    PubMed Central

    Sundberg, Mark L.; Michael, Jack

    1983-01-01

    Skinner's (1957) analysis of verbal behavior has received an unwarranted amount of criticism over the years, and the recently published reviews of Verbal Behavior by U. T. Place contribute to this body of negative literature. It is argued that Place, like those before him, has failed to appreciate several critical features of behaviorism and Skinner's analysis of verbal behavior. Place's “four major defects in Verbal Behavior” are reviewed and analyzed. The results seem to indicate that Place's dissatisfaction with the book would be greatly reduced by a better understanding of Skinner's work. PMID:22573462

  10. IL-17 Induction by ArtinM is Due to Stimulation of IL-23 and IL-1 Release and/or Interaction with CD3 in CD4+ T Cells.

    PubMed

    da Silva, Thiago Aparecido; Mariano, Vania Sammartino; Sardinha-Silva, Aline; de Souza, Maria Aparecida; Mineo, Tiago Wilson Patriarca; Roque-Barreira, Maria Cristina

    2016-01-01

    ArtinM is a D-mannose-binding lectin extracted from the seeds of Artocarpus heterophyllus that interacts with TLR2 N-glycans and activates antigen-presenting cells (APCs), as manifested by IL-12 production. In vivo ArtinM administration induces Th1 immunity and confers protection against infection with several intracellular pathogens. In the murine model of Candida albicans infection, it was verified that, in addition to Th1, ArtinM induces Th17 immunity manifested by high IL-17 levels in the treated animals. Herein, we investigated the mechanisms accounting for the ArtinM-induced IL-17 production. We found that ArtinM stimulates the IL-17 production by spleen cells in BALB/c or C57BL/6 mice, a response that was significantly reduced in the absence of IL-23, MyD88, or IL-1R. Furthermore, we showed that ArtinM directly induced the IL-23 mRNA expression and the IL-1 production by macrophages. Consistently, in cell suspensions depleted of macrophages, the IL-17 production stimulated by ArtinM was reduced by 53% and the exogenous IL-23 acted synergistically with ArtinM in promoting IL-17 production by spleen cell suspensions. We verified that the absence of IL-23, IL-1R, or MyD88 inhibited, but did not block, the IL-17 production by ArtinM-stimulated spleen cells. Therefore, we investigated whether ArtinM exerts a direct effect on CD4+ T cells in promoting IL-17 production. Indeed, spleen cell suspensions depleted of CD4+ T cells responded to ArtinM with very low levels of IL-17 release. Likewise, isolated CD4+ T cells under ArtinM stimulus augmented the expression of TGF-β mRNA and released high levels of IL-17. Considering the observed synergism between IL-23 and ArtinM, we used cells from IL-23 KO mice to assess the direct effect of lectin on CD4+ T cells. We verified that ArtinM increased the IL-17 production significantly, a response that was inhibited when the CD4+ T cells were pre-incubated with anti-CD3 antibody. In conclusion, ArtinM stimulates the production

  11. IL-17 Induction by ArtinM is Due to Stimulation of IL-23 and IL-1 Release and/or Interaction with CD3 in CD4+ T Cells

    PubMed Central

    da Silva, Thiago Aparecido; Mariano, Vania Sammartino; Sardinha-Silva, Aline; de Souza, Maria Aparecida; Mineo, Tiago Wilson Patriarca; Roque-Barreira, Maria Cristina

    2016-01-01

    ArtinM is a D-mannose-binding lectin extracted from the seeds of Artocarpus heterophyllus that interacts with TLR2 N-glycans and activates antigen-presenting cells (APCs), as manifested by IL-12 production. In vivo ArtinM administration induces Th1 immunity and confers protection against infection with several intracellular pathogens. In the murine model of Candida albicans infection, it was verified that, in addition to Th1, ArtinM induces Th17 immunity manifested by high IL-17 levels in the treated animals. Herein, we investigated the mechanisms accounting for the ArtinM-induced IL-17 production. We found that ArtinM stimulates the IL-17 production by spleen cells in BALB/c or C57BL/6 mice, a response that was significantly reduced in the absence of IL-23, MyD88, or IL-1R. Furthermore, we showed that ArtinM directly induced the IL-23 mRNA expression and the IL-1 production by macrophages. Consistently, in cell suspensions depleted of macrophages, the IL-17 production stimulated by ArtinM was reduced by 53% and the exogenous IL-23 acted synergistically with ArtinM in promoting IL-17 production by spleen cell suspensions. We verified that the absence of IL-23, IL-1R, or MyD88 inhibited, but did not block, the IL-17 production by ArtinM-stimulated spleen cells. Therefore, we investigated whether ArtinM exerts a direct effect on CD4+ T cells in promoting IL-17 production. Indeed, spleen cell suspensions depleted of CD4+ T cells responded to ArtinM with very low levels of IL-17 release. Likewise, isolated CD4+ T cells under ArtinM stimulus augmented the expression of TGF-β mRNA and released high levels of IL-17. Considering the observed synergism between IL-23 and ArtinM, we used cells from IL-23 KO mice to assess the direct effect of lectin on CD4+ T cells. We verified that ArtinM increased the IL-17 production significantly, a response that was inhibited when the CD4+ T cells were pre-incubated with anti-CD3 antibody. In conclusion, ArtinM stimulates the production

  12. Caracterisation de la cohesion de l'interface AMF/polymere dans une structure deformable adaptative

    NASA Astrophysics Data System (ADS)

    Fischer-Rousseau, Charles

    Les structures déformables adaptatives (SDA) sont appelées à jouer un rôle important en aéronautique entre autres. Les alliages à mémoire de forme (AMF) sont un des candidats les plus prometteurs. Beaucoup de travail reste toutefois à faire avant que ces structures rencontrent les exigences élevées reliées à leur intégration dans un contexte aéronautique. Des travaux de recherche ont montré que la résistance à la décohésion de l’interface AMF/polymère peut être un élément limitant dans la performance des SDA. Dans ce travail, l’effet sur la résistance à la décohésion de l’interface AMF/polymère de divers traitements de surface, géométries de fil et types de polymère est évalué. La géométrie du fil est modifiée par une combinaison spécifique de laminage à froid et de recuit postdéformation qui maintient les propriétés de mémoire de forme tout en permettant de réduire l’aire de la section transversale du fil. Le traitement thermomécanique le plus prometteur est proposé. Une nouvelle méthode d’évaluation de la résistance à la décohésion est développée. Plutôt que de tester les fils en arrachement et de mesurer la force maximale, les tests en contraction sont basés sur la capacité des fils d’AMF à se contracter s’ils ont été encastrés dans un état tiré et qu’ils sont chauffés par effet Joule. L’hypothèse qu’on pose est que ces tests sont une meilleure approximation des conditions rencontrées dans une SDA, où les fils se contractent plutôt qu’ils sont arrachés par une force externe à la structure. Bien qu’une décohésion partielle ait été observée pour tous les échantillons, l’aire de la surface où il y a décohésion tait plus grande pour les échantillons avec une pré-déformation plus grande. Le front de décohésion a semblé cesser de progresser après les cycles de chauffage initiaux lorsque la vitesse de chauffage était faible. Un modèle numérique simulant la

  13. Pseudotumeur cardiaque révélant une maladie de Behçet

    PubMed Central

    Nya, Fouad; Abdou, Abdessamad; Bamous, Mehdi; Moutakiallah, Younes; Atmani, Noureddine; Seghrouchni, Aniss; Houssa, Mahdi Ait; Boulahya, Abdellatif

    2017-01-01

    La thrombose intracardiaque est une complication rare de la maladie de Behçet (MB), qui peut se présenter comme une tumeur intracardiaque. Sa découverte précède, dans la moitié des cas, le diagnostic de MB. La mortalité élevée peut être en rapport avec des complications post-chirurgicales et/ou une atteinte associée des artères pulmonaires. Nous rapportons l’observation d’un jeune patient de 29 ans, aux antécédents d’aphtose bipolaire, qui a bénéficie d’une intervention chirurgicale après la découverte d’une tumeur de l’atrium et du ventricule droits. Il s’agissait d’un thrombus à l’examen anatomopathologique et dans les suites opératoires nous avons diagnostiqué une MB. L’évolution a été favorable sous traitement médical associant une corticothérapie, de la colchicine et des antivitamines K (AVK). La découverte d’une masse intracardiaque chez un sujet jeune doit faire évoquer le diagnostic de thrombus cardiaque et de maladie de Behçet, même en l’absence de facteur ethnique ou géographique prédisposant. PMID:28533874

  14. Elevated levels of IL-2 and IL-21 produced by CD4+ T cells in inflammatory bowel disease.

    PubMed

    Ebrahimpour, S; Shahbazi, M; Khalili, A; Tahoori, M T; Zavaran Hosseini, A; Amari, A; Aghili, B; Abediankenari, S; Mohammadizad, H; Mohammadnia-Afrouzi, M

    2017-01-01

    CD4+ T cells are considered as a subset of cells that play a pivotal role in the development of inflammatory bowel disease (IBD). The aim of this study was to assess the levels of interleukin (IL)-2, IL-21 and their receptors produced by CD4+ T cells in patients with inflammatory bowel disease. Thirty-two patients with ulcerative colitis (UC) and mean age of 37.93±10.37 years, as well as 22 patients with Crohn’s disease (CD) and mean age of 37.04±10.44 years, were studied. The healthy controls (HC) included 31 subjects with a mean age of 36.7±10.48 years. Peripheral blood mononuclear cells (PBMCs) were isolated from all the participants. The CD4+ T cells were isolated and the expression of IL-2 and IL-21 and also their receptors were examined by flow cytometry. The level of IL-2+ cells was significantly increased in UC patients compared with HC (40.71±6.04 vs 37.24±6.54, respectively, p=0.04). The level of IL-21+ cells was also significantly elevated in CD patients compared with HC (4.44±1 vs 3.83±0.74, respectively, p=0.02). Furthermore, we found a significant positive correlation between clinical activity index (CAI) and IL-21+ cells. According to the results, we hypothesize that the elevated level of IL-2+ and IL-21+ T cells and a positive correlation between IL-21+ cells with CAI in UC patients may contribute to the pathogenesis of disease. Moreover, the assessment of cells producing such cytokines constitutes a potential diagnostic and therapeutic strategy for IBD.

  15. The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development.

    PubMed

    Castro, Iris; Yu, Aixin; Dee, Michael J; Malek, Thomas R

    2011-11-15

    Recent work suggests that IL-2 and IL-15 induce distinctive levels of signaling through common receptor subunits and that such varied signaling directs the fate of Ag-activated CD8(+) T cells. In this study, we directly examined proximal signaling by IL-2 and IL-15 and CD8(+) T cell primary and memory responses as a consequence of varied CD122-dependent signaling. Initially, IL-2 and IL-15 induced similar p-STAT5 and p-S6 activation, but these activities were only sustained by IL-2. Transient IL-15-dependent signaling is due to limited expression of IL-15Rα. To investigate the outcome of varied CD122 signaling for CD8(+) T cell responses in vivo, OT-I T cells were used from mouse models where CD122 signals were attenuated by mutations within the cytoplasmic tail of CD122 or intrinsic survival function was provided in the absence of CD122 expression by transgenic Bcl-2. In the absence of CD122 signaling, generally normal primary response occurred, but the primed CD8(+) T cells were not maintained. In marked contrast, weak CD122 signaling supported development and survival of T central-memory (T(CM)) but not T effector-memory (T(EM)) cells. Transgenic expression of Bcl-2 in CD122(-/-) CD8(+) T cells also supported the survival and persistence of T(CM) cells but did not rescue T(EM) development. These data indicate that weak CD122 signals readily support T(CM) development largely through providing survival signals. However, stronger signals, independent of Bcl-2, are required for T(EM) development. Our findings are consistent with a model whereby low, intermediate, and high CD122 signaling support T(CM) memory survival, T(EM) programming, and terminal T effector cell differentiation, respectively.

  16. Characterization of αβ and γδ T cell subsets expressing IL-17A in ruminants and swine.

    PubMed

    Elnaggar, Mahmoud M; Abdellrazeq, Gaber S; Dassanayake, Rohana P; Fry, Lindsay M; Hulubei, Victoria; Davis, William C

    2018-08-01

    As part of our ongoing program to expand immunological reagents available for research in cattle, we developed a monoclonal antibody (mAb) to bovine interleukin-17A (IL-17A), a multifunctional cytokine centrally involved in regulating innate and adaptive immune responses. Initial comparative studies demonstrated the mAb recognizes a conserved epitope expressed on orthologues of IL-17A in sheep, goats and pigs. Comparative flow cytometric analyses of lymphocyte subsets stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin revealed differences in expression of IL-17A by CD4, CD8, and γδ T cells across ruminants and swine species. Results in cattle showed the largest proportion of IL-17A + cells were CD4 + followed by γδ and CD8 + T cells. Further analysis revealed the IL-17A + γδ T cell subset was comprised of WC1.1 + , WC1.2 + , and WC1 - subsets. Analysis of the IL-17A + CD8 + T cell subset revealed it was comprised of αβ and γδ T cell subsets. Results in sheep and goats revealed IL-17A is expressed mainly by CD4 + and CD8 + T cells, with little expression by γδ T cells. Analysis of IL-17A + CD8 + T cells showed the majority were CD8 + αβ in sheep, whereas they were CD8 + γδ in goats. The majority of the sheep and goat IL-17A + γδ T cells were WC1 + . Results obtained in swine showed expression of IL-17A by CD4, CD8, and γδ T cell subsets were similar to results reported in other studies. Comparison of expression of IL-17A with IFN-γ revealed subsets co-expressed IL-17A and IFN-γ in cattle, sheep, and goats. The new mAb expands opportunities for immunology research in ruminants and swine. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis

    PubMed Central

    Chang, Kai-Kai; Liu, Li-Bing; Jin, Li-Ping; Zhang, Bing; Mei, Jie; Li, Hui; Wei, Chun-Yan; Zhou, Wen-Jie; Zhu, Xiao-Yong; Shao, Jun; Li, Da-Jin; Li, Ming-Qing

    2017-01-01

    Endometriosis is an estrogen-dependent inflammatory disease. The anti-inflammatory cytokine IL-10 is also increased in endometriosis. IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. However, the mechanism of inducing IL-10-producing Th17 cells is still largely unknown. The present study investigated the differentiation mechanism and role of IL-10-producing Th17 cells in endometriosis. Here, we report that IL-10+Th17 cells are significantly increased in the peritoneal fluid of women with endometriosis, along with an elevation of IL-27, IL-6 and TGF-β. Compared with peripheral CD4+ T cells, endometrial CD4+ T cells highly expressed IL-27 receptors, especially the ectopic endometrium. Under external (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and local (estrogen, IL-6 and TGF-β) environmental regulation, IL-27 from macrophages and endometrial stromal cells (ESCs) induces IL-10 production in Th17 cells in vitro and in vivo. This process may be mediated through the interaction between c-musculoaponeurotic fibrosarconna (c-Maf) and retinoic acid-related orphan receptor gamma t (RORγt), and associated with the upregulation of downstream B lymphocyte-induced maturation protein-1 (Blimp-1). IL-10+Th17 cells, in turn, stimulate the proliferation and implantation of ectopic lesions and accelerate the progression of endometriosis. These results suggest that IL-27 is a pivotal regulator in endometriotic immune tolerance by triggering Th17 cells to produce IL-10 and promoting the rapid growth and implantation of ectopic lesions. This finding provides a scientific basis for potential therapeutic strategies aimed at preventing the development of endometriosis, especially for patients with high levels of IL-10+Th17 cells. PMID:28300844

  18. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer.

    PubMed

    Kryczek, Ilona; Wu, Ke; Zhao, Ende; Wei, Shuang; Vatan, Linhua; Szeliga, Wojciech; Huang, Emina; Greenson, Joel; Chang, Alfred; Roliński, Jacek; Radwan, Piotr; Fang, Jingyuan; Wang, Guobin; Zou, Weiping

    2011-04-01

    Foxp3(+)CD4(+) regulatory T (Treg) cells inhibit immune responses and temper inflammation. IL-17(+)CD4(+) T (Th17) cells mediate inflammation of autoimmune diseases. A small population of IL-17(+)Foxp3(+)CD4(+) T cells has been observed in peripheral blood in healthy human beings. However, the biology of IL-17(+)Foxp3(+)CD4(+) T cells remains poorly understood in humans. We investigated their phenotype, cytokine profile, generation, and pathological relevance in patients with ulcerative colitis. We observed that high levels of IL-17(+)Foxp3(+)CD4(+) T cells were selectively accumulated in the colitic microenvironment and associated colon carcinoma. The phenotype and cytokine profile of IL-17(+)Foxp3(+)CD4(+) T cells was overlapping with Th17 and Treg cells. Myeloid APCs, IL-2, and TGF-β are essential for their induction from memory CCR6(+) T cells or Treg cells. IL-17(+)Foxp3(+)CD4(+) T cells functionally suppressed T cell activation and stimulated inflammatory cytokine production in the colitic tissues. Our data indicate that IL-17(+)Foxp3(+) cells may be "inflammatory" Treg cells in the pathological microenvironments. These cells may contribute to the pathogenesis of ulcerative colitis through inducing inflammatory cytokines and inhibiting local T cell immunity, and in turn may mechanistically link human chronic inflammation to tumor development. Our data therefore challenge commonly held beliefs of the anti-inflammatory role of Treg cells and suggest a more complex Treg cell biology, at least in the context of human chronic inflammation and associated carcinoma.

  19. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes.

    PubMed

    Kotenko, S V; Izotova, L S; Mirochnitchenko, O V; Esterova, E; Dickensheets, H; Donnelly, R P; Pestka, S

    2001-01-26

    Interleukin-10 (IL-10)-related T cell-derived inducible factor (IL-TIF; provisionally designated IL-22) is a cytokine with limited homology to IL-10. We report here the identification of a functional IL-TIF receptor complex that consists of two receptor chains, the orphan CRF2-9 and IL-10R2, the second chain of the IL-10 receptor complex. Expression of the CRF2-9 chain in monkey COS cells renders them sensitive to IL-TIF. However, in hamster cells both chains, CRF2-9 and IL-10R2, must be expressed to assemble the functional IL-TIF receptor complex. The CRF2-9 chain (or the IL-TIF-R1 chain) is responsible for Stat recruitment. Substitution of the CRF2-9 intracellular domain with the IFN-gammaR1 intracellular domain changes the pattern of IL-TIF-induced Stat activation. The CRF2-9 gene is expressed in normal liver and kidney, suggesting a possible role for IL-TIF in regulating gene expression in these tissues. Each chain, CRF2-9 and IL-10R2, is capable of binding IL-TIF independently and can be cross-linked to the radiolabeled IL-TIF. However, binding of IL-TIF to the receptor complex is greater than binding to either receptor chain alone. Sharing of the common IL-10R2 chain between the IL-10 and IL-TIF receptor complexes is the first such case for receptor complexes with chains belonging to the class II cytokine receptor family, establishing a novel paradigm for IL-10-related ligands similar to the shared use of the gamma common chain (gamma(c)) by several cytokines, including IL-2, IL-4, IL-7, IL-9, and IL-15.

  20. Homeostasis of naive and memory CD4+ T cells: IL-2 and IL-7 differentially regulate the balance between proliferation and Fas-mediated apoptosis.

    PubMed

    Jaleco, Sara; Swainson, Louise; Dardalhon, Valérie; Burjanadze, Maryam; Kinet, Sandrina; Taylor, Naomi

    2003-07-01

    Cytokines play a crucial role in the maintenance of polyclonal naive and memory T cell populations. It has previously been shown that ex vivo, the IL-7 cytokine induces the proliferation of naive recent thymic emigrants (RTE) isolated from umbilical cord blood but not mature adult-derived naive and memory human CD4(+) T cells. We find that the combination of IL-2 and IL-7 strongly promotes the proliferation of RTE, whereas adult CD4(+) T cells remain relatively unresponsive. Immunological activity is controlled by a balance between proliferation and apoptotic cell death. However, the relative contributions of IL-2 and IL-7 in regulating these processes in the absence of MHC/peptide signals are not known. Following exposure to either IL-2 or IL-7 alone, RTE, as well as mature naive and memory CD4(+) T cells, are rendered only minimally sensitive to Fas-mediated cell death. However, in the presence of the two cytokines, Fas engagement results in a high level of caspase-dependent apoptosis in both RTE as well as naive adult CD4(+) T cells. In contrast, equivalently treated memory CD4(+) T cells are significantly less sensitive to Fas-induced cell death. The increased susceptibility of RTE and naive CD4(+) T cells to Fas-induced apoptosis correlates with a significantly higher IL-2/IL-7-induced Fas expression on these T cell subsets than on memory CD4(+) T cells. Thus, IL-2 and IL-7 regulate homeostasis by modulating the equilibrium between proliferation and apoptotic cell death in RTE and mature naive and memory T cell subsets.

  1. A subset of IL-10-producing gammadelta T cells protect the liver from Listeria-elicited, CD8(+) T cell-mediated injury.

    PubMed

    Rhodes, Katherine A; Andrew, Elizabeth M; Newton, Darren J; Tramonti, Daniela; Carding, Simon R

    2008-08-01

    Although gammadelta T cells play a role in protecting tissues from pathogen-elicited damage to bacterial, viral and parasitic pathogens, the mechanisms involved in the damage and in the protection have not been clearly elucidated. This has been addressed using a murine model of listeriosis, which in mice lacking gammadelta T cells (TCRdelta(-/-)) is characterised by severe and extensive immune-mediated hepatic necrosis. We show that these hepatic lesions are caused by Listeria-elicited CD8(+) T cells secreting high levels of TNF-alpha that accumulate in the liver of Listeria-infected TCRdelta(-/-) mice. Using isolated populations of gammadelta T cells from wild-type and cytokine-deficient strains of mice to reconstitute TCRdelta(-/-) mice, the TCR variable gene 4 (Vgamma4)(+) subset of gammadelta T cells was shown to protect against liver injury. Hepatoprotection was dependent upon their ability to produce IL-10 after TCR-mediated interactions with Listeria-elicited macrophages and CD8(+) T cells. IL-10-producing Vgamma4(+) T cells also contribute to controlling CD8(+) T cell expansion and to regulating and reducing TNF-alpha secretion by activated CD8(+) T cells. This effect on TNF-alpha production was directly attributed to IL-10. These findings identify a novel mechanism by which pathogen-elicited CD8(+) T cells are regulated via interactions with, and activation of, IL-10-producing hepatoprotective gammadelta T cells.

  2. Enforced IL-10 Expression Confers Type 1 Regulatory T Cell (Tr1) Phenotype and Function to Human CD4+ T Cells

    PubMed Central

    Andolfi, Grazia; Fousteri, Georgia; Rossetti, Maura; Magnani, Chiara F; Jofra, Tatiana; Locafaro, Grazia; Bondanza, Attilio; Gregori, Silvia; Roncarolo, Maria-Grazia

    2012-01-01

    Type 1 regulatory T (Tr1) cells are an inducible subset of CD4+ Tr cells characterized by high levels of interleukin (IL)-10 production and regulatory properties. Several protocols to generate human Tr1 cells have been developed in vitro. However, the resulting population includes a significant fraction of contaminating non-Tr1 cells, representing a major bottleneck for clinical application of Tr1 cell therapy. We generated an homogeneous IL-10–producing Tr1 cell population by transducing human CD4+ T cells with a bidirectional lentiviral vector (LV) encoding for human IL-10 and the marker gene, green fluorescent protein (GFP), which are independently coexpressed. The resulting GFP+ LV-IL-10–transduced human CD4+ T (CD4LV-IL-10) cells expressed, upon T-cell receptor (TCR) activation, high levels of IL-10 and concomitant low levels of IL-4, and markers associated with IL-10. Moreover, CD4LV-IL-10 T cells displayed typical Tr1 features: the anergic phenotype, the IL-10, and transforming growth factor (TGF)-β dependent suppression of allogeneic T-cell responses, and the ability to suppress in a cell-to-cell contact independent manner in vitro. CD4LV-IL-10 T cells were able to control xeno graft-versus-host disease (GvHD), demonstrating their suppressive function in vivo. These results show that constitutive over-expression of IL-10 in human CD4+ T cells leads to a stable cell population that recapitulates the phenotype and function of Tr1 cells. PMID:22692497

  3. Que peut-on voir avec des neutrons? Une introduction pour des non spécialistes

    NASA Astrophysics Data System (ADS)

    Schweizer, J.

    2005-11-01

    Le neutron est une particule élémentaire qui a été découverte en 1932 par James Chadwick. Ses caractéristiques principales sont résumées dans le tableau I. Il a été utilisé pour la première fois par Clifford Shull en 1946 comme outil pour des expériences de diffusion. Cette technique s'est depuis constamment développée pour concerner tous les aspects de la matière condensée: physique, chimie, matériaux, biologie. Il s'agit d'un outil tout à fait exceptionnel car le neutron possède des propriétés uniques et particulièrement adaptées pour ces études.

  4. IL-6 inhibits upregulation of membrane-bound TGF-beta 1 on CD4+ T cells and blocking IL-6 enhances oral tolerance

    PubMed Central

    Kuhn, Chantal; Rezende, Rafael Machado; M'Hamdi, Hanane; da Cunha, Andre Pires; Weiner, Howard L.

    2016-01-01

    Oral administration of antigen induces regulatory T cells that express latent membrane-bound TGF-beta (LAP) and that have been shown to play an important role in the induction of oral tolerance. We developed an in vitro model to study modulation of LAP+ on CD4+ T cells. The combination of anti-CD3 mAb, anti-CD28 mAb and recombinant IL-2 induced expression of LAP on naïve CD4+ T cells, independent of FoxP3 or exogenous TGF-β. In vitro generated CD4+LAP+FoxP3− T cells were suppressive in vitro, inhibiting proliferation of naïve CD4+ T cells and IL-17A secretion by Th17 cells. Assessing the impact of different cytokines and neutralizing antibodies against cytokines we found that LAP induction was decreased in the presence of IL-6 and IL-21, and to a lesser extent by IL-4 and TNFα. IL-6 abrogated the in vitro induction of CD4+LAP+ T cells by STAT3 dependent inhibition of Lrrc32 (GARP), the adapter protein that tethers TGF-beta to the membrane. Oral tolerance induction was enhanced in mice lacking expression of IL-6R by CD4+ T cells and by treatment of wild-type mice with neutralizing anti-IL-6 mAb. These results suggest that pro-inflammatory cytokines interfere with oral tolerance induction and that blocking the IL-6 pathway is a potential strategy for enhancing oral tolerance in the setting of autoimmune and inflammatory diseases. PMID:28039301

  5. CCR6 and NK1.1 distinguish between IL-17A and IFN-gamma-producing gammadelta effector T cells.

    PubMed

    Haas, Jan D; González, Frano H Malinarich; Schmitz, Susanne; Chennupati, Vijaykumar; Föhse, Lisa; Kremmer, Elisabeth; Förster, Reinhold; Prinz, Immo

    2009-12-01

    Gammadelta T cells are a potent source of innate IL-17A and IFN-gamma, and they acquire the capacity to produce these cytokines within the thymus. However, the precise stages and required signals that guide this differentiation are unclear. Here we show that the CD24(low) CD44(high) effector gammadelta T cells of the adult thymus are segregated into two lineages by the mutually exclusive expression of CCR6 and NK1.1. Only CCR6+ gammadelta T cells produced IL-17A, while NK1.1+ gammadelta T cells were efficient producers of IFN-gamma but not of IL-17A. Their effector phenotype correlated with loss of CCR9 expression, particularly among the NK1.1+ gammadelta T cells. Accordingly, both gammadelta T-cell subsets were rare in gut-associated lymphoid tissues, but abundant in peripheral lymphoid tissues. There, they provided IL-17A and IFN-gamma in response to TCR-specific and TCR-independent stimuli. IL-12 and IL-18 induced IFN-gamma and IL-23 induced IL-17A production by NK1.1+ or CCR6+ gammadelta T cells, respectively. Importantly, we show that CCR6+ gammadelta T cells are more responsive to TCR stimulation than their NK1.1+ counterparts. In conclusion, our findings support the hypothesis that CCR6+ IL-17A-producing gammadelta T cells derive from less TCR-dependent selection events than IFN-gamma-producing NK1.1+ gammadelta T cells.

  6. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells

    PubMed Central

    Akitsu, Aoi; Ishigame, Harumichi; Kakuta, Shigeru; Chung, Soo-hyun; Ikeda, Satoshi; Shimizu, Kenji; Kubo, Sachiko; Liu, Yang; Umemura, Masayuki; Matsuzaki, Goro; Yoshikai, Yasunobu; Saijo, Shinobu; Iwakura, Yoichiro

    2015-01-01

    Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4+ and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4+ T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6+ subset of CCR2+ γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6+ cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner. PMID:26108163

  7. Les hémodialysés HVC sont-ils vraiment des patients difficiles à traiter?

    PubMed Central

    Krati, Khadija; Cherquaoui, Hind; Oubaha, Sofia; Samlani, Zouhour

    2015-01-01

    L'hépatite C demeure la principale infection virale chez l'hémodialysé, dont la prise en charge thérapeutique ainsi que la gestion de ses effets secondaires restent difficiles. Il s'agit d'une étude rétrospective portant sur tous les patients atteints d'hépatite C chronique ayant une insuffisance rénale chronique sous hémodialyse, suivis au service de gastroentérologie au CHU Mohamed VI de Marrakech sur une période de Janvier 2004 à Décembre 2014. Sur un total de 355 cas d'hépatite virale C, 13 patients étaient hémodialysés (3,66%). Dix patients ont été traités, soit 76,94% des cas. Le traitement n’était pas indiqué chez 2 patients ayant une fibrose minime sans cytolyse. Il était contre-indiqué chez une patiente multitarée. Deux malades ont eu une réponse virologique rapide et 5 une réponse virologique précoce. Le taux de réponse virologique soutenue était de 40%, 30% des patients étaient non répondeurs. Le traitement fut arrêté chez 2 patientes pour effets secondaires sévères. Un seul patient a été candidat à une transplantation rénale. En analyse multivariée, la réponse virologique soutenue a été significativement associée à certains facteurs prédictifs de bonne réponse thérapeutique: Age jeune ≤40 ans (P=0,0057), fibrose minime F1-F2 (P=0,03), génotype non 1 (P=0,0064), charge virale préthérapeutique <800000 UI/ml (P=0,013), et l'absence d'arrêt thérapeutique (P=0,028). La gestion efficace des effets secondaires du traitement de HVC permet d'obtenir chez l'hémodialysé un taux de réponse virologique soutenue avoisinant celui de la population générale. PMID:27022433

  8. IL-6 Inhibits Upregulation of Membrane-Bound TGF-β 1 on CD4+ T Cells and Blocking IL-6 Enhances Oral Tolerance.

    PubMed

    Kuhn, Chantal; Rezende, Rafael Machado; M'Hamdi, Hanane; da Cunha, Andre Pires; Weiner, Howard L

    2017-02-01

    Oral administration of Ag induces regulatory T cells that express latent membrane-bound TGF-β (latency-associated peptide [LAP]) and have been shown to play an important role in the induction of oral tolerance. We developed an in vitro model to study modulation of LAP + on CD4 + T cells. The combination of anti-CD3 mAb, anti-CD28 mAb, and recombinant IL-2 induced expression of LAP on naive CD4 + T cells, independent of Foxp3 or exogenous TGF-β. In vitro generated CD4 + LAP + Foxp3 - T cells were suppressive in vitro, inhibiting proliferation of naive CD4 + T cells and IL-17A secretion by Th17 cells. Assessing the impact of different cytokines and neutralizing Abs against cytokines, we found that LAP induction was decreased in the presence of IL-6 and IL-21, and to a lesser extent by IL-4 and TNF-α. IL-6 abrogated the in vitro induction of CD4 + LAP + T cells by STAT3-dependent inhibition of Lrrc32 (glycoprotein A repetitions predominant [GARP]), the adapter protein that tethers TGF-β to the membrane. Oral tolerance induction was enhanced in mice lacking expression of IL-6R by CD4 + T cells and by treatment of wild-type mice with neutralizing anti-IL-6 mAb. These results suggest that proinflammatory cytokines interfere with oral tolerance induction and that blocking the IL-6 pathway is a potential strategy for enhancing oral tolerance in the setting of autoimmune and inflammatory diseases. Copyright © 2017 by The American Association of Immunologists, Inc.

  9. Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis.

    PubMed

    Owen, David L; Mahmud, Shawn A; Vang, Kieng B; Kelly, Ryan M; Blazar, Bruce R; Smith, Kendall A; Farrar, Michael A

    2018-06-15

    The cytokine IL-2 is critical for promoting the development, homeostasis, and function of regulatory T (Treg) cells. The cellular sources of IL-2 that promote these processes remain unclear. T cells, B cells, and dendritic cells (DCs) are known to make IL-2 in peripheral tissues. We found that T cells and DCs in the thymus also make IL-2. To identify cellular sources of IL-2 in Treg cell development and homeostasis, we used Il2 FL/FL mice to selectively delete Il2 in T cells, B cells, and DCs. Because IL-15 can partially substitute for IL-2 in Treg cell development, we carried out the majority of these studies on an Il15 -/- background. Deletion of Il2 in B cells, DCs, or both these subsets had no effect on Treg cell development, either in wild-type (WT) or Il15 -/- mice. Deletion of Il2 in T cells had minimal effects in WT mice but virtually eliminated developing Treg cells in Il15 -/- mice. In the spleen and most peripheral lymphoid organs, deletion of Il2 in B cells, DCs, or both subsets had no effect on Treg cell homeostasis. In contrast, deletion of Il2 in T cells led to a significant decrease in Treg cells in either WT or Il15 -/- mice. The one exception was the mesenteric lymph nodes where significantly fewer Treg cells were observed when Il2 was deleted in both T cells and DCs. Thus, T cells are the sole source of IL-2 needed for Treg cell development, but DCs can contribute to Treg cell homeostasis in select organs. Copyright © 2018 by The American Association of Immunologists, Inc.

  10. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4

    PubMed Central

    Walsh, James T.; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R.; Gadani, Sachin; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina; Siffrin, Volker; Radjavi, Ali; Fernandez-Castaneda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala-Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan

    2015-01-01

    A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell–mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4–producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4–deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4–deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell–derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4–producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration. PMID:25607842

  11. IL-7 signaling imparts polyfunctionality and stemness potential to CD4+ T cells

    PubMed Central

    Ding, Zhi-Chun; Liu, Chufeng; Cao, Yang; Habtetsion, Tsadik; Kuczma, Michal; Pi, Wenhu; Kong, Heng; Cacan, Ercan; Greer, Susanna F.; Cui, Yan; Blazar, Bruce R.; Munn, David H.; Zhou, Gang

    2016-01-01

    ABSTRACT The functional status of CD4+ T cells is a critical determinant of antitumor immunity. Polyfunctional CD4+ T cells possess the ability to concomitantly produce multiple Th1-type cytokines, exhibiting a functional attribute desirable for cancer immunotherapy. However, the mechanisms by which these cells are induced are neither defined nor it is clear if these cells can be used therapeutically to treat cancer. Here, we report that CD4+ T cells exposed to exogenous IL-7 during antigenic stimulation can acquire a polyfunctional phenotype, characterized by their ability to simultaneously express IFNγ, IL-2, TNFα and granzyme B. This IL-7-driven polyfunctional phenotype was associated with increased histone acetylation in the promoters of the effector genes, indicative of increased chromatin accessibility. Moreover, forced expression of a constitutively active (CA) form of STAT5 recapitulated IL-7 in inducing CD4+ T-cell polyfunctionality. Conversely, the expression of a dominant negative (DN) form of STAT5 abolished the ability of IL-7 to induce polyfunctional CD4+ T cells. These in-vitro-generated polyfunctional CD4+ T cells can traffic to tumor and expand intratumorally in response to immunization. Importantly, adoptive transfer of polyfunctional CD4+ T cells following lymphodepletive chemotherapy was able to eradicate large established tumors. This beneficial outcome was associated with the occurrence of antigen epitope spreading, activation of the endogenous CD8+ T cells and persistence of donor CD4+ T cells exhibiting memory stem cell attributes. These findings indicate that IL-7 signaling can impart polyfunctionality and stemness potential to CD4+ T cells, revealing a previously unknown property of IL-7 that can be exploited in adoptive T-cell immunotherapy. PMID:27471650

  12. Blocking IL-2 Signal In Vivo with an IL-2 Antagonist Reduces Tumor Growth through the Control of Regulatory T Cells.

    PubMed

    Carmenate, Tania; Ortíz, Yaquelín; Enamorado, Michel; García-Martínez, Karina; Avellanet, Janet; Moreno, Ernesto; Graça, Luis; León, Kalet

    2018-05-15

    IL-2 is critical for peripheral tolerance mediated by regulatory T (Treg) cells, which represent an obstacle for effective cancer immunotherapy. Although IL-2 is important for effector (E) T cell function, it has been hypothesized that therapies blocking IL-2 signals weaken Treg cell activity, promoting immune responses. This hypothesis has been partially tested using anti-IL-2 or anti-IL-2R Abs with antitumor effects that cannot be exclusively attributed to lack of IL-2 signaling in vivo. In this work, we pursued an alternative strategy to block IL-2 signaling in vivo, taking advantage of the trimeric structure of the IL-2R. We designed an IL-2 mutant that conserves the capacity to bind to the αβ-chains of the IL-2R but not to the γ c -chain, thus having a reduced signaling capacity. We show our IL-2 mutein inhibits IL-2 Treg cell-dependent differentiation and expansion. Moreover, treatment with IL-2 mutein reduces Treg cell numbers and impairs tumor growth in mice. A mathematical model was used to better understand the effect of the mutein on Treg and E T cells, suggesting suitable strategies to improve its design. Our results show that it is enough to transiently inhibit IL-2 signaling to bias E and Treg cell balance in vivo toward immunity. Copyright © 2018 by The American Association of Immunologists, Inc.

  13. Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness.

    PubMed

    Kirstein, Frank; Nieuwenhuizen, Natalie E; Jayakumar, Jaisubash; Horsnell, William G C; Brombacher, Frank

    2016-06-01

    TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. Human T cells expressing BEND3 on their surface represent a novel subpopulation that preferentially produces IL-6 and IL-8.

    PubMed

    Shiheido, Hirokazu; Kitagori, Koji; Sasaki, Chiyomi; Kobayashi, Shio; Aoyama, Takane; Urata, Kozue; Oku, Takuma; Hirayama, Yoshitaka; Yoshitomi, Hiroyuki; Hikida, Masaki; Yoshifuji, Hajime; Mimori, Tsuneyo; Watanabe, Takeshi; Shimizu, Jun

    2014-06-01

    BEN domain-containing protein 3 (BEND3) has no transmembrane region, is localized in the cytoplasm, and is involved in chromatin function and transcription. We here identified a novel subpopulation of human T cells that expressed BEND3 on their cell surface (BEND3(+) T cells). BEND3(+) T cells consisted of approximately 3% of T cells in the peripheral blood, were present in both CD4(+) and CD8(+) T cells, and were also observed in cord blood. The stimulation of BEND3(+) T cells through the TCR/CD3 complex led to the production of various kinds of cytokines; however, the levels of IL-6 and IL-8 produced by BEND3(+) T cells were higher than those by BEND3(-) T cells. The proportion of BEND3(+) T cells was also increased in some patients with inflammatory diseases. Taken together, these results indicate that BEND3(+) T cells are a new subpopulation of T cells in terms of their cytokine profile. Further analyses on BEND3(+) T cells may be of importance and useful in understanding human T cell immunology.

  15. T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

    PubMed Central

    Clarkson, Benjamin D.S.; Ling, Changying; Shi, Yejie; Harris, Melissa G.; Rayasam, Aditya; Sun, Dandan; Salamat, M. Shahriar; Kuchroo, Vijay; Lambris, John D.; Sandor, Matyas

    2014-01-01

    T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, but the relevant T cell–derived mediators of tissue injury remain unknown. Using a mouse model of transient focal brain ischemia, we report that IL-21 is highly up-regulated in the injured mouse brain after cerebral ischemia. IL-21–deficient mice have smaller infarcts, improved neurological function, and reduced lymphocyte accumulation in the brain within 24 h of reperfusion. Intracellular cytokine staining and adoptive transfer experiments revealed that brain-infiltrating CD4+ T cells are the predominant IL-21 source. Mice treated with decoy IL-21 receptor Fc fusion protein are protected from reperfusion injury. In postmortem human brain tissue, IL-21 localized to perivascular CD4+ T cells in the area surrounding acute stroke lesions, suggesting that IL-21–mediated brain injury may be relevant to human stroke. PMID:24616379

  16. IL-10 suppresses Th17 cells and promotes regulatory T cells in the CD4+ T cell population of rheumatoid arthritis patients.

    PubMed

    Heo, Yu-Jung; Joo, Young-Bin; Oh, Hye-Jwa; Park, Mi-Kyung; Heo, Yang-Mi; Cho, Mi-La; Kwok, Seung-Ki; Ju, Ji-Hyeon; Park, Kyung-Su; Cho, Seok Goo; Park, Sung-Hwan; Kim, Ho-Youn; Min, Jun-Ki

    2010-01-04

    Interleukin-17-producing CD4(+) T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including autoimmune arthritis. IL-10 promotes the generation of Foxp3(+) regulatory T cells via the IL-10 receptor signal. The objective of this study was to examine whether IL-10, which acts as an anti-inflammatory cytokine, has a suppressive effect on the activation of human Th17 cells. Expression of IL-17 and IL-10 was examined immunohistochemically in tissue obtained from rheumatoid arthritis patients. Human peripheral blood CD4(+) T cells were isolated and cultured under various stimulatory conditions. Th17 cells and regulatory T (Treg) cells were detected by flow cytometry. The gene expression of related cytokines and transcription factors were assessed by ELISA and RT-PCR. IL-17 was overexpressed in rheumatoid arthritis patients. IL-10 treatment significantly decreased the numbers of IL-17-producing and RORc-expressing cells among human CD4(+) T cells that had been activated in vitro by Th17-differentiating conditions in autoimmune arthritis patients. IL-10 induced Foxp3(+) regulatory T cells in the human CD4(+) T cell population. Our results demonstrate that IL-17 is overexpressed in autoimmune disease patients and that IL-10 suppresses IL-17 expression. IL-10 may be useful in the treatment of autoimmune diseases.

  17. Intermittent IL-7 Signaling Essential for T cell Homeostasis | Center for Cancer Research

    Cancer.gov

    In order for the immune system to mount an appropriate response to foreign antigens throughout a person’s life, the body must maintain a sufficient population of circulating mature, naïve T cells, a process known as T cell homeostasis. Previous studies revealed that this process depends upon signaling from the cytokine interleukin-7 (IL-7) as well as from the T cell antigen receptor (TCR). Intriguingly, signals from each pathway affect the other and lead to their alternating activation: IL-7 binding to its receptor leads to increasing expression of the TCR co-receptor CD8; sufficient CD8 expression allows TCRs to signal when bound to self-ligands, blocking IL-7 signaling; suppressed IL-7 signals lead to down-regulation of CD8 and ligand disengagement, which allows T cells to again respond to IL-7. Alfred Singer, M.D., and his colleagues in CCR’s Experimental Immunology Branch set out to understand how this intricate pathway promotes T cell survival.

  18. T cells expanded in presence of IL-15 exhibit increased antioxidant capacity and innate effector molecules

    PubMed Central

    Kaur, Navtej; Naga, Osama S.; Norell, Håkan; Al-Khami, Amir A.; Scheffel, Matthew J.; Chakraborty, Nitya G.; Voelkel-Johnson, Christina; Mukherji, Bijay; Mehrotra, Shikhar

    2011-01-01

    Persistence of effector cytotoxic T lymphocytes (CTLs) during an immunological response is critical for successfully controlling a viral infection or tumor growth. Various cytokines are known to play an important part in regulating the immune response. The IL-2 family of cytokines that includes IL-2 and IL-15 are known to function as growth and survival factors for antigen-experienced T cells. IL-2 and IL-15 possess similar properties, including the ability to induce T cell proliferation. Whereas long term IL-2 exposure has been shown to promote apoptosis and limit CD8+ memory T cell survival and proliferation, it is widely believed that IL-15 can inhibit apoptosis and helps maintain a memory CD8+ T-cell population. However, mechanisms for superior outcomes for IL-15 as compared to IL-2 are still under investigation. Our data shows that human T cells cultured in the presence of IL-15 exhibit increased expression of anti-oxidant molecules Glutathione reductase (GSR), Thioredoxin reductase 1 (TXNDR1), Peroxiredoxin (PRDX), Superoxide dismutase (SOD). An increased expression of cell-surface thiols, intracellular glutathione, and thioredoxins was also noted in IL-15 cultured T cells. Additionally, IL-15 cultured T cells also showed an increase in cytolytic effector molecules. Apart from increased level of Granzyme A and Granzyme B, IL-15 cultured T cells exhibit increased accumulation of reactive oxygen (ROS) and reactive nitrogen (RNS) species as compared to IL-2 cultured T cells. Overall, this study suggests that T cells cultured in IL-15 show increase persistence not only due to increased anti-apoptotic proteins but also due to increased anti-oxidant levels, which is further complimented by increased cytolytic effector functions. PMID:21602054

  19. IL-15 signaling promotes adoptive effector T-cell survival and memory formation in irradiation-induced lymphopenia.

    PubMed

    Xu, Aizhang; Bhanumathy, Kalpana Kalyanasundaram; Wu, Jie; Ye, Zhenmin; Freywald, Andrew; Leary, Scot C; Li, Rongxiu; Xiang, Jim

    2016-01-01

    Lymphopenia promotes naïve T-cell homeostatic proliferation and adoptive effector T-cell survival and memory formation. IL-7 plays a critical role in homeostatic proliferation, survival and memory formation of naïve T-cells in lymphopenia, and its underlying molecular mechanism has also been well studied. However, the mechanism for adoptively transferred effector T-cell survival and memory formation is not fully understood. Here, we transferred in vitro-activated transgenic OT-I CD8(+) effector T-cells into irradiation (600 rads)-induced lymphopenic C57BL/6, IL-7 knockout (KO) and IL-15 KO mice, and investigated the survival and memory formation of transferred T-cells in lymphopenia. We demonstrate that transferred T-cells prolong their survival and enhance their memory in lymphopenic mice, in a manner that depends on IL-15 signaling, but not IL-7. We determine that in vitro stimulation of naïve or effector T-cells with IL-7 and IL-15 reduces IL-7Rα, and increases and/or maintains IL-15Rβ expression, respectively. Consistent with these findings, the expression of IL-7Rα and IL-15Rβ is down- and up-regulated, respectively, in vivo on transferred T-cells in an early phase post T-cell transfer in lymphopenia. We further show that in vitro IL-15 restimulation-induced memory T-cells (compared to IL-2 restimulation-induced effector T-cells) and in vivo transferred T-cells in irradiated IL-15-sufficient C57BL/6 mice (compared to IL-15-deficient IL-15 KO mice) have increased mitochondrial content, but less NADH and lower mitochondrial potential (ΔΨm), and demonstrate greater phosphorylation of signal transducers and activators of transcription-5 (STAT5) and Unc-51-like kinase-1 (ULK1), and higher expression of B-cell leukemia/lymphoma-2 (Bcl2) and memory-, autophagy- and mitochondrial biogenesis-related molecules. Irradiation-induced lymphopenia promotes effector T-cell survival via IL-15 signaling the STAT5/Bcl2 pathway, enhances T-cell memory formation via IL

  20. STAT1 is Constitutively Activated in the T/C28a2 Immortalized Juvenile Human Chondrocyte Line and Stimulated by IL-6 Plus Soluble IL-6R.

    PubMed

    Meszaros, Evan C; Malemud, Charles J

    2015-04-01

    T/C28a2 immortalized juvenile human chondrocytes were employed to determine the extent to which activation of Signal Transducers and Activators of Transcription-1 (STAT1) occurred in response to recombinant human interleukin-6 (rhIL-6) or rhIL-6 in combination with the soluble IL-6 receptor (sIL-6R). Two forms of STAT1, STAT1A and STAT1B, were identified on SDS-PAGE and western blotting with anti-STAT1 antibody. Western blotting revealed that STAT1 was constitutively phosphorylated (p-STAT1). Although incubation of T/C28a2 chondrocytes with rhIL-6 (50 ng/ml) increased p-STAT1A by Δ=22.3% after 30 min, this percent difference failed to reach significance by Chi-square analysis. Similarly, no effect of rhIL-6 (Δ=+10.7%) on p-STAT1B was seen at 30 min. In contrast, although the combination of rhIL-6 plus sIL-6R had no effect on p-STAT1A, rhIL-6 plus sIL-6R increased p-STAT1B by Δ=73.3% (p<0.0001) after 30 min compared to the control group and by Δ=56.7% (p<0.0001) compared to rhIL-6 alone. Janex-1, a Janus kinase-3-specific inhibitor (100 μM) partially reduced the effect of rhIL-6 on p-STAT1B by Δ=27.7% (p<0.05). The results of this study showed that STAT1A/STAT1B was constitutively activated in T/C28a2 chondrocytes. Although rhIL-6 increased p-STAT1B to a small extent, the combination of rhIL-6 plus sIL-6R was far more effective in stimulating STAT1B phosphorylation compared to controls or rhIL-6 alone. These data support the likelihood that although JAK3-mediated activation of STAT1 in T/C28a2 chondrocytes may involve the IL-6/IL-6R/gp130 pathway, these results indicated that STAT1 activation in response to IL-6 preferentially involved IL-6 trans -signaling via sIL-6R.

  1. Une recension des écrits concernant la réalité psychoaffective des femmes ayant une vulvodynie : Difficultés rencontrées et stratégies développées

    PubMed Central

    Cantin-Drouin, Maude; Damant, Dominique; Turcotte, Daniel

    2008-01-01

    HISTORIQUE : Au cours des trois dernières décennies, une attention grandissante a été portée à l’étude du syndrome de vulvodynie, soit un inconfort vulvaire chronique inexpliqué, éprouvé en l’absence de pathologie précisée. En plus d’avoir des répercussions physiques, l’expérience de la vulvodynie comporte une dimension psychosociale. OBJECTIF : Cet article vise à faire une recension des écrits sur la réalité psychoaffective des femmes qui éprouvent une vulvodynie. MÉTHODE : Une recherche documentaire basée sur une exploration systématique de textes présentant des résultats de recherche et recensés dans les principales banques de données en sciences sociales, dont Dissertation Abstracts, Current Contents et PsycINFO, a été réalisée. RÉSULTATS : Cette recension des écrits révèle, malgré la présence de certains résultats divergents, que les femmes ayant une vulvodynie affrontent souvent des difficultés identitaires et psychologiques, qui sont influencées notamment par les normes sociales de sexualité et de féminité. Pour composer avec ces difficultés, les femmes développent différentes stratégies visant à diminuer le stress occasionné par la douleur et à améliorer leur bien-être psychologique. CONCLUSION : Les difficultés relationnelles et psychologiques vécues par les femmes ayant une vulvodynie ne découlent pas seulement de la douleur physique, mais aussi du sens qu’elles lui accordent, souvent influencé par les discours sociaux sur l’hétérosexualité et la féminité. Il importe donc d’intervenir auprès des femmes en tenant compte de l’influence du contexte social tout en poursuivant le développement des connaissances sur les aspects psychosociaux de cette expérience. PMID:18592063

  2. IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury.

    PubMed

    Stremska, Marta E; Jose, Sheethal; Sabapathy, Vikram; Huang, Liping; Bajwa, Amandeep; Kinsey, Gilbert R; Sharma, Poonam R; Mohammad, Saleh; Rosin, Diane L; Okusa, Mark D; Sharma, Rahul

    2017-09-01

    CD4 + Foxp3 + regulatory T cells (Tregs) protect the kidney during AKI. We previously found that IL-2, which is critical for Treg homeostasis, upregulates the IL-33 receptor (ST2) on CD4 + T cells, thus we hypothesized that IL-2 and IL-33 cooperate to enhance Treg function. We found that a major subset of Tregs in mice express ST2, and coinjection of IL-2 and IL-33 increased the number of Tregs in lymphoid organs and protected mice from ischemia-reperfusion injury (IRI) more efficiently than either cytokine alone. Accordingly, we generated a novel hybrid cytokine (IL233) bearing the activities of IL-2 and IL-33 for efficient targeting to Tregs. IL233 treatment increased the number of Tregs in blood and spleen and prevented IRI more efficiently than a mixture of IL-2 and IL-33. Injection of IL233 also increased the numbers of Tregs in renal compartments. Moreover, IL233-treated mice had fewer splenic Tregs and more Tregs in kidneys after IRI. In vitro , splenic Tregs from IL233-treated mice suppressed CD4 + T cell proliferation better than Tregs from saline-treated controls. IL233 treatment also improved the ability of isolated Tregs to inhibit IRI in adoptive transfer experiments and protected mice from cisplatin- and doxorubicin-induced nephrotoxic injury. Finally, treatment with IL233 increased the proportion of ST2-bearing innate lymphoid cells (ILC2) in blood and kidneys, and adoptive transfer of ILC2 also protected mice from IRI. Thus, the novel IL233 hybrid cytokine, which utilizes the cooperation of IL-2 and IL-33 to enhance Treg- and ILC2-mediated protection from AKI, bears strong therapeutic potential. Copyright © 2017 by the American Society of Nephrology.

  3. Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.

    PubMed

    Klevorn, Lauryn E; Berrien-Elliott, Melissa M; Yuan, Jinyun; Kuehm, Lindsey M; Felock, Gregory D; Crowe, Sean A; Teague, Ryan M

    2016-12-01

    Interleukin-2 (IL2) was among the earliest reagents used for cancer immunotherapy due to its ability to support the survival and function of tumor-reactive T cells. However, treatment with IL2 is accompanied by off-target toxicity and low response rates in patients. In mouse models, these issues are largely overcome when IL2 is administered as a cytokine/antibody complex (IL2c). The complex has a longer serum half-life and can be designed for preferential cytokine delivery to specific cells of interest. Early studies showed IL2c could boost antitumor immunity in mice by activating tumor-reactive CD8 + T cells. But such functional T cells are often limited in the tumor microenvironment, where instead unresponsive tolerant T cells are eventually eliminated by apoptosis, representing a major obstacle to the success of cancer immunotherapy. We found that IL2c treatment rescued tumor-specific CD8 + T cells from a state of established tolerance, providing effective immunotherapy in tumor-bearing mice. Expression of the transcription factor T-bet was necessary to drive intratumoral IFNγ production and effector activity by T cells rescued with IL2c. Furthermore, IL2c promoted T-bet expression in human CD4 + and CD8 + T cells in humanized tumor-bearing mice, but also increased the frequency of Foxp3 + regulatory T cells. Our study reveals a novel role for IL2c as a powerful immunotherapeutic reagent capable of reversing tolerance in tumor-reactive T cells, and provides the first evidence that IL2c influences human T cells in vivo, highlighting the translational potential to modulate human antitumor immune responses. Cancer Immunol Res; 4(12); 1016-26. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells.

    PubMed

    Hurton, Lenka V; Singh, Harjeet; Najjar, Amer M; Switzer, Kirsten C; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A; Champlin, Richard E; Cooper, Laurence J N

    2016-11-29

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (T SCM ) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR + T cells with preserved T SCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19 + leukemia. Long-lived T cells were CD45RO neg CCR7 + CD95 + , phenotypically most similar to T SCM , and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR + T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.

  5. Pathomimie de l'enfant: à propos d'une observation

    PubMed Central

    Abilkassem, Rachid; Dini, Nezha; Ourai, Hakim; Kmari, Mohamed; Agadr, Aomar

    2013-01-01

    La pathomimie cutanée se définit comme une maladie factice, provoquée dans un etat de conscience claire par le patient lui-même, au niveau du revêtement cutanéo-muqueux et/ou des phanères. Rare chez l'enfant, il s'agit d'une manifestation psychopathologique potentiellement grave et souvent difficile à prendre en charge. Nous rapportons le cas d'une fillette de 10 ans présentant une pathomimie sous forme de lésions excoriées multiples du visage. PMID:23504605

  6. T cell-derived IL-10 determines leishmaniasis disease outcome and is suppressed by a dendritic cell based vaccine.

    PubMed

    Schwarz, Tobias; Remer, Katharina A; Nahrendorf, Wiebke; Masic, Anita; Siewe, Lisa; Müller, Werner; Roers, Axel; Moll, Heidrun

    2013-01-01

    In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cell-specific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10-deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10-deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFN-γ or IFN-γ and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection.

  7. Vγ4 γδ T Cells Provide an Early Source of IL-17A and Accelerate Skin Graft Rejection.

    PubMed

    Li, Yashu; Huang, Zhenggen; Yan, Rongshuai; Liu, Meixi; Bai, Yang; Liang, Guangping; Zhang, Xiaorong; Hu, Xiaohong; Chen, Jian; Huang, Chibing; Liu, Baoyi; Luo, Gaoxing; Wu, Jun; He, Weifeng

    2017-12-01

    Activated γδ T cells have been shown to accelerate allograft rejection. However, the precise role of skin-resident γδ T cells and their subsets-Vγ5 (epidermis), Vγ1, and Vγ4 (dermis)-in skin graft rejection have not been identified. Here, using a male to female skin transplantation model, we demonstrated that Vγ4 T cells, rather than Vγ1 or Vγ5 T cells, accelerated skin graft rejection and that IL-17A was essential for Vγ4 T-cell-mediated skin graft rejection. Moreover, we found that Vγ4 T cells were required for early IL-17A production in the transplanted area, both in skin grafts and in the host epidermis around grafts. Additionally, the chemokine (C-C motif) ligand 20-chemokine receptor 6 pathway was essential for recruitment of Vγ4 T cells to the transplantation area, whereas both IL-1β and IL-23 induced IL-17A production from infiltrating cells. Lastly, Vγ4 T-cell-derived IL-17A promoted the accumulation of mature dendritic cells in draining lymph nodes to subsequently regulate αβ T-cell function after skin graft transplantation. Taken together, our data reveal that Vγ4 T cells accelerate skin graft rejection by providing an early source of IL-17A. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Association of IL8 -251A/T, IL12B -1188A/C and TNF-α -238A/G polymorphisms with Tourette syndrome in a family-based association study in a Chinese Han population.

    PubMed

    Liu, Shiguo; Yi, Mingji; Wang, Meijian; Sun, Yuping; Che, Fengyuan; Ma, Xu

    2011-05-16

    An earlier study indicated a possible relationship between Tourette syndrome (TS) and the cytokines. To explore this further, we analyzed the association of the polymorphisms, IL8 -251A/T, IL12B -1188A/C and TNF-α -238A/G, in the IL8, IL12B and TNF-α cytokine genes with TS in a Chinese Han population. A total of 108 patients diagnosed with TS and their parents were recruited for the study. The genetic contributions of the IL8 -251A/T, IL12B -1188A/C, and TNF-α -238A/G polymorphisms were evaluated using polymerase chain reaction and restriction enzyme digestion (PCR-RFLP) and haplotype relative risk (HRR) and transmission disequilibrium test (TDT) statistics. Our results revealed no significant associations between the IL8 -251A/T, IL12B -1188A/C and TNF-α -238A/G polymorphisms and TS (for IL8 -251A/T, TDT=0.418, df=1, P=0.518; HRR=2.17, X(2)=3.000, P=0.083, 95%CI: 0.900-5.230; for IL12B -1188A/C, TDT=1.131, df=1, P=0.288; HRR=1.27, X(2)=0.35, P=0.549, 95%CI: 0.580-2.790; for TNF-α -238A/G, TDT=2.793, df=1, P=0.095; HRR=0.27, X(2)=2.90, P=0.089, 95%CI: 0.061-1.217). This result was confirmed using haplotype-based haplotype relative risk (HHRR) which allows the two alleles in each genotype to be considered separately. Our data suggests that the IL-8 -251A/T, IL-12B -1188A/C and TNF-α -238A/G polymorphisms may not be associated with susceptibility to TS in the Chinese Han population studied. However, these results need to be replicated using larger datasets collected from different populations. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

  9. IL-27 promotes IL-10 production by effector Th1 CD4+ T cells; a critical mechanism for protection from severe immunopathology during malaria infection1

    PubMed Central

    Freitas do Rosário, Ana Paula; Lamb, Tracey; Spence, Philip; Stephens, Robin; Lang, Agathe; Roers, Axel; Muller, Werner; O’Garra, Anne; Langhorne, Jean

    2012-01-01

    Infection with the malaria parasite, Plasmodium, is characterized by excessive inflammation. The establishment of a precise balance between the pro- and anti-inflammatory responses is critical to guarantee control of the parasite and survival of the host. Interleukin (IL)-10, a key regulatory cytokine produced by many cells of the immune system, has been shown to protect mice against pathology during acute Plasmodium chabaudi chabaudi AS model of malaria. However, the critical cellular source of IL-10 is still unknown. Here, we demonstrate that T cell-derived IL-10 is necessary for the control of pathology during acute malaria, as mice bearing specific deletion of Il10 in T cells fully reproduce the phenotype observed in Il10−/− mice, with significant weight loss, drop in temperature and increased mortality. Furthermore, we show that IFN-γ+ Th1 cells are the main producers of IL-10 throughout acute infection, expressing high levels of CD44 and ICOS and low levels of CD127. Although Foxp3+ regulatory CD4+ T cells produce IL-10 during infection, highly activated IFN-γ+ Th1 cells were shown to be the essential and sufficient source of IL-10 to guarantee protection against severe immune-mediated pathology. Finally, in this model of malaria we demonstrate that the generation of protective IL10+IFN-γ+ Th1 cells is dependent on IL-27 signaling, and independent of IL-21. PMID:22205023

  10. Human T cells expressing BEND3 on their surface represent a novel subpopulation that preferentially produces IL-6 and IL-8

    PubMed Central

    Shiheido, Hirokazu; Kitagori, Koji; Sasaki, Chiyomi; Kobayashi, Shio; Aoyama, Takane; Urata, Kozue; Oku, Takuma; Hirayama, Yoshitaka; Yoshitomi, Hiroyuki; Hikida, Masaki; Yoshifuji, Hajime; Mimori, Tsuneyo; Watanabe, Takeshi; Shimizu, Jun

    2014-01-01

    BEN domain-containing protein 3 (BEND3) has no transmembrane region, is localized in the cytoplasm, and is involved in chromatin function and transcription. We here identified a novel subpopulation of human T cells that expressed BEND3 on their cell surface (BEND3+ T cells). BEND3+ T cells consisted of approximately 3% of T cells in the peripheral blood, were present in both CD4+ and CD8+ T cells, and were also observed in cord blood. The stimulation of BEND3+ T cells through the TCR/CD3 complex led to the production of various kinds of cytokines; however, the levels of IL-6 and IL-8 produced by BEND3+ T cells were higher than those by BEND3− T cells. The proportion of BEND3+ T cells was also increased in some patients with inflammatory diseases. Taken together, these results indicate that BEND3+ T cells are a new subpopulation of T cells in terms of their cytokine profile. Further analyses on BEND3+ T cells may be of importance and useful in understanding human T cell immunology. PMID:25400923

  11. Shp1 regulates T cell homeostasis by limiting IL-4 signals

    PubMed Central

    Johnson, Dylan J.; Pao, Lily I.; Dhanji, Salim; Murakami, Kiichi

    2013-01-01

    The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and is generally viewed as a negative regulatory molecule. Mutations in Ptpn6, which encodes Shp1, result in widespread inflammation and premature death, known as the motheaten (me) phenotype. Previous studies identified Shp1 as a negative regulator of TCR signaling, but the severe systemic inflammation in me mice may have confounded our understanding of Shp1 function in T cell biology. To define the T cell–intrinsic role of Shp1, we characterized mice with a T cell–specific Shp1 deletion (Shp1fl/fl CD4-cre). Surprisingly, thymocyte selection and peripheral TCR sensitivity were unaltered in the absence of Shp1. Instead, Shp1fl/fl CD4-cre mice had increased frequencies of memory phenotype T cells that expressed elevated levels of CD44. Activation of Shp1-deficient CD4+ T cells also resulted in skewing to the Th2 lineage and increased IL-4 production. After IL-4 stimulation of Shp1-deficient T cells, Stat 6 activation was sustained, leading to enhanced Th2 skewing. Accordingly, we observed elevated serum IgE in the steady state. Blocking or genetic deletion of IL-4 in the absence of Shp1 resulted in a marked reduction of the CD44hi population. Therefore, Shp1 is an essential negative regulator of IL-4 signaling in T lymphocytes. PMID:23797092

  12. CD8+IL-17+ T Cells Mediate Neutrophilic Airway Obliteration in T-bet–Deficient Mouse Lung Allograft Recipients

    PubMed Central

    Dodd-o, Jeffrey M.; Coon, Tiffany A.; Miller, Hannah L.; Ganguly, Sudipto; Popescu, Iulia; O'Donnell, Christopher P.; Cardenes, Nayra; Levine, Melanie; Rojas, Mauricio; Weathington, Nathaniel M.; Zhao, Jing; Zhao, Yutong; McDyer, John F.

    2015-01-01

    Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet−/− recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T-bet−/− recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8+ T cells producing allospecific IL-17 and/or IFN-γ, in contrast to IFN-γ–dominant responses in WT mice. CD4+ T cells produced IL-17 but not IFN-γ responses in T-bet−/− recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8+IFN-γ+ responses in both T-bet−/− and WT mice but had no attenuating effect on lung rejection pathology in T-bet−/− recipients or on the development of obliterative airway inflammation that occurred only in T-bet−/− recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade–resistant rejection pathology and airway inflammation in T-bet−/− recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet−/− allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet–deficient recipients of complete MHC-mismatched lung allografts develop costimulation blockade–resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8+IL-17+ T cells. Our data support T-bet–deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation

  13. IL-17 and γδ T-lymphocytes play a critical role in innate immunity against Nocardia asteroides GUH-2

    PubMed Central

    Tam, Stanley; Maksaereekul, Saipiroon; Hyde, Dallas M.; Godinez, Ivan; Beaman, Blaine L.

    2012-01-01

    The early host response during pulmonary nocardiosis is highly dependent on neutrophils and the successful clearance of bacteria in tissue. The data presented in this study showed that IL-17 mediated the neutrophil response following intranasal inoculation with Nocardia asteroides strain GUH-2. Flow cytometry revealed that neutrophil levels in C57BL/6 mice were increased by day 1 post inoculation and remained elevated until day 3, during which time the majority of bacterial clearance occurred. Intracellular cytokine staining for IL-17 showed a 3.5- to 5-fold increase in IL-17 producing T-lymphocytes that were predominately comprised by CD4−CD8− γδ T-lymphocytes. The importance of IL-17 and γδ T-cells was determined by the in vivo administration of antibody, capable of blocking IL-17 binding or TCR δ, respectively. Neutralization of either IL-17 or γδ T-cells in Nocardia treated mice resulted in attenuated neutrophil infiltration. Paralleling this impaired neutrophil recruitment, nearly a 10-fold increase in bacterial burden was observed in both anti-IL-17 and anti-TCR δ treated animals. Together, these data indicate a protective role for IL-17 and suggest that IL-17 producing γδ T-lymphocytes contribute to neutrophil infiltration during pulmonary nocardiosis. PMID:22634423

  14. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

    PubMed Central

    Hurton, Lenka V.; Singh, Harjeet; Najjar, Amer M.; Switzer, Kirsten C.; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A.; Champlin, Richard E.; Cooper, Laurence J. N.

    2016-01-01

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19+ leukemia. Long-lived T cells were CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials. PMID:27849617

  15. Une forme exceptionnelle de la luxation perilunaire du carpe

    PubMed Central

    Elouakili, Issam; Ouchrif, Younes; Najib, Abdeljaouad; Ouakrim, Redouane; Lamrani, Omar; Kharmaz, Mohammed; Ismael, Farid; Lahlou, Abdo; Elouadghiri, Mohammed; El Bardouni, Ahmed; Mahfoud, Mustapha; Berrada, Mohammed Saleh; El Yaccoubi, Mouradh

    2014-01-01

    Les luxations périlunaires (LPL) du carpe sont des lésions extrêmement rares, qui peuvent passer inaperçue en raison d'un tableau clinique souvent trompeur, des radiographies en profil non strict ou d'interprétation difficile. Nous rapportons l'observation d'une luxation périlunaire stade III selon la classification de Witvoët et Allieu chez un patient de 32 ans, il s'agit d'une forme encore plus rare voire exceptionnelle et qui peut induire de sérieux problèmes en raison de la sévérité des dommages ligamentaires et du risque de nécrose du semilunaire plus important dans ce type de lésions. Le traitement est toujours chirurgical et doit être réalisé dans les plus brefs délais afin d’éviter les complications. PMID:25404968

  16. Expression of the T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD

    PubMed Central

    Doe, Camille; Bafadhel, Mona; Siddiqui, Salman; Desai, Dhananjay; Mistry, Vijay; Rugman, Paul; McCormick, Margaret; Woods, Joanne; May, Richard; Sleeman, Matthew A.; Anderson, Ian K.

    2010-01-01

    Background: Asthma and COPD are characterized by airway dysfunction and inflammation. Neutrophilic airway inflammation is a common feature of COPD and is recognized in asthma, particularly in severe disease. The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway inflammation, but their expression in asthma and COPD is uncertain. Methods: We assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects. Sputum IL-17 concentration was measured in 165 subjects with asthma and 27 with COPD. Results: The median (interquartile range) IL-17A cells/mm2 submucosa was increased in mild to moderate asthma (2.1 [2.4]) compared with healthy control subjects (0.4 [2.8]) but not in severe asthma (P = .04). In COPD, IL-17A+ cells/mm2 submucosa were increased (0.5 [3.7]) compared with nonsmoking control subjects (0 [0]) but not compared with smoking control subjects (P = .046). IL-17F+ cells/mm2 submucosa were increased in severe asthma (2.7 [3.6]) and mild to moderate asthma (1.6 [1.0]) compared with healthy controls subjects (0.7 [1.4]) (P = .001) but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count (rs = 0.5, P = .005). The sputum IL-17 concentration in COPD was increased compared with asthma (2 [0-7] pg/mL vs 0 [0-2] pg/mL, P < .0001) and was correlated with post-bronchodilator FEV1% predicted (r = −0.5, P = .008) and FEV1/FVC (r = −0.4, P = .04). Conclusions: Our findings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic inflammation. PMID:20538817

  17. Insuffisance rénale aigüe: présentation rare d’une maladie d’Addison

    PubMed Central

    Salhi, Houda

    2016-01-01

    La maladie d’Addison est une pathologie rare, qui se manifeste fréquemment par des signes cliniques non spécifiques. Ce qui peut causer un retard diagnostic et thérapeutique. Cette maladie peut se présenter comme un tableau d’insuffisance rénale aigue. Nous rapportons le cas d’un patient présentant une maladie d’Addison qui a été pris en charge initialement comme une insuffisance rénale aigue secondaire à un myélome multiple et dont le diagnostic a été redressé par la suite. Le patient s’est spectaculairement amélioré après mis en place de traitement par réhydratation par voie intraveineuse; hydrocortisone injectable. PMID:27800088

  18. IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection

    PubMed Central

    Chiodi, Francesca; Bekele, Yonas; Lantto Graham, Rebecka; Nasi, Aikaterini

    2017-01-01

    IL-7 was previously shown to upregulate the expression of molecules important for interaction of CD4+ T cells with B cells. It is poorly studied whether IL-7 has a role in the biology of T follicular helper (Tfh) cells and whether IL-7 dysregulates the expression of B-cell costimulatory molecules on Tfh cells. We review the literature and provide arguments in favor of IL-7 being involved in the biology of human Tfh cells. The CD127 IL-7 receptor is expressed on circulating Tfh and non-Tfh cells, and we show that IL-7, but not IL-6 or IL-21, upregulates the expression of CD70 and PD-1 on these cells. We conclude that IL-7, a cytokine whose level is elevated during HIV-1 infection, may have a role in increased expression of B cell costimulatory molecules on Tfh cells and lead to abnormal B cell differentiation. PMID:28473831

  19. IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection.

    PubMed

    Chiodi, Francesca; Bekele, Yonas; Lantto Graham, Rebecka; Nasi, Aikaterini

    2017-01-01

    IL-7 was previously shown to upregulate the expression of molecules important for interaction of CD4+ T cells with B cells. It is poorly studied whether IL-7 has a role in the biology of T follicular helper (Tfh) cells and whether IL-7 dysregulates the expression of B-cell costimulatory molecules on Tfh cells. We review the literature and provide arguments in favor of IL-7 being involved in the biology of human Tfh cells. The CD127 IL-7 receptor is expressed on circulating Tfh and non-Tfh cells, and we show that IL-7, but not IL-6 or IL-21, upregulates the expression of CD70 and PD-1 on these cells. We conclude that IL-7, a cytokine whose level is elevated during HIV-1 infection, may have a role in increased expression of B cell costimulatory molecules on Tfh cells and lead to abnormal B cell differentiation.

  20. Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.

    PubMed

    Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

    2014-12-01

    Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion-induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  1. Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax

    PubMed Central

    Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

    2014-01-01

    Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion–induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo. PMID:25175936

  2. The effect of interleukin (IL)-21 and CD4+ CD25++ T cells on cytokine production of CD4+ responder T cells in patients with myasthenia gravis.

    PubMed

    Alahgholi-Hajibehzad, M; Durmuş, H; Aysal, F; Gülşen-Parman, Y; Oflazer, P; Deymeer, F; Saruhan-Direskeneli, G

    2017-11-01

    Impairment of the suppressive function of regulatory T (T reg ) cells has been reported in myasthenia gravis (MG). In this study, cytokine-related mechanisms that may lead to the defect of T reg were investigated in patients with anti-acetylcholine receptor antibody-positive MG (AChR + MG). Proliferation and cytokine production of responder T (T resp ) cells in response to polyclonal activation were measured in a suppression assay. The effect of interleukin (IL)-21 on suppression was evaluated in vitro in co-culture. IL-21 increased the proliferation of T resp cells in T resp /T reg co-cultures. T resp cells from patients with MG secreted significantly lower levels of IL-2. In patients with MG, IL-2 levels did not change with the addition of T reg to cultures, whereas it decreased significantly in controls. In T resp /T reg co-cultures, IL-4, IL-6 and IL-10 production increased in the presence of T reg in patients. Interferon (IFN)-γ was decreased, whereas IL-17A was increased in both patient and control groups. IL-21 inhibited the secretion of IL-4 in MG and healthy controls (HC), and IL-17A in HC only. The results demonstrated that IL-21 enhances the proliferation of T resp cells in the presence of T reg . An effect of IL-21 mainly on T resp cells through IL-2 is implicated. © 2017 British Society for Immunology.

  3. Quelle place pour l’anesthésie locorégionale chez les brûlés?

    PubMed Central

    Chaibdraa, A.; Medjelekh, M.S.; Saouli, A.; Bentakouk, M.C.

    2015-01-01

    Summary La pratique de l’anesthésie locorégionale chez les brûlés est limitée par de nombreux facteurs. Elle est considérée comme marginale dans l’approche multimodale du traitement de la douleur par excès de nociception. Ce travail rétrospectif, sur une période de 3 années, porte sur les anesthésies locorégionales (ALR) réalisées. Les résultats obtenus vont permettre, en regard de la rareté des données de la littérature, de formuler quelques suggestions sur la place de cette technique. Il a été recensé 634 ALR, dont 96% chez des adultes. Les membres inférieurs sont les plus concernés (76%). Des anesthésies rachidiennes ont été pratiquées chez 32 patients dont 4 enfants. Les incidents sont peu fréquents (3%) et sans gravité. L’ALR peut représenter une option utile dans la stratégie multimodale de prise en charge de la douleur, la réhabilitation passive précoce et la chirurgie de recouvrement par la greffe de peau. Elle mérite d’être explorée en ambulatoire, dans la mesure où 95% des brûlés ne sont pas hospitalisés. La place de l’anesthésie-locorégionale chez les brûlés devrait susciter plus d’intérêts, pour permettre d’établir des protocoles fondés sur une réflexion pluridisciplinaire. PMID:27279806

  4. Two distinct populations of bovine IL-17⁺ T-cells can be induced and WC1⁺IL-17⁺γδ T-cells are effective killers of protozoan parasites.

    PubMed

    Peckham, R K; Brill, R; Foster, D S; Bowen, A L; Leigh, J A; Coffey, T J; Flynn, R J

    2014-06-25

    IL-17 has emerged as a key player in the immune system, exhibiting roles in protection from infectious diseases and promoting inflammation in autoimmunity. Initially thought to be CD4 T-cell-derived, the sources of IL-17 are now known to be varied and belong to both the innate and adaptive arms of the immune system. Mechanisms for inducing IL-17 production in lymphoid cells are thought to rely on appropriate antigenic stimulation in the context of TGF-β1, IL-6 and/or IL-1β. Using culture protocols adapted from human studies, we have effectively induced both bovine CD4(+) and WC1(+) γδ T-cells to produce IL-17 termed Th17 and γδ17 cells, respectively. The negative regulatory effect of IFN-γ on mouse and human IL-17 production can be extended to the bovine model, as addition of IFN-γ decreases IL-17 production in both cell types. Furthermore we show that infection with the protozoan Neospora caninum will induce fibroblasts to secrete pro-IL-17 factors thereby inducing a γδ17 phenotype that preferentially kills infected target cells. Our study identifies two T-cell sources of IL-17, and is the first to demonstrate a protective effect of IL-17(+) T-cells in ruminants. Our findings offer further opportunities for future adjuvants or vaccines which could benefit from inducing these responses.

  5. Etude par Imagerie à faible Niveau dans le proche Infrarouge d'une Emission de la haute Atmosphère

    NASA Astrophysics Data System (ADS)

    Pautet, Pierre-Dominique

    2000-12-01

    Le travail effectué a eu pour but la mise en place d'un protocole d'observation et de traitement des images, ainsi que les outils appropriés, visant à l'étude d'une émission de la haute atmosphère terrestre dans le proche infrarouge. Il existe actuellement des télescopes comme le VLT (Very Large Telescope), installé au Chili, qui permettent d'observer des astres et des galaxies distants de plusieurs millions de parsecs. A cause de l'expansion de l'Univers, des objets situés aussi loin s'éloignent très rapidement de nous. Le spectre de leur émission qui nous parvient alors est décalé vers le rouge ou l'infrarouge, du fait de l'effet Doppler. Il faut donc observer ces objets dans des longueurs d'onde appropriées. Malheureusement, l'atmosphère terrestre qui nous sépare d'eux est aussi le siège de nombreuses émissions qui peuvent venir perturber les mesures. De toutes ces émissions, la principale est due au radical OH dont les raies de rotation-vibration couvrent tout le spectre entre 0,7 et 2,5 microns. Cette émission a lieu au niveau d'une couche assez fine de la haute atmosphère appelée mésopause et située à environ 85 kilomètres d'altitude. Le travail effectué a eu pour but de mettre en évidence les principales caractéristiques de cette émission qui n'est pas uniforme et constante dans le temps. Un programme d'observations dans le proche infrarouge a été élaboré. Plusieurs algorithmes de traitement d'image ont été développés. Un programme d'inversion de perspective a été mis au point pour une utilisation en temps réel sur le terrain. Les caractéristiques des images peuvent être ensuite analysées. La première partie du mémoire comporte une description des différentes émissions lumineuses que l'on peut observer la nuit lorsque l'on regarde la voûte céleste. Ces émissions peuvent avoir deux origines: astronomique ou atmosphérique. Le problème de l'absorption atmosphérique et plus précisément les conditions

  6. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma.

    PubMed

    Willerslev-Olsen, Andreas; Krejsgaard, Thorbjørn; Lindahl, Lise M; Litvinov, Ivan V; Fredholm, Simon; Petersen, David L; Nastasi, Claudia; Gniadecki, Robert; Mongan, Nigel P; Sasseville, Denis; Wasik, Mariusz A; Bonefeld, Charlotte M; Geisler, Carsten; Woetmann, Anders; Iversen, Lars; Kilian, Mogens; Koralov, Sergei B; Odum, Niels

    2016-03-10

    Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis. © 2016 by The American Society of Hematology.

  7. [Polymorphism of TNF-alpha (308 A/G), IL-10 (1082 A/G, 819 C/T 592 A/C), IL-6 (174 G/C), and IFN-gamma (874 A/T); genetically conditioned cytokine synthesis level in children with diabetes type 1].

    PubMed

    Siekiera, Urszula; Jarosz-Chobot, P; Janusz, J; Koehler, Brygida

    2002-01-01

    Type 1 diabetes is a genetically conditioned autoimmune disease. Genes that account for strong clustering of the disease susceptibility are located within the HLA region. There is also considerable individual variation in the immune response and role of cytokine genes in the disease predisposition. The aim of our research was identification of the genetically controlled TNF-alpha, IL-10, IL-6, IFN-gamma secretion profile in children with diabetes type 1. We have examined 36 children with diabetes type 1 and 36 healthy individuals. DNA was extracted from mononuclear peripheral blood cells. For identification of the cytokine polymorphism PCR-SSP method was used. Patients with diabetes type 1 differ from the group of healthy persons in the cytokine synthesis level and in the cytokine genotypes distribution. Genotype TNF-alpha (A/G) as well as IL-10 (ATA/ATA) was found only in group of children with diabetes but not in the control group. Genotypes IL-10 (GCC/GCC), IL-6 (C/C), IFN-gamma (T/T) were observed with decreased frequency in children with diabetes type 1. No differences between patients and control group in the frequency of IL-10 (GCC/ACC) (GCC/ATA), (ACC/ACC) (ACC/ATA) IL-6 (G/G), (G/C) and IFN-gamma (T/A), (A/A) genotypes were observed. Children with diabetes type 1 were more frequent "high producers" of TNF-alpha and IL-6. It is possible to us molecular method to estimate the genetically controlled immune reactivity. It is a very important immunogenetic factor of the disease predisposition.

  8. CD8+ T cells induce complete regression of advanced ovarian cancers by an interleukin (IL)-2/IL-15 dependent mechanism.

    PubMed

    Yang, Taimei; Wall, Erika M; Milne, Katy; Theiss, Patty; Watson, Peter; Nelson, Brad H

    2007-12-01

    In vitro studies suggest that ovarian cancer evades immune rejection by fostering an immunosuppressive environment within the peritoneum; however, the functional responses of ovarian cancer-specific T cells have not been directly investigated in vivo. Therefore, we developed a new murine model to enable tracking of tumor-specific CD8(+) T-cell responses to advanced ovarian tumors. The ovarian tumor cell line ID8 was transfected to stably express an epitope-tagged version of HER-2/neu (designated Neu(OT-I/OT-II)). After i.p. injection into C57BL/6 mice, ID8 cells expressing Neu(OT-I/OT-II) gave rise to disseminated serous adenocarcinomas with extensive ascites. CD8(+) T cells expressing a transgenic T-cell receptor specific for the OT-I epitope of Neu(OT-I/OT-II) were adoptively transferred into tumor-bearing mice, and functional responses were monitored. Cytokine signaling requirements were evaluated by comparing the responses of wild-type donor T cells with those with genetic deletion of the interleukin (IL)-2/IL-15 receptor beta subunit (CD122) or the IL-2 receptor alpha subunit (CD25). On adoptive transfer into tumor-bearing hosts, wild-type OT-I T cells underwent a striking proliferative response, reaching peak densities of approximately 40% and approximately 90% of CD8(+) T cells in peripheral blood and ascites, respectively. OT-I cells infiltrated and destroyed tumor tissue, and ascites completely resolved within 10 days. By contrast, CD122(-/-) OT-I cells and CD25(-/-) OT-I cells proliferated in blood but failed to accumulate in ascites or tumor tissue or induce tumor regression. Contrary to expectation, advanced ovarian cancers can support extraordinary CD8(+) T-cell proliferation and antitumor activity through an IL-2/IL-15-dependent mechanism.

  9. IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage.

    PubMed

    Barik, Subhasis; Miller, Mindy M; Cattin-Roy, Alexis N; Ukah, Tobechukwu K; Chen, Weirong; Zaghouani, Habib

    2017-10-15

    Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation toward a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4Rα and IL-13Rα1 give rise to myeloid cells but not T cells. In this article, we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment toward the myeloid cells. Indeed, HR + ETPs, but not HR - ETPs, exhibit activated STAT6 transcription factor, which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, the myeloid-specific transcription factor C/EBPα, usually under the control of Notch1, is upregulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR + ETPs, which regain T lineage potential. In addition, upon stimulation with IL-4 or IL-13, HR - ETPs expressing virally transduced HR also exhibit STAT6 phosphorylation and downregulation of Notch1, leading to inhibition of lymphoid, but not myeloid, lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice, which would impact T cell development. Copyright © 2017 by The American Association of Immunologists, Inc.

  10. Manipulating memory CD8 T cell numbers by timed enhancement of IL-2 signals1

    PubMed Central

    Kim, Marie T.; Kurup, Samarchith P.; Starbeck-Miller, Gabriel R.; Harty, John T.

    2016-01-01

    Due to the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. Here, we show that dendritic cell (DC) immunization coupled with relatively early (days 1–3) or late (days 4–6) administration of enhanced IL-2-signals both increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation, marked Bim mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles more conducive to memory formation. Of note, down-regulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T (Treg) cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role of CTLA-4 in down-regulating B7-ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and αCTLA-4 blockade resulted in lower memory CD8 T cell numbers compared to the DC + early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 co-stimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation and thus, should be considered in future T cell vaccination strategies. PMID:27439516

  11. Intracellular IL-10 detection in T cells by flowcytometry: the use of protein transport inhibitors revisited.

    PubMed

    Muris, Anne-Hilde; Damoiseaux, Jan; Smolders, Joost; Cohen Tervaert, Jan Willem; Hupperts, Raymond; Thewissen, Mariëlle

    2012-07-31

    In the past two decades, interleukin-10 (IL-10) has gained much attention as an important regulatory cytokine involved in self-tolerance. Functional assessment of IL-10 producing immune cells is traditionally done by stimulation and measurement of cytokine production by flowcytometry. Thereby a protein transport inhibitor like monensin is used to accumulate the cytokine of interest intracellularly. In this study we elaborated on the monensin effect on cytokine detection and focused on IL-10 detection in human T cells. Peripheral blood mononuclear cells (PBMC) of 32 study subjects were isolated and stimulated with PMA/ionomycin, in the absence and presence of monensin, and stained intracellularly for IFN-γ, IL-4, IL-10 and IL-17A. Our results re-established that detection of IFN-γ+ and IL-4+ T cells benefited from the presence of monensin during stimulation. However, stimulation in the presence of monensin yielded lower proportions of IL-10+ T cells (0.45% (0.28-0.80) versus 0.80% (0.50-1.50) of CD4+ T cells, p<0.01), although monensin addition did result in an increased MFI (2431 (1273-4959) versus 1928 (1147-3760), p<0.01). Detectable fractions of IL-17A+ CD4+ T cells were not affected by monensin. A shorter incubation time, but not lower monensin concentrations, was effective in improving the detection of IL-10+ T cells. We found a strong correlation between the fraction of IL-10+ CD4+ T cells in the presence and absence of monensin (R=0.80 p<0.01). Next to this, also the detection of IL-10+ NK-T cells and IL-10+ monocytes, but not IL-10+ B cells, is impaired in the presence of monensin. This study shows that the effect of monensin on cytokine accumulation is time and cytokine dependent. Due to the use of monensin, previous research may have underestimated the number of IL-10+ leukocytes or may even have not been able to detect them at all. It is important to consider this for future research or when interpreting historical IL-10 data. Copyright © 2012

  12. The role of IL-1beta in reduced IL-7 production by stromal and epithelial cells: a model for impaired T-cell numbers in the gut during HIV-1 infection.

    PubMed

    Thang, P H; Ruffin, N; Brodin, D; Rethi, B; Cam, P D; Hien, N T; Lopalco, L; Vivar, N; Chiodi, F

    2010-08-01

    Interleukin (IL)-7 is a key cytokine in T-cell homeostasis. Stromal cells, intestinal epithelial cells and keratinocytes are known to produce this cytokine. The mechanisms and cellular factors regulating IL-7 production are still unclear. We assessed whether IL-1beta and interferon (IFN)-gamma, cytokines produced during inflammatory conditions, may impact on IL-7 production. We used human intestinal epithelial cells (DLD-1 cell line) and bone marrow stromal cells (HS27 cell line), known to produce IL-7; IL-7 production was evaluated at the mRNA and protein levels. To assess whether treatment of HS27 cells with IL-1beta and/or IFN-gamma leads to changes in the gene expression of cytokines, Toll-like receptors (TLRs) and chemokines, we analysed gene expression profiles using the whole-genome microarray Human Gene 1.0 ST. We found that IFN-gamma enhanced the expression of IL-7 mRNA (P < 0.001) in both cell lines. IL-1beta treatment led to a significant down-regulation (P < 0.001) of IL-7 mRNA expression in both cell lines. The IL-7 concentration in supernatants collected from treated DLD-1 and HS27 cell cultures reflected the trend of IL-7 mRNA levels. The gene profiles revealed dramatic changes in expression of cytokines and their receptors (IL-7/IL-7R alpha; IL-1alpha,IL-1beta/IL-1R1; IFN-gamma/IFN-gammaR1), of IFN regulatory factors (IRF-1 and 2), of TLRs and of important chemo-attractants for T cells. The microarray results were verified by additional methods. Our results are discussed in the setting of inflammation and T-cell survival in the gut compartment during HIV-1 infection where stromal and epithelial cells may produce factors that contribute to impaired IL-7 homeostasis and homing of T cells.

  13. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

    PubMed Central

    Mukherjee, Malini; Grada, Zakaria; Pignata, Antonella; Landi, Daniel; Navai, Shoba A.; Wakefield, Amanda; Bielamowicz, Kevin; Chow, Kevin K.H.; Brawley, Vita S.; Byrd, Tiara T.; Krebs, Simone; Gottschalk, Stephen; Wels, Winfried S.; Baker, Matthew L.; Dotti, Gianpietro; Mamonkin, Maksim; Brenner, Malcolm K.

    2016-01-01

    In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape. PMID:27427982

  14. IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

    PubMed Central

    Le Saout, Cecile; Luckey, Megan A.; Villarino, Alejandro V.; Smith, Mindy; Hasley, Rebecca B.; Myers, Timothy G.; Imamichi, Hiromi; Park, Jung-Hyun; O’Shea, John J.; Lane, H. Clifford

    2017-01-01

    IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7–dependent STAT1 and STAT5 activation. Consequently, the IL-7–induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, “switching on” an alternate IL-7–dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients. PMID:29202461

  15. Etiologies des hypertensions artérielles endocrines: à propos d'une série de cas

    PubMed Central

    Bouznad, Naima; El Mghari, Ghizlane; El Ansari, Nawal

    2016-01-01

    Les hypertensions artérielles (HTA) d'origine endocrine restent une cause rare d'HTA, sa prévalence globale n'excède pas 4% des hypertendus. L'intérêt de la recherche des HTA endocrines réside dans la gravité de certaines formes parfois mortelles et le caractère potentiellement curable et réversible de ces HTA. Le but du travail est de déterminer le profil clinique, para clinique, étiologique et thérapeutique des HTA secondaires d'origine endocrine chez les patients suivis au service d'endocrinologie au CHU Mohamed IV à Marrakech. Il s'agit d'une étude descriptive prospective s’étalant sur une période de 4 ans incluant 45 patients ayant une HTA endocrinienne. La moyenne d’âge est de 44,89 ans, avec une nette prédominance du sexe féminine (sexe ratio de 0,49). Les étiologies des HTA endocrines étaient dominées par le phéochromocytome (17 cas), l'hypercorticisme (11 cas) et l'acromégalie (8 cas). L'HTA était paroxystique dans 24,4%. Elle était d'emblée sevère classée grade 3 dans 40% des cas. L'HTA a été compliquée de cardiopathie dans 24% des cas et de néphropathie dans 20% des cas. Le traitement curatif a permis une guérison de l'HTA chez 60% (27 cas). Le diagnostic des HTA secondaires endocrines est parfois difficile du fait de l'absence de spécificité clinique. Il n'est pas exceptionnel que l'HTA soit l'unique manifestation de la maladie. Dans notre travail nous notons le caractère paroxystique et sévère de l'HTA. Le caractère éventuellement curable des HTA endocrines, dans plus des deux tiers des cas, fait qu'il est important de la dépister devant toute HTA sévère, résistante au traitement, ou en présence de signes cliniques, biologiques ou radiologiques évocateurs. PMID:27303586

  16. Nickel Sulfate Promotes IL-17A Producing CD4+ T Cells by an IL-23-Dependent Mechanism Regulated by TLR4 and Jak-STAT Pathways.

    PubMed

    Bechara, Rami; Antonios, Diane; Azouri, Hayat; Pallardy, Marc

    2017-10-01

    Allergic contact dermatitis, caused by nickel, is a delayed-type hypersensitivity reaction, and 14.5% of the general population may be affected in Europe. Among a wide range of cytokines, the IL-12 family has unique structural and immunological characteristics. Whereas IL-12p70 promotes T helper (Th) 1 cell polarization, IL-23 promotes Th17 cell development and both have been isolated from nickel-allergic patients. In this work, we were interested in understanding the mechanism behind nickel-induced Th17 cell development. We showed that nickel induced an early production of IL-23 in human monocyte-derived dendritic cells along with an increase in the expression of il-23p19 and il-12p40 mRNA. However, the production of a significant level of IL-12p70 required an additional signal such as IFN-γ. Moreover, nickel-treated monocyte-derived dendritic cells induced an increase in the percentage of IL-17A + CD4 + T cells, an effect reduced by IL-23 neutralization. We then investigated the molecular mechanism of IL-23 production. Our results showed that toll-like receptor 4, p38 mitogen-activated protein kinase, and NF-κB were involved in IL-23 production induced by nickel. However, Jak-signal transducer and activator of transcription activation seems to maintain the IL-23/IL-12p70 balance by limiting IL-23 production and promoting Th1 polarization. These results indicate that nickel-induced Th17 cell development is dependent on the production of IL-23 by human monocyte-derived dendritic cells via toll-like receptor 4, p38 mitogen-activated protein kinase, NF-κB, and Jak-signal transducer and activator of transcription pathways. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Induction of an interleukin-1 receptor (IL-1R) on monocytic cells. Evidence that the receptor is not encoded by a T cell-type IL-1R mRNA.

    PubMed

    Spriggs, M K; Lioubin, P J; Slack, J; Dower, S K; Jonas, U; Cosman, D; Sims, J E; Bauer, J

    1990-12-25

    Primary human monocytes and the human monocytic cell line THP-1 were induced to express receptors for interleukin-1 alpha (IL-1 alpha) and IL-1 beta. Treatment of primary monocytes with dexamethasone resulted in a 10-fold increase in receptor number over untreated cells, to approximately 2,000 receptors/cell. Treatment of THP-1 cells with phorbol ester followed by prostaglandin E2 and dexamethasone resulted in the expression of approximately 30,000 receptors/cell. Competitive binding assays on THP-1 cells showed that both IL-1 alpha and IL-1 beta bind to the same receptor. The monocyte IL-1R is significantly smaller (63 kDa) than the T cell IL-1R (80 kDa) and is immunologically distinct. However, induction of monocytes and monocytic cell lines leads to the appearance of an abundant mRNA of approximately 5,000 bases which hybridizes to a cDNA probe from the T cell-type IL-1R. Sequence data obtained from a cDNA clone of this mRNA indicate that the message is identical to the T cell IL-1R mRNA throughout the coding region. A smaller mRNA, also homologous to the T cell IL-1R mRNA, accumulated in induced THP-1 cells and has a shorter 3'-untranslated region than the larger. Data are presented which suggest that neither form of this message encodes the 63-kDa IL-1R, but rather that this protein is the product of a separate nonhomologous mRNA.

  18. Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology.

    PubMed

    Pyle, Chloe J; Uwadiae, Faith I; Swieboda, David P; Harker, James A

    2017-09-01

    Interleukin-6 is a pleiotropic, pro-inflammatory cytokine that can promote both innate and adaptive immune responses. In humans with respiratory virus infections, such as Respiratory Syncytial Virus (RSV), elevated concentrations of IL-6 are associated with more severe disease. In contrast the polymorphisms in the Il6 promoter which favour lower IL-6 production are associated with increased risk of both RSV and Rhinovirus infections. To determine the precise contribution of IL-6 to protection and pathology we used murine models of respiratory virus infection. RSV infection resulted in increased IL-6 production both in the airways and systemically which remained heightened for at least 2 weeks. IL-6 depletion early, but not late, during RSV or Influenza A virus infection resulted in significantly increased disease associated with an influx of virus specific TH1 and cytotoxic CD8+ T cells, whilst not affecting viral clearance. IL-6 acted by driving production of the immunoregulatory cytokine IL-27 by macrophages and monocytes, which in turn promoted the local maturation of regulatory T cells. Concordantly IL-27 was necessary to regulate TH1 responses in the lungs, and sufficient to limit RSV induced disease. Overall we found that during respiratory virus infection the prototypic inflammatory cytokine IL-6 is a critical anti-inflammatory regulator of viral induced immunopathology in the respiratory tract through its induction of IL-27.

  19. Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology

    PubMed Central

    Swieboda, David P.

    2017-01-01

    Interleukin-6 is a pleiotropic, pro-inflammatory cytokine that can promote both innate and adaptive immune responses. In humans with respiratory virus infections, such as Respiratory Syncytial Virus (RSV), elevated concentrations of IL-6 are associated with more severe disease. In contrast the polymorphisms in the Il6 promoter which favour lower IL-6 production are associated with increased risk of both RSV and Rhinovirus infections. To determine the precise contribution of IL-6 to protection and pathology we used murine models of respiratory virus infection. RSV infection resulted in increased IL-6 production both in the airways and systemically which remained heightened for at least 2 weeks. IL-6 depletion early, but not late, during RSV or Influenza A virus infection resulted in significantly increased disease associated with an influx of virus specific TH1 and cytotoxic CD8+ T cells, whilst not affecting viral clearance. IL-6 acted by driving production of the immunoregulatory cytokine IL-27 by macrophages and monocytes, which in turn promoted the local maturation of regulatory T cells. Concordantly IL-27 was necessary to regulate TH1 responses in the lungs, and sufficient to limit RSV induced disease. Overall we found that during respiratory virus infection the prototypic inflammatory cytokine IL-6 is a critical anti-inflammatory regulator of viral induced immunopathology in the respiratory tract through its induction of IL-27. PMID:28953978

  20. Cytokines affecting CD4+T regulatory cells in transplant tolerance. III. Interleukin-5 (IL-5) promotes survival of alloantigen-specific CD4+ T regulatory cells.

    PubMed

    Hall, Bruce M; Plain, Karren M; Tran, Giang T; Verma, Nirupama D; Robinson, Catherine M; Nomura, Masaru; Boyd, Rochelle; Hodgkinson, Suzanne J

    2017-08-01

    CD4 + T cells mediate antigen-specific allograft tolerance, but die in culture without activated lymphocyte derived cytokines. Supplementation of the media with cytokine rich supernatant, from ConA activated spleen cells, preserves the capacity of tolerant cells to transfer tolerance and suppress rejection. rIL-2 or rIL-4 alone are insufficient to maintain these cells, however. We observed that activation of naïve CD4 + CD25 + FOXP3 + Treg with alloantigen and the Th2 cytokine rIL-4 induces them to express interleukin-5 specific receptor alpha (IL-5Rα) suggesting that IL-5, a Th2 cytokine that is produced later in the immune response may promote tolerance mediating Treg. This study examined if recombinant IL-5(rIL-5) promoted survival of tolerant CD4 + , especially CD4 + CD25 + T cells. CD4 + T cells, from DA rats tolerant to fully allogeneic PVG heart allografts surviving over 100days without on-going immunosuppression, were cultured with PVG alloantigen and rIL-5. The ability of these cells to adoptively transfer tolerance to specific-donor allograft and suppress normal CD4 + T cell mediated rejection in adoptive DA hosts was examined. Tolerant CD4 + CD25 + T cells' response to rIL-5 and expression of IL-5Rα was also assessed. rIL-5 was sufficient to promote transplant tolerance mediating CD4 + T cells' survival in culture with specific-donor alloantigen. Tolerant CD4 + T cells cultured with rIL-5 retained the capacity to transfer alloantigen-specific tolerance and inhibited naïve CD4 + T cells' capacity to effect specific-donor graft rejection. rIL-5 promoted tolerant CD4 + CD25 + T cells' proliferation in vitro when stimulated with specific-donor but not third-party stimulator cells. Tolerant CD4 + CD25 + T cells expressed IL-5Rα. This study demonstrated that IL-5 promoted the survival of alloantigen-specific CD4 + CD25 + T cells that mediate transplant tolerance. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15.

    PubMed

    Freeman, Christine M; Han, MeiLan K; Martinez, Fernando J; Murray, Susan; Liu, Lyrica X; Chensue, Stephen W; Polak, Timothy J; Sonstein, Joanne; Todt, Jill C; Ames, Theresa M; Arenberg, Douglas A; Meldrum, Catherine A; Getty, Christi; McCloskey, Lisa; Curtis, Jeffrey L

    2010-06-01

    Lung CD8(+) T cells might contribute to progression of chronic obstructive pulmonary disease (COPD) indirectly via IFN-gamma production or directly via cytolysis, but evidence for either mechanism is largely circumstantial. To gain insights into these potential mechanisms, we analyzed clinically indicated lung resections from three human cohorts, correlating findings with spirometrically defined disease severity. Expression by lung CD8(+) T cells of IL-18R and CD69 correlated with severity, as did mRNA transcripts for perforin and granzyme B, but not Fas ligand. These correlations persisted after correction for age, smoking history, presence of lung cancer, recent respiratory infection, or inhaled corticosteroid use. Analysis of transcripts for killer cell lectin-like receptor G1, IL-7R, and CD57 implied that lung CD8(+) T cells in COPD do not belong to the terminally differentiated effector populations associated with chronic infections or extreme age. In vitro stimulation of lung CD8(+) T cells with IL-18 plus IL-12 markedly increased production of IFN-gamma and TNF-alpha, whereas IL-15 stimulation induced increased intracellular perforin expression. Both IL-15 and IL-18 protein expression could be measured in whole lung tissue homogenates, but neither correlated in concentration with spirometric severity. Although lung CD8(+) T cell expression of mRNA for both T-box transcription factor expressed in T cells and GATA-binding protein 3 (but not retinoic acid receptor-related orphan receptor gamma or alpha) increased with spirometric severity, stimulation of lung CD8(+) T cells via CD3epsilon-induced secretion of IFN-gamma, TNF-alpha, and GM-CSF, but not IL-5, IL-13, and IL-17A. These findings suggest that the production of proinflammatory cytokines and cytotoxic molecules by lung-resident CD8(+) T cells contributes to COPD pathogenesis.

  2. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas.

    PubMed

    Kim, Peter S; Kwilas, Anna R; Xu, Wenxin; Alter, Sarah; Jeng, Emily K; Wong, Hing C; Schlom, Jeffrey; Hodge, James W

    2016-03-29

    Interleukin (IL)-15-N72D superagonist-complexed with IL-15RαSushi-Fc fusion protein (IL-15SA/IL-15RαSu-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15RαSu-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15RαSu-Fc significantly expanded natural killer (NK) and CD8+ T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b+, CD27hi; high effector) NK cells, leading to enhanced function on a per-cell basis. CD8+ T cell subset analysis determined that IL-15SA/IL-15RαSu-Fc significantly increased IL-15 responding memory (CD122+, CD44+) CD8+ T cells, in particular those having the innate (NKG2D+, PD1-) phenotype. In 4T1 breast tumor-bearing mice, IL-15SA/IL-15RαSu-Fc induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8+ T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of CT26 colon carcinoma cells, particularly when IL-15SA/IL-15RαSu-Fc was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1. Altogether, these studies showed for the first time that IL-15SA/IL-15RαSu-Fc (1) promoted the development of high effector NK cells and CD8+ T cell responders of the innate phenotype, (2) enhanced function of NK cells, and (3) played a vital role in reducing tumor metastasis and ultimately survival, especially in combination with checkpoint inhibitors.

  3. IL-33 and IgE stimulate mast cell production of IL-2 and regulatory T cell expansion in allergic dermatitis.

    PubMed

    Salamon, P; Shefler, I; Moshkovits, I; Munitz, A; Horwitz Klotzman, D; Mekori, Y A; Hershko, A Y

    2017-11-01

    We have previously shown that mast cells (MCs) suppress chronic allergic dermatitis in mice. The underlying mechanism involves MC-derived IL-2, which supports regulatory T cell (Treg) response at the site of inflammation. However, it is not clear what are the factors that drive MCs to produce IL-2. To understand the mechanisms that lead to IL-2 production from MCs in chronic allergic dermatitis. Isolated murine bone marrow-derived MCs (BMMCs) were incubated with various stimulators, and IL-2 production was assessed by RT-PCR and ELISA. The response of signalling pathways was evaluated by MAPK inhibitors and Western blot analysis. The effect of MC-IL-2 on Tregs was studied by incubation of splenic T cells with conditioned media obtained from activated BMMCs. Dermatitis was elicited by repeated exposures of mouse ears to oxazolone. MCs in mouse and human skin samples were evaluated by immunostaining. BMMCs released IL-2 in response to IL-33, and IL-2 production was further enhanced by concomitant FcεRI activation. The effect of IL-33 was mediated by activation of the MAPK family members. IL-2 in conditioned media from IL-33 and IgE-stimulated BMMCs led to considerable expansion of Tregs in vitro. IL-33 levels were elevated in oxazolone-challenged ears along with increased numbers of IL-2-expressing MCs. Human skin with chronic inflammation also contained IL-2-expressing MCs that colocalized with IL-33 staining in the dermis. IL-33, in collaboration with IgE, is critical for MC-IL-2 production in allergic skin disease, thus leading to Treg stimulation and suppression of allergic dermatitis. © 2017 John Wiley & Sons Ltd.

  4. A CB2-Selective Cannabinoid Suppresses T-cell Activities and Increases Tregs and IL-10

    PubMed Central

    Robinson, Rebecca H.; Meissler, Joseph J.; Fan, Xiaoxuan; Yu, Daohai; Adler, Martin W.; Eisenstein, Toby K.

    2015-01-01

    We have previously shown that agonists selective for the cannabinoid receptor 2 (CB2), including O-1966, inhibit the Mixed Lymphocyte Reaction (MLR), an in vitro correlate of organ graft rejection, predominantly through effects on T-cells. Current studies explored the mechanism of this immunosuppression by O-1966 using mouse spleen cells. Treatment with O-1966 dose-relatedly decreased levels of the active nuclear forms of the transcription factors NF-κB and NFAT in wild-type T-cells, but not T-cells from CB2 knockout (CB2R k/o) mice. Additionally, a gene expression profile of purified T-cells from MLR cultures generated using a PCR T-cell activation array showed that O-1966 decreased mRNA expression of CD40 ligand and CyclinD3, and increased mRNA expression of Src-like-adaptor 2 (SLA2), Suppressor of Cytokine Signaling 5 (SOCS5), and IL-10. The increase in IL-10 was confirmed by measuring IL-10 protein levels in MLR culture supernatants. Further, an increase in the percentage of regulatory T-cells (Tregs) was observed in MLR cultures. Pretreatment with anti-IL-10 resulted in a partial reversal of the inhibition of proliferation and blocked the increase of Tregs. Additionally, O-1966 treatment caused a dose-related decrease in the expression of CD4 in MLR cultures from wild-type, but not CB2R k/o, mice. These data support the potential of CB2-selective agonists as useful therapeutic agents to prolong graft survival in transplant patients, and strengthens their potential as a new class of immunosuppressive agents with broader applicability. PMID:25980325

  5. Lupus érythémateux systémique induit par l'isoniazide: une complication rare à craindre

    PubMed Central

    Jguirim, Mahbouba; Jbeli, Amna; Brahim, Hajer Ben; Mhenni, Amira; Youssef, Monia; Touzi, Mongi; Zrour, Sawssen; Bejia, Ismail; Bergaoui, Naceur

    2015-01-01

    Le lupus induit est défini comme un syndrome lupique généralement cutanéo-articulaire secondaire à une exposition continue à un traitement et qui disparaît après arrêt de celle-ci. Nous rapportons deux cas de lupus induit par l'isoniazide. Il s'agissait de deux femmes âgées respectivement de 30 et 35 ans. Elles présentaient un lupus induit par l'isoniazide après un et deux mois de traitement d'une tuberculose ganglionnaire. La maladie s'est manifestée par des signes articulaires, une éruption cutanée, une leucopénie et une anémie. Les anticorps antinucléaires et les anticorps antihistone étaient présents dans le sérum des deux malades. L’évolution était favorable après arrêt de l'isoniazide et une corticothérapie per os. Les médicaments antituberculeux notamment l'isoniazide sont responsables d'effets indésirables fréquents. Le lupus induit doit être évoqué lorsqu'un patient présente un tableau clinico-biologique évocateur. PMID:26430478

  6. Etiologie Rare de Sinusites Nosocomiales en Milieu de Reanimation - A Propos d'une Observation

    PubMed Central

    Messadi, A.A.; Oueslati, S.; Thabet, L.; Bousselmi, K.; Menif, E.

    2006-01-01

    Summary Les sinusites nosocomiales ne sont pas rares en réanimation. Elles surviennent en général dans les suites d'une intubation nasotrachéale voire même orotrachéale. Le tubage gastrique peut être à lui seul à l'origine d'une sinusite nosocomiale. Nous rapportons le cas d'une patiente hospitalisée qui a été victime de brûlures étendues chez qui la sonde nasogastrique a été à l'origine d'une pansinusite dont l'issue a été fatale. PMID:21991055

  7. Mathematical Model of Naive T Cell Division and Survival IL-7 Thresholds.

    PubMed

    Reynolds, Joseph; Coles, Mark; Lythe, Grant; Molina-París, Carmen

    2013-01-01

    We develop a mathematical model of the peripheral naive T cell population to study the change in human naive T cell numbers from birth to adulthood, incorporating thymic output and the availability of interleukin-7 (IL-7). The model is formulated as three ordinary differential equations: two describe T cell numbers, in a resting state and progressing through the cell cycle. The third is introduced to describe changes in IL-7 availability. Thymic output is a decreasing function of time, representative of the thymic atrophy observed in aging humans. Each T cell is assumed to possess two interleukin-7 receptor (IL-7R) signaling thresholds: a survival threshold and a second, higher, proliferation threshold. If the IL-7R signaling strength is below its survival threshold, a cell may undergo apoptosis. When the signaling strength is above the survival threshold, but below the proliferation threshold, the cell survives but does not divide. Signaling strength above the proliferation threshold enables entry into cell cycle. Assuming that individual cell thresholds are log-normally distributed, we derive population-average rates for apoptosis and entry into cell cycle. We have analyzed the adiabatic change in homeostasis as thymic output decreases. With a parameter set representative of a healthy individual, the model predicts a unique equilibrium number of T cells. In a parameter range representative of persistent viral or bacterial infection, where naive T cell cycle progression is impaired, a decrease in thymic output may result in the collapse of the naive T cell repertoire.

  8. A Critical Role for IL-17RB Signaling in HTLV-1 Tax-Induced NF-κB Activation and T-Cell Transformation

    PubMed Central

    Lavorgna, Alfonso; Matsuoka, Masao; Harhaj, Edward William

    2014-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia (ATL) and the neuroinflammatory disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein functions as a potent viral oncogene that constitutively activates the NF-κB transcription factor to transform T cells; however, the underlying mechanisms remain obscure. Here, using next-generation RNA sequencing we identified the IL-25 receptor subunit IL-17RB as an aberrantly overexpressed gene in HTLV-1 immortalized T cells. Tax induced the expression of IL-17RB in an IκB kinase (IKK) and NF-κB-dependent manner. Remarkably, Tax activation of the canonical NF-κB pathway in T cells was critically dependent on IL-17RB expression. IL-17RB and IL-25 were required for HTLV-1-induced immortalization of primary T cells, and the constitutive NF-κB activation and survival of HTLV-1 transformed T cells. IL-9 was identified as an important downstream target gene of the IL-17RB pathway that drives the proliferation of HTLV-1 transformed cells. Furthermore, IL-17RB was overexpressed in leukemic cells from a subset of ATL patients and also regulated NF-κB activation in some, but not all, Tax-negative ATL cell lines. Together, our results support a model whereby Tax instigates an IL-17RB-NF-κB feed-forward autocrine loop that is obligatory for HTLV-1 leukemogenesis. PMID:25340344

  9. A Novel Immunoregulatory Function for IL-23: Inhibition of IL-12 Dependent IFN-γ Production

    PubMed Central

    Sieve, Amy N.; Meeks, Karen D.; Lee, Suheung; Berg, Rance E.

    2011-01-01

    Summary Most studies investigating the function of IL-23 have concluded that it promotes IL-17 secreting T cells. While some reports have also characterized IL-23 as having redundant pro-inflammatory effects with IL-12, we have instead found that IL-23 antagonizes IL-12 induced secretion of IFN-γ. When splenocytes or purified populations of T cells are cultured with IL-23, IFN-γ secretion in response to IL-12 is dramatically reduced. The impact of IL-23 is most prominent in CD8 T cells, but is also observed in NK and CD4 T cells. Mechanistically, the IL-23 receptor is not required for this phenomenon, and IL-23 inhibits signaling through the IL-12 receptor by reducing IL-12 induced signal transducer and activator of transcription 4 (STAT4) phosphorylation. IL-23 is also able to reduce IFN-γ secretion by antagonizing endogenously produced IL-12 from Listeria monocytogenes (LM) infected macrophages. In vivo, LM infection induces higher serum IFN-γ levels and a greater percentage of IFN-γ+CD8+ T cells in IL-23p19 deficient mice as compared to wild-type mice. This increase in IFN-γ production coincides with increased LM clearance at days 2–3 post-infection. Our data suggest that IL-23 may be a key factor in determining the responsiveness of lymphocytes to IL-12 and their subsequent secretion of IFN-γ. PMID:20458705

  10. Effect of anti-IL-15 administration on T cell and NK cell homeostasis in rhesus macaques

    PubMed Central

    DeGottardi, Maren Q.; Okoye, Afam A.; Vaidya, Mukta; Talla, Aarthi; Konfe, Audrie L.; Reyes, Matthew D.; Clock, Joseph A.; Duell, Derick M.; Legasse, Alfred W.; Sabnis, Amit; Park, Byung S.; Axthelm, Michael K.; Estes, Jacob D.; Reinmann, Keith A.; Sekaly, Rafick-Pierre; Picker, Louis J.

    2016-01-01

    IL-15 has been implicated as a key regulator of T and NK cell homeostasis in multiple systems; however, its specific role in maintaining peripheral T and NK cell populations relative to other gamma-chain (γc) cytokines has not been fully defined in primates. Here, we address this question by determining the effect of IL-15 inhibition with a rhesusized, anti-IL-15 mAb on T and NK cell dynamics in rhesus macaques. Strikingly, anti-IL-15 treatment resulted in rapid depletion of NK cells, and both CD4+ and CD8+ effector memory T cells (TEM) in blood and tissues, with little to no effect on naïve or central memory T cells. Importantly, whereas depletion of NK cells was nearly complete and maintained as long as anti-IL-15 treatment was given, TEM depletion was countered by the onset of massive TEM proliferation, which almost completely restored circulating TEM numbers. Tissue TEM, however, remained significantly reduced, and most TEM maintained very high turnover throughout anti-IL-15 treatment. In the presence of IL-15 inhibition, TEM became increasingly more sensitive to IL-7 stimulation in vivo, and transcriptional analysis of TEM in IL-15-inhibited monkeys revealed engagement of the JAK/STAT signaling pathway, suggesting alternative γc cytokine signaling may support TEM homeostasis in the absence of IL-15. Thus, IL-15 plays a major role in peripheral maintenance of NK cells and TEM. However, whereas most NK cell populations collapse in the absence of IL-15, TEM can be maintained in the face of IL-15 inhibition by the activity of other homeostatic regulators, most likely IL-7. PMID:27430715

  11. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells.

    PubMed

    Wang, Yifeng; Shi, Jingwen; Yan, Jiacong; Xiao, Zhengtao; Hou, Xiaoxiao; Lu, Peiwen; Hou, Shiyue; Mao, Tianyang; Liu, Wanli; Ma, Yuanwu; Zhang, Lianfeng; Yang, Xuerui; Qi, Hai

    2017-08-01

    Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle-reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory-associated phenotypes with signs of affinity maturation and localized toward the GC border. After being transferred into adoptive hosts, GC-MP cells reconstituted a secondary response like genuine memory B cells. GC-MP cells expressed the interleukin 9 (IL-9) receptor and responded to IL-9. Acute treatment with IL-9 or antibody to IL-9 accelerated or retarded the positioning of GC-MP cells toward the GC edge and exit from the GC, and enhanced or inhibited the development of memory B cells, which required B cell-intrinsic responsiveness to IL-9. Follicular helper T cells (T FH cells) produced IL-9, and deletion of IL-9 from T cells or, more specifically, from GC T FH cells led to impaired memory formation of B cells. Therefore, the GC development of memory B cells is promoted by T FH cell-derived IL-9.

  12. L’expérience d’une patiente qui reçoit des soins pour la démence

    PubMed Central

    Frank, Christopher; Forbes, Rev Faye

    2017-01-01

    Résumé Objectif Permettre aux médecins de famille de comprendre « l’expérience vécue » de la démence de la bouche d’une personne atteinte de démence—Faye Forbes, ministre anglicane de 64 ans atteinte de la maladie d’Alzheimer, qui donne son point de vue sur comment vivre avec la démence—et utiliser cette information pour améliorer les soins et les résultats. Sources d’information Une recherche a été effectuée dans MEDLINE sur Ovid entre janvier 2005 et février 2015, à l’aide des mots-clés anglais suivants : dementia, caregiver, perspectives et quality of health care. Les articles qui s’adressaient aux médecins de famille ont été sélectionnés. Des revues pertinentes et des articles de recherche originaux ont été utilisés, le cas échéant, s’ils s’appliquaient aux personnes atteintes de démence et à leurs soignants. Message principal Plusieurs cadres de référence organisent les principales expériences décrites par les patients et leurs soignants. Nous avons utilisé une revue de la littérature qualitative pour fournir un cadre de référence résumant l’expérience de Faye, en fonction des thèmes suivants : tenter d’obtenir un diagnostic, accéder au soutien et aux services, besoins en matière d’information, prise en charge de la maladie, et communication et attitudes. Conclusion Les médecins doivent tenir compte de ces thèmes lorsqu’ils planifient la prise en charge des personnes atteintes de démence. Il importe de tenter de comprendre l’expérience et le point de vue des personnes atteintes de démence et de leurs soignants afin de pouvoir dispenser des soins optimaux. PMID:28115451

  13. IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates.

    PubMed

    Picker, Louis J; Reed-Inderbitzin, Edward F; Hagen, Shoko I; Edgar, John B; Hansen, Scott G; Legasse, Alfred; Planer, Shannon; Piatak, Michael; Lifson, Jeffrey D; Maino, Vernon C; Axthelm, Michael K; Villinger, Francois

    2006-06-01

    HIV infection selectively targets CD4+ effector memory T (T EM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the T EM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ T EM cells with little effect on the naive or central memory T (T CM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. T EM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ T EM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4 + T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.

  14. Colloquy to Paul Musset

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    None

    2007-12-13

    En honneur de Paul Musset il a été décidé de faire plutôt un colloque scientifique à la place d'une cérémonie. Plusieurs personnes temoignent de leurs estime et amitié pour ce physicien et ses activités

  15. The Class III Kinase Vps34 Promotes T Lymphocyte Survival through Regulating IL-7Rα Surface Expression

    PubMed Central

    McLeod, Ian X.; Zhou, Xiang; Li, Qi-Jing; Wang, Fan; He, You-Wen

    2011-01-01

    IL-7Rα mediated signals are essential for naive T lymphocyte survival. Recent studies show that IL-7Rα is internalized and either recycled to cell surface or degraded. However, how the intracellular process of IL-7Rα trafficking is regulated is unclear. Here we show that Vps34, the class III phosphatidylinositol 3-kinase, plays a critical role in proper IL-7Rα intracellular trafficking. Mice lacking Vps34 in T lymphocytes had a severely reduced T lymphocyte compartment. Vps34-deficient T lymphocytes exhibit increased death and reduced IL-7Rα surface expression, though three major forms of autophagy remain intact. Intracellular IL-7Rα in normal T lymphocytes at steady-state is trafficked through either early endosome/multivesicular bodies (MVB) to the late endosome-Golgi for surface expression or to the lysosome for degradation. However, Vps34-deficient T cells have mislocalized intracellular Eea1, HRS, and Vps36 protein levels, the combined consequence of which is the inability to mobilize internalized IL-7Rα into the retromer pathway for surface display. Our studies reveal that Vps34, though dispensible for autophagy induction, is a critical regulator of naïve T cell homeostasis, modulating IL-7Rα trafficking, signaling, and recycling. PMID:22021616

  16. The Yin and Yang aspects of IL-27 in induction of cancer-specific T-cell responses and immunotherapy.

    PubMed

    Li, Ming-Song; Liu, Zhenzhen; Liu, Jin-Qing; Zhu, Xiaotong; Liu, Zhihao; Bai, Xue-Feng

    2015-01-01

    Accumulating evidences from animal studies have indicated that both endogenous and exogenous IL-27, an IL-12 family of cytokine, can increase antitumor T-cell activities and inhibit tumor growth. IL-27 can modulate Treg responses, and program effector T cells into a unique T-effector stem cell (TSEC) phenotype, which enhances T-cell survival in the tumor microenvironment. However, animal studies also suggest that IL-27 induces molecular pathways such as IL-10, PD-L1 and CD39, which may downregulate tumor-specific T-cell responses. In this review paper, we will discuss the Yin and Yang aspects of IL-27 in the induction of tumor-specific T-cell responses, and the potential impacts of these functions of IL-27 in the design of cancer immunotherapy.

  17. IL-7Rαlow memory CD8+ T cells are significantly elevated in patients with systemic lupus erythematosus.

    PubMed

    Kim, Jung-Sik; Cho, Bon-A; Sim, Ji Hyun; Shah, Kamini; Woo, Connie M; Lee, Eun Bong; Lee, Dong-Sup; Kang, Jae Seung; Lee, Wang Jae; Park, Chung-Gyu; Craft, Joe; Kang, Insoo; Kim, Hang-Rae

    2012-09-01

    Human effector memory (EM) CD8(+) T cells include IL-7Rα(high) and IL-7Rα(low) cells with distinct cellular characteristics, including the expression of cytotoxic molecules. Both NK cells and the NK cell-associated molecule 2B4 that is expressed on CD8(+) T cells promote cytotoxicity. Here we analysed the expression of 2B4 on IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells and its contribution to cytotoxicity. We also analysed the frequency of IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells in patients with SLE or lupus and in healthy individuals given the potential role of cytotoxic CD8(+) T cells in the pathogenesis of lupus. We used flow cytometry to measure the expression of 2B4 on IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells as well as the frequency of these cell populations in the peripheral blood of healthy individuals and patients with SLE. Also, 2B4-mediated cytotoxicity was quantitated in IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells using target cells with CD48 antigen. We found that IL-7Rα(high) EM CD8(+) T cells had higher levels of 2B4 expression compared with IL-7Rα(low) EM CD8(+) T cells. Triggering 2B4 enhanced the cytotoxic function of IL-7Rα(low) EM CD8(+) T cells against target cells. We also noticed that patients with SLE had an increased frequency of IL-7Rα(low) EM CD8(+) T cells that correlated with disease manifestation. Our findings show that SLE patients have increased IL-7Rα(low) EM CD8(+) T cells, possibly contributing to tissue damage through 2B4-mediated cytotoxicity.

  18. Role of leptin and ghrelin in induction of differentiation of IL-17-producing and T-regulatory cells.

    PubMed

    Orlova, E G; Shirshev, S V

    2014-04-01

    We studied isolated and combined effects of leptin and ghrelin on the formation of IL-producing and T-regulatory cells. Leptin in concentrations comparable with its normal blood concentration during pregnancy (trimester II-III) promotes differentiation of peripheral blood CD4(+) cells to IL-17-producing cells and enhances IL-17A production, but suppresses the formation of T-regulatory cells in vitro. In contrast, ghrelin in a concentration typical of trimester I-II of pregnancy reduces the number of IL-17-producing cells, but stimulated the formation of T-regulatory cells. The effects of leptin and ghrelin in combination typical of trimester I-II of pregnancy stimulated the formation of T-regulatory cells, while in combination typical of trimester II-III did not shift the balance of T-regulatory cells and IL-17-producing cells, but stimulated the formation of IL-17A. We conclude that leptin and ghrelin play an important role in the maintenance of the balance of IL-17-producing and T-regulatory cells during pregnancy.

  19. Expression of fusion IL2-B7.1(IgV+C) and effects on T lymphocytes.

    PubMed

    Kong, Linghong; Li, Yaochen; Yang, Ye; Li, Kangsheng

    2007-12-01

    The search for an effective immunotherapeutic treatment for tumors is an important area of cancer research. To prepare a more effective form of the bifunctional fusion protein IL2-B7.1(IgV+C) and analyze its effect on the stimulation of T lymphocyte proliferation, we used DNAStar 5.03 software to predict the structural diversity and biochemical character of IL2-B7.1(IgV+C). We then prepared fusion protein IL2-B7.1(IgV+C) by establishing its prokaryotic expression system, and tested its effect on the stimulation of T lymphocytes in vitro. The results indicated that IL2-B7.1(IgV+C) correctly formed a secondary structure in which both IL2 and B7.1(IgV+C) maintained their original hydrophilicity and epitopes. Western blot analysis revealed that IL2-B7.1(IgV+C) was efficiently expressed. Our analysis of CTLL-2 and T-cell proliferation showed that recombinant human (rh) IL2-B7.1(IgV+C) exerted the combined stimulating effects of both rhIL2 and rh B7.1(IgV+C) on cell proliferation, and that these effects could be blocked by adding either anti-IL2 or anti-B7.1 monoclonal antibodies. A >2-fold increase in [3H]TdR incorporation compared with that of cells treated with recombinant protein IL2, or B7.1(IgV+C) alone, revealed that rhIL2-B7.1(IgV+C) had dose-dependent synergetic effects on T-cell activation in the presence of anti-CD3 monoclonal antibody. We concluded that the augmented potency of rhIL2-B7.1(IgV+C) resulted in a stronger stimulation of T-cell proliferation than either rhB7.1(IgV+C) or rhIL2 alone.

  20. Negative regulation of NKG2D expression by IL-4 in memory CD8 T cells.

    PubMed

    Ventre, Erwan; Brinza, Lilia; Schicklin, Stephane; Mafille, Julien; Coupet, Charles-Antoine; Marçais, Antoine; Djebali, Sophia; Jubin, Virginie; Walzer, Thierry; Marvel, Jacqueline

    2012-10-01

    IL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses.

  1. Regulatory role of Vγ1 γδ T cells in tumor immunity through IL-4 production.

    PubMed

    Hao, Jianlei; Dong, Siyuan; Xia, Siyuan; He, Weifeng; Jia, Hao; Zhang, Song; Wei, Jun; O'Brien, Rebecca L; Born, Willi K; Wu, Zhenzhou; Wang, Puyue; Han, Jihong; Hong, Zhangyong; Zhao, Liqing; Yin, Zhinan

    2011-11-15

    It has been demonstrated that the two main subsets of peripheral γδ T cells, Vγ1 and Vγ4, have divergent functions in many diseases models. Recently, we reported that Vγ4 γδ T cells played a protective role in tumor immunity through eomesodermin-controlled mechanisms. However, the precise roles of Vγ1 γδ T cells in tumor immunity, especially whether Vγ1 γδ T cells have any interaction with Vγ4 γδ T cells, remain unknown. We demonstrated in this paper that Vγ1 γδ T cells suppressed Vγ4 γδ T cell-mediated antitumor function both in vitro and in vivo, and this suppression was cell contact independent. Using neutralizing anti-IL-4 Ab or IL-4(-/-) mice, we determined the suppressive factor derived from Vγ1 γδ T cells was IL-4. Indeed, treatment of Vγ4 γδ T cells with rIL-4 significantly reduced expression levels of NKG2D, perforin, and IFN-γ. Finally, Vγ1 γδ T cells produced more IL-4 and expressed significantly higher level of GATA-3 upon Th2 priming in comparison with Vγ4 γδ T cells. Therefore, to our knowledge, our results established for the first time a negative regulatory role of Vγ1 γδ T cells in Vγ4 γδ T cell-mediated antitumor immunity through cell contact-independent and IL-4-mediated mechanisms. Selective depletion of this suppressive subset of γδ T cells may be beneficial for tumor immune therapy.

  2. Silence et divulgation dans des familles d’adolescents vivant avec le VIH depuis la naissance : une exploration qualitative

    PubMed Central

    Proulx-Boucher, Karène; Blais, Martin; Fernet, Mylène; Richard, Marie-Ève; Otis, Joanne; Josy Lévy, Joseph; Samson, Johanne; Lapointe, Normand; Morin, Guylaine; Thériault, Jocelyne; Trottier, Germain

    2011-01-01

    OBJECTIF : Les études ciblant les enfants nés avec le VIH se sont principalement intéressées à la période précédant l’annonce du diagnostic à l’enfant. L’objectif de cette étude est d’explorer les dynamiques de communication intrafamiliale suivant l’annonce du diagnostic. MÉTHODOLOGIE : Vingt-neuf jeunes (de dix à 18 ans) vivant avec le VIH depuis la naissance ont accordé des entrevues individuelles semi-dirigées portant sur : 1) le dévoilement du statut sérologique, 2) leurs relations familiales et 3) l’éducation sexuelle en milieu familial. Les témoignages ont fait l’objet d’une analyse de contenu. RÉSULTATS : Les jeunes ont appris en moyenne à l’âge de 11 ans leur diagnostic VIH+. La dynamique qui s’installe après cette annonce apparaît régie par le silence : les échanges qui s’ensuivent portent en majorité sur des questions relatives à la médication et à la prévention d’une transmission sexuelle du virus. Ce silence préserverait l’équilibre familial en occupant trois fonctions : protéger la mère d’un sentiment de culpabilité à l’égard de la transmission, assurer l’harmonie familiale, se sentir normal face aux autres. Le diagnostic de l’adolescent n’est généralement pas révélé à la famille élargie, préservant ainsi leur intégration au sein de la famille en les protégeant du rejet, de la trahison et du jugement. EXPOSÉ : Les fonctions du silence et du secret occupent une place stabilisatrice importante au sein de la famille. Toutefois, elles contribuent à isoler les adolescents d’une forme de soutien affectif dont ils ont pourtant besoin. Des pistes d’intervention sont suggérées. PMID:22851894

  3. Mycobacterium tuberculosis PstS1 amplifies IFN-γ and induces IL-17/IL-22 responses by unrelated memory CD4+ T cells via dendritic cell activation.

    PubMed

    Palma, Carla; Schiavoni, Giovanna; Abalsamo, Laura; Mattei, Fabrizio; Piccaro, Giovanni; Sanchez, Massimo; Fernandez, Carmen; Singh, Mahavir; Gabriele, Lucia

    2013-09-01

    The immunological mechanisms that modulate protection during Mycobacterium tuberculosis (Mtb) infection or vaccination are not fully understood. Secretion of IFN-γ and, to a lesser extent, of IL-17 by CD4(+) T cells plays a major role both in protection and immunopathology. Few Mtb Ags interacting with DCs affect priming, activation, and regulation of Ag-unrelated CD4(+) T-cell responses. Here we demonstrate that PstS1, a 38 kDa-lipoprotein of Mtb, promotes Ag-independent activation of memory T lymphocytes specific for Ag85B or Ag85A, two immunodominant protective Ags of Mtb. PstS1 expands CD4(+) and CD8(+) memory T cells, amplifies secretion of IFN-γ and IL-22 and induces IL-17 production by effector memory cells in an Ag-unrelated manner in vitro and in vivo. These effects were mediated through the stimulation of DCs, particularly of the CD8α(-) subtype, which respond to PstS1 by undergoing phenotypic maturation and by secreting IL-6, IL-1β and, to a lower extent, IL-23. IL-6 secretion by PstS1-stimulated DCs was required for IFN-γ, and to a lesser extent for IL-22 responses by Ag85B-specific memory T cells. These results may open new perspectives for immunotherapeutic strategies to control Th1/Th17 immune responses in Mtb infections and in vaccinations against tuberculosis. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. IL-2 complex treatment amplifies CD8+ T cell mediated immunity following herpes simplex virus-1 infection.

    PubMed

    Rajasagi, Naveen K; Rouse, Barry T

    2016-12-01

    CD8 + T cells play an important role in controlling numerous virus infections and some tumors and therefore several strategies have been adopted to modulate CD8 + T cell responses. One such approach includes treatment with IL-2 bound to a monoclonal antibody against IL-2 (IL-2 complex) which was shown to enhance CD8 + T cell responses and provide protection against some cancers and pathogens. This report analyses the value of IL-2 complex therapy to protect against a cutaneous virus infection as occurs with herpes simplex virus-1 (HSV-1) infection. Treatment with IL-2 complex after infection reduced virus levels and lesion severity in a zosteriform model of HSV infection in mice. Furthermore, IL-2 complex treatment expanded HSV-1-gB epitope-specific CD8 + T cells, IFN-γ and TNF-α producing CD8 + T cells as well as cells that produced more than one cytokine. In addition, IL-2 complex therapy recipients showed enhanced cytolytic activity of CD8 + T cells as shown by increased granzyme B expression and lytic granule release. Taken, together, these studies demonstrate that IL-2 complex therapy can be useful to boost protection against a cutaneous virus infection. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  5. Crusted scabies is associated with increased IL-17 secretion by skin T cells.

    PubMed

    Liu, X; Walton, S F; Murray, H C; King, M; Kelly, A; Holt, D C; Currie, B J; McCarthy, J S; Mounsey, K E

    2014-11-01

    Scabies is an ectoparasitic infestation by the mite Sarcoptes scabiei. Although commonly self-limiting, a fraction of patients develop severely debilitating crusted scabies. The immune mechanisms underlying the development of crusted scabies are unclear, and undertaking longitudinal infection studies in humans is difficult. We utilized a porcine model to compare cellular immune responses in peripheral blood and skin of pigs with different clinical manifestations of scabies (n = 12), and in uninfected controls (n = 6). Although clinical symptoms were not evident until at least 4 weeks post-infestation, the numbers of peripheral IFNγ-secreting CD4(+) T cells and γδ T cells increased in infected pigs from week 1 post-infestation. γδ T cells remained increased in the blood at week 15 post-infestation. At week 15, skin cell infiltrates from pigs with crusted scabies had significantly higher CD8(+) T cell, γδ T cell and IL-17(+) cell numbers than those with ordinary scabies. Peripheral IL-17 levels were not increased, suggesting that localized skin IL-17-secreting T cells may play a critical role in the pathogenesis of crusted scabies development. Given the potential of anti-IL-17 immunotherapy demonstrated for other inflammatory skin diseases, this study may provide a novel therapeutic avenue for patients with recurrent crusted scabies. © 2014 John Wiley & Sons Ltd.

  6. Modulation of CD4+ and CD8+ T Cell Function and Cytokine Responses in Strongyloides stercoralis Infection by Interleukin-27 (IL-27) and IL-37.

    PubMed

    Anuradha, Rajamanickam; Munisankar, Saravanan; Bhootra, Yukthi; Dolla, Chandrakumar; Kumaran, Paul; Nutman, Thomas B; Babu, Subash

    2017-11-01

    Strongyloides stercoralis infection is associated with diminished antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4 + and CD8 + T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis -infected individuals and 10 uninfected individuals stimulated with parasite antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with parasite antigen stimulation. There was no induction of any T cell response in uninfected individuals following parasite antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection. Copyright © 2017 American Society for Microbiology.

  7. Telomerase Is Involved in IL-7-Mediated Differential Survival of Naive and Memory CD4+ T Cells1

    PubMed Central

    Yang, Yinhua; An, Jie; Weng, Nan-ping

    2008-01-01

    IL-7 plays an essential role in T cell maintenance and survival. The survival effect of IL-7 is thought to be mediated through regulation of Bcl2 family proteins. After a comparative analysis of IL-7-induced growth and cell death of human naive and memory CD4+ T cells, we observed that more memory CD4+ T cells underwent cell division and proceeded to apoptosis than naive cells in response to IL-7. However, IL-7-induced expressions of Bcl2 family members (Bcl2, Bcl-xL, Bax, and Bad) were similar between naive and memory cells. Instead, we found that IL-7 induced higher levels of telomerase activity in naive cells than in memory cells, and the levels of IL-7-induced telomerase activity had a significant inverse correlation with cell death in CD4+ T cells. Furthermore, we showed that reducing expression of telomerase reverse transcriptase and telomerase activity significantly increased cell death of IL-7-cultured CD4+ T cells. Together, these findings demonstrate that telomerase is involved in IL-7-mediated differential survival of naive and memory CD4+ T cells. PMID:18322183

  8. Association of IL-1β +3954 C/T and IL-10-1082 G/A cytokine gene polymorphisms with susceptibility to tuberculosis.

    PubMed

    Meenakshi, P; Ramya, S; Shruthi, T; Lavanya, J; Mohammed, H H; Mohammed, S A; Vijayalakshmi, V; Sumanlatha, G

    2013-07-01

    Tuberculosis (TB) constitutes the major cause of death due to infectious diseases. Cytokines play a major role in defence against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding various cytokines have been associated with tuberculosis susceptibility. Household contacts (HHC) are at increased risk of developing the disease. In this study, we examined the association of IL-1β and IL-10 cytokine gene polymorphisms with risk of developing tuberculosis in TB patients, their HHC and healthy controls (HC) using JavaStat and SPSS. Multifactor dimensionality reduction (MDR) analyses were performed to explore the potential gene-gene interactions. The genotype and allele frequencies of IL-1β +3954C/T polymorphism did not vary significantly between TB patients and HC. GG (P < 0.005, OR = 0.219 and 95% CI = 0.059-0.735) and GA (P < 0.0001, OR = 2.938 and 95% CI = 1.526-5.696) genotypes of IL-10-1082 G/A polymorphism were found to be significantly associated with patients versus HC. HHC with CC (P < 0.03, OR = 1.833 and 95% CI = 1.1-3.35) genotype in IL-1β and GA (P < 0.0001, OR = 4.612 and 95% CI = 2.225-9.702) genotype in IL-10 were at increased risk of developing tuberculosis. MDR tests revealed high-risk genotypes in IL-1β and IL-10 based on the association model. Our results demonstrate that the polymorphisms of IL-1β and IL-10 genes may be valuable markers to predict the risk for the development of TB in household contacts. © 2013 John Wiley & Sons Ltd.

  9. Follicular T helper cells and IL-21 in rheumatic diseases.

    PubMed

    Rasmussen, Tue Kruse

    2016-10-01

    Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are lifelong diseases with increased mortality and chronic pains. They are both characterized by immunological imbalances causing the immune system attack and destroy the bodies own tissues (called autoimmune disease). The best treatment, we are currently able to offer these patients, cause significant side-effects and can not prevent significant loss of quality of life. At the heart of the disease mechanisms in RA and SLE are subsets of immune cells called T and B cells. These cell types produce proteins (called antibodies), which under normal circumstances protect the body against disease. In RA and SLE these cells produce antibodies that are directed at the bodies own tissues (called autoantibodies), causing inflammation and tissue damage. The cause of this loss of tolerance is still unknown. Interleukin 21 (IL-21) is thought to exert key functions in controlling and directing the T and B cell responses leading to formation of antibodies and autoantibodies alike. IL-21 is a signaling molecule secreted by a subpopulation of T cells called follicular T helper (Tfh) cells. IFNα is another signaling molecule of key importance in autoimmune disease. Stratification of SLE patients by their responsiveness to IFNα has proven a crucial tool in stratifying patients in terms of disease development and treatment response. The aim of this PhD study is to investigate the role of IL-21 and IFNα, and their effects on Tfh cells and B cells and the formation of autoantibodies in RA and SLE. The first part of this study addresses whether plasma levels of IL-21 influence disease activity in rheumatic disease. We further investigate the distribution of IL-21-producing Tfh cells in these patients. We find that IL-21 plasma levels correlate to disease activity and radiological progression in RA, and that the IL-21-producing Tfh cell are increased in the blood and synovial fluid of these patients. These findings

  10. MAR binding protein SMAR1 favors IL-10 mediated regulatory T cell function in acute colitis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mirlekar, Bhalchandra; Patil, Sachin; Bopanna, Ramanamurthy

    2015-08-21

    T{sub reg} cells are not only crucial for controlling immune responses to autoantigens but also prevent those directed towards commensal pathogens. Control of effector immune responses by T{sub reg} cells depend on their capacity to accumulate at inflammatory site and accordingly accommodate to inflammatory environment. Till date, the factors associated with maintaining these aspects of T{sub reg} phenotype is not understood properly. Here we have shown that a known nuclear matrix binding protein SMAR1 is selectively expressed more in colonic T{sub reg} cells and is required for their ability to accumulate at inflammatory site and to sustain high levels ofmore » Foxp3 and IL-10 expression during acute colitis. Elimination of anti-inflammatory subsets revealed a protective role for IL-10 producing T{sub reg} cells in SMAR1{sup −/−} mice. Moreover, a combined action of Foxp3 and SMAR1 restricts effector cytokine production and enhance the production of IL-10 by colonic T{sub reg} cells that controls acute colitis. This data highlights a critical role of SMAR1 in maintaining T{sub reg} physiology during inflammatory disorders. - Highlights: • SMAR1 is essential to sustain high level of Foxp3 and IL-10 in T{sub reg} cells. • SMAR1{sup −/−} T{sub reg} cells produce pro-inflammatory cytokine IL-17 leads to inflammation. • IL-10 administration can control the inflammation in SMAR1{sup −/−} mice. • Both Foxp3 and SMAR1 maintain T{sub reg} phenotype that controls colitis.« less

  11. Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells

    PubMed Central

    Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A; Gray, Simon M; Guan, Tianxia; Lu, Yisi; Kobayashi, Yasushi; Flavell, Richard A; Kleinstein, Steven H; Craft, Joe; Kaech, Susan M

    2016-01-01

    Memory CD8+ T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4+ regulatory T cells (Treg cells) was necessary for the maturation of memory CD8+ T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell–derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase ‘restored’ the maturation of memory CD8+ T cells in IL-10-deficient mice. Our data indicate that Treg cell–derived IL-10 is needed to insulate CD8+ T cells from inflammatory signals, and reveal that the resolution phase of infection is a critical period that influences the quality and function of developing memory CD8+ T cells. PMID:26147684

  12. Regulation of allergic airway inflammation by adoptive transfer of CD4+ T cells preferentially producing IL-10.

    PubMed

    Matsuda, Masaya; Doi, Kana; Tsutsumi, Tatsuya; Fujii, Shinya; Kishima, Maki; Nishimura, Kazuma; Kuroda, Ikue; Tanahashi, Yu; Yuasa, Rino; Kinjo, Toshihiko; Kuramoto, Nobuyuki; Mizutani, Nobuaki; Nabe, Takeshi

    2017-10-05

    Anti-inflammatory pharmacotherapy for asthma has mainly depended on the inhalation of glucocorticoids, which non-specifically suppress immune responses. If the anti-inflammatory cytokine interleukin (IL)-10 can be induced by a specific antigen, asthmatic airway inflammation could be suppressed when individuals are exposed to the antigen. The purpose of this study was to develop cellular immunotherapeutics for atopic diseases using IL-10-producing CD4 + T cells. Spleen cells isolated from ovalbumin (OVA)-sensitized mice were cultured with the antigen, OVA and growth factors, IL-21, IL-27 and TGF-β for 7 days. After the 7-day culture, the CD4 + T cells were purified using a murine CD4 magnetic beads system. When the induced CD4 + T cells were stimulated by OVA in the presence of antigen-presenting cells, IL-10 was preferentially produced in vitro. When CD4 + T cells were adoptively transferred to OVA-sensitized mice followed by intratracheal OVA challenges, IL-10 was preferentially produced in the serum and bronchoalveolar lavage fluid in vivo. IL-10 production coincided with the inhibition of eosinophilic airway inflammation and epithelial mucus plugging. Most of the IL-10-producing CD4 + T cells were negative for Foxp3 and GATA-3, transcription factors of naturally occurring regulatory T cells and Th2 cells, respectively, but double positive for LAG-3 and CD49b, surface markers of inducible regulatory T cells, Tr1 cells. Collectively, most of the induced IL-10-producing CD4 + T cells could be Tr1 cells, which respond to the antigen to produce IL-10, and effectively suppressed allergic airway inflammation. The induced Tr1 cells may be useful for antigen-specific cellular immunotherapy for atopic diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells

    PubMed Central

    Bacchetta, Rosa; Lucarelli, Barbarella; Sartirana, Claudia; Gregori, Silvia; Lupo Stanghellini, Maria T.; Miqueu, Patrick; Tomiuk, Stefan; Hernandez-Fuentes, Maria; Gianolini, Monica E.; Greco, Raffaella; Bernardi, Massimo; Zappone, Elisabetta; Rossini, Silvano; Janssen, Uwe; Ambrosi, Alessandro; Salomoni, Monica; Peccatori, Jacopo; Ciceri, Fabio; Roncarolo, Maria-Grazia

    2013-01-01

    T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent disease recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSCT (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10-anergized donor T cells (IL-10-DLI) contained T regulatory type 1 (Tr1) cells specific for the host alloantigens, limiting donor-vs.-host-reactivity, and memory T cells able to respond to pathogens. IL-10-DLI were infused in 12 patients with the goal of improving immune reconstitution after haplo-HSCT without increasing the risk of graft-versus-host-disease (GvHD). IL-10-DLI led to fast immune reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vβ repertoire and T-cell functions progressively normalized after IL-10-DLI. These four patients are alive, in complete disease remission and immunosuppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted (IR) patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1-specific biomarkers in vivo. Gene-expression profiles of IR patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders. PMID:24550909

  14. Nucléation, ascension et éclatement d'une bulle de champagne

    NASA Astrophysics Data System (ADS)

    Liger-Belair, G.

    2006-03-01

    verre ou de la flûte. Dans la majorité des cas, il s'agit de fibres de cellulose creuses dont les propriétés géométriques permettent le piégeage d'une poche d'air en leur sein au moment du versement. Un modèle de piégeage a été construit et met en avant le rôle fondamental joué par la vitesse du versement. Plus cette vitesse augmente, plus on augmente la probabilité de piéger des poches d'air au sein de ces fibres, provoquant ainsi une effervescence plus importante. La dynamique de production des bulles a également été filmée in situ à l'aide de la caméra, puis modélisée en utilisant les équations de la diffusion adaptées à la géométrie de notre fibre supposée approximativement cylindrique. Nous avons montré que le temps caractéristique de production d'une bulle par la fibre est largement gouverné par la croissance de cette petite poche de gaz par diffusion du CO{2} dissous vers la poche. Nous avons démontré que la convection du liquide joue un rôle essentiel lors du transfert de masse du CO{2} dissous vers la poche. En effet, un modèle purement diffusif ne permet pas du tout de reproduire la dynamique de croissance expérimentale de ces poches de gaz piégées au cœur des fibres. Nous avons également pu mettre en évidence des changements spectaculaires dans la dynamique de bullage de certains sites de nucléation suivis au cours du temps pendant le processus de dégazage. Ces observations font de la fibre de cellulose immergée dans le champagne le plus petit système de bullage non-linéaire observé à ce jour. Dynamique ascensionnelle Pour mesurer la vitesse d'une bulle tout au long de son trajet vers la surface libre du champagne, nous avons tiré profit de la production répétitive de bulles au niveau des sites de nucléation. Par la mise en place d'un dispositif expérimental simple qui associe une lumière stroboscopique et un appareil photographique muni de bagues macros, nous avons pu accéder à l'observation fine des

  15. Une cause rare de compression médullaire: kyste arachnoïdien épidural rachidien (à propos de 03 cas)

    PubMed Central

    El Saqui, Abderrazzak; Aggouri, Mohamed; Benzagmout, Mohamed; Chakour, Khalid; Chaoui, Mohamed El Faiz

    2017-01-01

    Le kyste arachnoïdien épidural rachidien (KAER) est une affection bénigne, de physiopathologie encore incertaine. Il est le plus souvent asymptomatique mais peut causer des séquelles neurologiques graves surtout quand le traitement n'est pas instauré à temps. Nous rapportons l'expérience du service de Neurochirurgie CHU Hassan II- Fès concernant la prise en charge du KAER à travers l'analyse rétrospective de trois cas. Il s'agit de deux patients de sexe masculin et d'une femme, d'âge moyen de 35 ans (Extrêmes: 16 et 56 ans), tous admis pour un tableau de compression médullaire lente. Tous nos patients ont bénéficié d'une IRM médullaire qui a mis en évidence une collection liquidienne de siège épidural, ayant le même signal que le LCR, comprimant la moelle en regard. Le siège de la collection était thoracique dans tous les cas. Tous nos patients ont été opérés par voie postérieure avec exérèse du kyste et ligature du collet dans deux cas et une plastie durale dans un seul cas. L'étude anatomopathologique a conclu en un kyste arachnoïdien. L'évolution postopératoire était favorable dans tous les cas. Ce travail a comme objectif de mettre le point sur cette pathologie tout en insistant sur la nécessité d'une prise en charge précoce, vu la tendance vers l'aggravation progressive en l'absence de thérapie adaptée et rappeler les particularités cliniques, paracliniques et thérapeutiques de cette affection. PMID:28533855

  16. Increased IL-2 production in T cells by xanthohumol through enhanced NF-AT and AP-1 activity.

    PubMed

    Choi, Jin Myung; Kim, Hyun Jung; Lee, Kwang Youl; Choi, Hyun Jin; Lee, Ik-Soo; Kang, Bok Yun

    2009-01-01

    Xanthohumol (XN) is a major chalcone found in hop, which is used to add bitterness and flavor to beer. In this study, we investigated the effects of XN on the production of interlukin-2 (IL-2), a potent T cell growth factor. Treatment with XN significantly increased IL-2 production in mouse EL-4 T cells activated with phorbol 12-myristate 13-acetate (PMA) plus ionomycin (Io) in a dose-dependent manner. To further characterize its regulatory mechanism of XN on increased IL-2 production, the effects of XN on IL-2 promoter activity and the activity of several transcription factors modulating IL-2 expression were analyzed. XN enhanced activity of the IL-2 promoter, which contains distal and proximal regulatory elements in PMA/Io-activated EL-4 T cells. Furthermore, the activity of NF-AT and AP-1 was enhanced but NF-kappaB activity was not influenced by XN in PMA/Io-activated EL-4 T cells. These results suggest that XN increased IL-2 production at the transcriptional levels via the up-regulation of NF-AT and AP-1 in PMA/Io-activated EL-4 T cells.

  17. IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis.

    PubMed

    Barik, Subhasis; Ellis, Jason S; Cascio, Jason A; Miller, Mindy M; Ukah, Tobechukwu K; Cattin-Roy, Alexis N; Zaghouani, Habib

    2017-10-01

    IL-4 and IL-13 have been defined as anti-inflammatory cytokines that can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis. However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). In this study, we used mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Rα/IL-13Rα1 (13R) heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice-deficient for the HR (13R -/- ) are more susceptible to experimental allergic encephalomyelitis than mice sufficient for the HR (13R +/+ ) and develop early onset and more severe disease. Moreover, Th17 cells from 13R -/- mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R +/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression, leading to control of immune-mediated CNS inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity. Copyright © 2017 by The American Association of Immunologists, Inc.

  18. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family.

    PubMed

    Cayrol, Corinne; Girard, Jean-Philippe

    2018-01-01

    Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8 + T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells. © 2017 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

  19. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment.

    PubMed

    Kryczek, Ilona; Wei, Shuang; Zou, Linhua; Altuwaijri, Saleh; Szeliga, Wojciech; Kolls, Jay; Chang, Alfred; Zou, Weiping

    2007-06-01

    Th17 cells play an active role in inflammation and autoimmune diseases. However, the nature and regulation of Th17 in the context of tumor immunity remain unknown. In this study, we show that parallel to regulatory T (Treg) cells, IL-17(+) CD4(+) and CD8(+) T cells are kinetically induced in multiple tumor microenvironments in mice and humans. Treg cells play a crucial role in tumor immune pathogenesis and temper immune therapeutic efficacy. IL-2 is crucial for the production and function of Treg cells. We now show that IL-2 reduces IL-17(+) T cell differentiation in the tumor microenvironment accompanied with an enhanced Treg cell compartment in vitro and in vivo. Altogether, our work demonstrates a dynamic differentiation of IL-17(+) T cells in the tumor microenvironment, reveals a novel role for IL-2 in controlling the balance between IL-17(+) and Treg cells, and provides new insight of IL-17(+) T cells in tumor immune pathology and therapy.

  20. IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

    PubMed Central

    Stubbs, Andrew P.; Vroegindeweij, Eric M.; Smits, Willem K.; van Marion, Ronald; Dinjens, Winand N. M.; Horstmann, Martin; Kuiper, Roland P.; Zaman, Guido J. R.; van der Spek, Peter J.; Pieters, Rob; Meijerink, Jules P. P.

    2016-01-01

    Background Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment. Methods and Findings We performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome. To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we

  1. IL-15/IL-15 receptor biology: a guided tour through an expanding universe.

    PubMed

    Budagian, Vadim; Bulanova, Elena; Paus, Ralf; Bulfone-Paus, Silvia

    2006-08-01

    The cytokine interleukin-15 (IL-15) has a key role in promoting survival, proliferation and activation of natural killer (NK) and CD8+ T cells. Despite its functional similarities to IL-2, IL-15 affects a wider range of target cell populations and utilizes different mechanisms of signaling. Here, we review recent advances in the IL-15-mediated signaling, and in the functional properties on cells besides T lymphocytes and NK cells. These are discussed in the context of their potential clinical and therapeutic relevance.

  2. Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

    PubMed

    Lee, Dhong Hyun; Zandian, Mandana; Kuo, Jane; Mott, Kevin R; Chen, Shuang; Arditi, Moshe; Ghiasi, Homayon

    2017-05-01

    We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

  3. Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice

    PubMed Central

    Lee, Dhong Hyun; Zandian, Mandana; Mott, Kevin R.; Chen, Shuang

    2017-01-01

    We have established two mouse models of central nervous system (CNS) demyelination that differ from most other available models of multiple sclerosis (MS) in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT) HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice. PMID:28542613

  4. Rapid and Rigorous IL-17A Production by a Distinct Subpopulation of Effector Memory T Lymphocytes Constitutes a Novel Mechanism of Toxic Shock Syndrome Immunopathology.

    PubMed

    Szabo, Peter A; Goswami, Ankur; Mazzuca, Delfina M; Kim, Kyoungok; O'Gorman, David B; Hess, David A; Welch, Ian D; Young, Howard A; Singh, Bhagirath; McCormick, John K; Haeryfar, S M Mansour

    2017-04-01

    Toxic shock syndrome (TSS) is caused by staphylococcal and streptococcal superantigens (SAgs) that provoke a swift hyperinflammatory response typified by a cytokine storm. The precipitous decline in the host's clinical status and the lack of targeted therapies for TSS emphasize the need to identify key players of the storm's initial wave. Using a humanized mouse model of TSS and human cells, we herein demonstrate that SAgs elicit in vitro and in vivo IL-17A responses within hours. SAg-triggered human IL-17A production was characterized by remarkably high mRNA stability for this cytokine. A distinct subpopulation of CD4 + effector memory T (T EM ) cells that secrete IL-17A, but not IFN-γ, was responsible for early IL-17A production. We found mouse "T EM -17" cells to be enriched within the intestinal epithelium and among lamina propria lymphocytes. Furthermore, interfering with IL-17A receptor signaling in human PBMCs attenuated the expression of numerous inflammatory mediators implicated in the TSS-associated cytokine storm. IL-17A receptor blockade also abrogated the secondary effect of SAg-stimulated PBMCs on human dermal fibroblasts as judged by C/EBP δ expression. Finally, the early IL-17A response to SAgs was pathogenic because in vivo neutralization of IL-17A in humanized mice ameliorated hepatic and intestinal damage and reduced mortality. Together, our findings identify CD4 + T EM cells as a key effector of TSS and reveal a novel role for IL-17A in TSS immunopathogenesis. Our work thus elucidates a pathogenic, as opposed to protective, role for IL-17A during Gram-positive bacterial infections. Accordingly, the IL-17-IL-17R axis may provide an attractive target for the management of SAg-mediated illnesses. Copyright © 2017 by The American Association of Immunologists, Inc.

  5. Mathematical Models of the Impact of IL2 Modulation Therapies on T Cell Dynamics

    PubMed Central

    León, Kalet; García-Martínez, Karina; Carmenate, Tania

    2013-01-01

    Several reports in the literature have drawn a complex picture of the effect of treatments aiming to modulate IL2 activity in vivo. They seem to promote either immunity or tolerance, probably depending on the specific context, dose, and timing of their application. Such complexity might derive from the pleiotropic role of IL2 in T cell dynamics. To theoretically address the latter possibility, our group has developed several mathematical models for Helper, Regulatory, and Memory T cell population dynamics, which account for most well-known facts concerning their relationship with IL2. We have simulated the effect of several types of therapies, including the injection of: IL2; antibodies anti-IL2; IL2/anti-IL2 immune-complexes; and mutant variants of IL2. We studied the qualitative and quantitative conditions of dose and timing for these treatments which allow them to potentiate either immunity or tolerance. Our results provide reasonable explanations for the existent pre-clinical and clinical data, predict some novel treatments, and further provide interesting practical guidelines to optimize the future application of these types of treatments. PMID:24376444

  6. Autocrine Complement Inhibits IL10-Dependent T-Cell Mediated Antitumor Immunity to Promote Tumor Progression

    PubMed Central

    Wang, Yu; Sun, Sheng-Nan; Liu, Qing; Yu, Yang-Yang; Guo, Jian; Wang, Kun; Xing, Bao-Cai; Zheng, Qing-Feng; Campa, Michael J.; Patz, Edward F.; Li, Shi-You; He, You-Wen

    2016-01-01

    In contrast to its inhibitory effects on many cells, IL-10 activates CD8+ tumor infiltrating lymphocytes (TILs) and enhances their antitumor activity. However, CD8+ TILs do not routinely express IL-10 as autocrine complement C3 inhibits IL-10 production through complement receptors C3aR and C5aR. CD8+ TILs from C3-deficient mice, however, express IL-10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T cell- and IL-10-dependent manner; human TILs expanded with IL-2 plus IL-10 increase the killing of primary tumors in vitro compared to IL-2 treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the PD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL-10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. PMID:27297552

  7. IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis

    PubMed Central

    Unsinger, Jacqueline; McGlynn, Margaret; Kasten, Kevin R.; Hoekzema, Andrew S.; Watanabe, Eizo; Muenzer, Jared T.; McDonough, Jacquelyn S.; Tschoep, Johannes; Ferguson, Thomas A.; McDunn, Jonathan E.; Morre, Michel; Hildeman, David A.; Caldwell, Charles C.; Hotchkiss, Richard S.

    2010-01-01

    Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-γ production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-γ– and T cell-dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis-induced PUMA, a heretofore unreported effect of IL-7. If additional animal studies support its efficacy in sepsis and if current clinical trials continue to confirm its safety in diverse settings, rhIL-7 should be strongly considered for clinical trials in sepsis. PMID:20200277

  8. Association of -31T>C and -511 C>T polymorphisms in the interleukin 1 beta (IL1B) promoter in Korean keratoconus patients.

    PubMed

    Kim, So-Hee; Mok, Jee-Won; Kim, Hyun-Seok; Joo, C K

    2008-01-01

    To investigate the genetic association between unrelated Korean keratoconus patients and interleukin 1 alpha (IL1A), interleukin 1 beta (IL1B), and IL1 receptor antagonist (IL1RN) gene polymorphisms. We investigated the association between IL1A (rs1800587, rs2071376, and rs17561), IL1B (rs1143627, rs16944, rs1143634, and rs1143633), and IL1RN (rs419598, rs423904, rs424078, and rs315952, variable number tandem repeat [VNTR]) polymorphisms in 100 unrelated Korean keratoconus patients. One hundred control individuals without any corneal disease were selected from the general population. Polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) analysis and direct sequencing were used to screen for genetic variations in the IL1 gene cluster. Haplotypes for the IL1 gene cluster were constructed using Haploview version 4.0. We analyzed a total of 12 polymorphic sites in the IL1 gene cluster. Among them, the -511 (rs16944) and -31 (rs1143627) positions in the promoter region of IL1B were significantly different between patient and control groups. The C allele of rs16944 (-511C>T, p=0.022, odds ratio of risk [OR]=1.46, 95% confidence intervals [CI] 0.94<2.27) and the T allele of rs1143627 (-31T>C, p=0.025, OR=1.43, 95% CI 0.92<2.22) were associated with a significantly increased risk of keratoconus in Korean patients. Linkage of the two alleles, -31*C and -511*T, was associated with an increased risk for keratoconus with OR=2.38 (p=0.012, 95% CI=1.116-5.046). The *C/*A genotype of rs2071376 in IL1A intron 6 was significantly different between the keratoconus patients and control subjects (p=0.034, OR=0.59, 95% CI 0.32<1.11). Other polymorphisms did not show an association with keratoconus risk. This is the first report of IL1 gene cluster mutation screening in Korean keratoconus patients. Significant differences in allelic frequency of IL1B between keratoconus patients and the control group suggest that IL1B polymorphisms may play a role in the

  9. Colloquy to Paul Musset

    ScienceCinema

    None

    2017-12-09

    En honneur de Paul Musset il a été décidé de faire plutôt un colloque scientifique à la place d'une cérémonie. Plusieurs personnes temoignent de leurs estime et amitié pour ce physicien et ses activités

  10. IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro.

    PubMed

    Alves, Nuno L; Hooibrink, Berend; Arosa, Fernando A; van Lier, René A W

    2003-10-01

    Recent studies in mice have shown that although interleukin 15 (IL-15) plays an important role in regulating homeostasis of memory CD8+ T cells, it has no apparent function in controlling homeostatic proliferation of naive T cells. We here assessed the influence of IL-15 on antigen-independent expansion and differentiation of human CD8+ T cells. Both naive and primed human T cells divided in response to IL-15. In this process, naive CD8+ T cells successively down-regulated CD45RA and CD28 but maintained CD27 expression. Concomitant with these phenotypic changes, naive cells acquired the ability to produce interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), expressed perforin and granzyme B, and acquired cytotoxic properties. Primed CD8+ T cells, from both noncytotoxic (CD45RA-CD27+) and cytotoxic (CD45RA+CD27-) subsets, responded to IL-15 and yielded ample numbers of cytokine-secreting and cytotoxic effector cells. In summary, all human CD8+ T-cell subsets had the ability to respond to IL-15, which suggests a generic influence of this cytokine on CD8+ T-cell homeostasis in man.

  11. Nécrolyse épidermique liée à l'application cutanée d'une solution d'hydroxyde de potassium

    PubMed Central

    Korsaga-Somé, Nina; Tapsoba, Patrice; Ouédraogo, Muriel Sidnoma; Ilboudo, Léopold Baowendsom; Barro-Traoré, Fatou; Niamba, Pascal; Traoré, Adama

    2015-01-01

    Dans nos régions, une solution d'hydroxyde de potassium est régulièrement utilisée en application sur la peau comme traitement traditionnel dans le but de traiter un prurit ou une éruption cutanée. Dans notre pratique quotidienne, nous observons de plus en plus de réactions cutanées à ce type de traitement. Nous rapportons un cas de nécrolyse épidermique généralisée suite à l'application d'une solution concentrée d'hydroxyde de potassium. Il s'agissait d'une patiente de 51 ans, séropositive au VIH2, et au virus de l'hépatite virale C, mais non éligible au traitement antirétroviral. Elle était hospitalisée pour des décollements épidermiques nécrolytiques quasi-généralisés survenue le lendemain de l'application une solution de concentré de potasse sur tout le tégument. Cette solution avait été appliquée dans le but de traiter une éruption micropapuleuse prurigineuse généralisée (exanthème maculo-papuleux) survenue suite à a prise de cotrimoxazole. La réépidermisation était totale sans séquelle après un mois de suivi. Le diagnostic nécrolyse épidermique toxique ou syndrome de Lyell qui met souvent en jeu le pronostic vital avait été écarté devant la conservation de l'état général, l'absence d'atteinte muqueuse et la rapide cicatrisation. Certains traitements traditionnels ont fait la preuve au cours du temps de leur efficacité, mais un mésusage peut être à l'origine d'effets secondaires graves. PMID:26587148

  12. IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis

    PubMed Central

    Grabie, Nir; Delfs, Michael W.; Westrich, Jason R.; Love, Victoria A.; Stavrakis, George; Ahmad, Ferhaan; Seidman, Christine E.; Seidman, Jonathan G.; Lichtman, Andrew H.

    2003-01-01

    Cardiac antigen–specific CD8+ T cells are involved in the autoimmune component of human myocarditis. Here, we studied the differentiation and migration of pathogenic CD8+ T cell effector cells in a new mouse model of autoimmune myocarditis. A transgenic mouse line was derived that expresses cardiac myocyte restricted membrane-bound ovalbumin (CMy-mOva). The endogenous adaptive immune system of CMy-mOva mice displays tolerance to ovalbumin. Adoptive transfer of naive CD8+ T cells from the ovalbumin-specific T cell receptor–transgenic (TCR-transgenic) OT-I strain induces myocarditis in CMy-mOva mice only after subsequent inoculation with ovalbumin-expressing vesicular stomatitis virus (VSV-Ova). OT-I effector T cells derived in vitro in the presence or absence of IL-12 were adoptively transferred into CMy-mOva mice, and the consequences were compared. Although IL-12 was not required for the generation of cytolytic and IFN-γ–producing effector T cells, only effectors primed in the presence of IL-12 infiltrated CMy-mOva hearts in significant numbers, causing lethal myocarditis. Furthermore, analysis of OT-I effectors collected from a mediastinal draining lymph node indicated that only effectors primed in vitro in the presence of IL-12 proliferated in vivo. These data demonstrate the importance of IL-12 in the differentiation of pathogenic CD8+ T cells that can cause myocarditis. PMID:12618521

  13. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells

    PubMed Central

    Ben-Sasson, Shlomo Z.; Hogg, Alison; Hu-Li, Jane; Wingfield, Paul; Chen, Xi; Crank, Michelle; Caucheteux, Stephane; Ratner-Hurevich, Maya; Berzofsky, Jay A.; Nir-Paz, Ran

    2013-01-01

    Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory. PMID:23460726

  14. IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates

    PubMed Central

    Picker, Louis J.; Reed-Inderbitzin, Edward F.; Hagen, Shoko I.; Edgar, John B.; Hansen, Scott G.; Legasse, Alfred; Planer, Shannon; Piatak, Michael; Lifson, Jeffrey D.; Maino, Vernon C.; Axthelm, Michael K.; Villinger, Francois

    2006-01-01

    HIV infection selectively targets CD4+ effector memory T (TEM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the TEM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ TEM cells with little effect on the naive or central memory T (TCM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. TEM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2′-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ TEM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4+ T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets. PMID:16691294

  15. IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8⁺ T cell avidity following HIV-1 recombinant pox viral vaccination.

    PubMed

    Wijesundara, Danushka K; Jackson, Ronald J; Tscharke, David C; Ranasinghe, Charani

    2013-09-23

    We have shown that mucosal HIV-1 recombinant pox viral vaccination can induce high, avidity HIV-specific CD8(+) T cells with reduced interleukin (IL)-4 and IL-13 expression compared to, systemic vaccine delivery. In the current study how these cytokines act to regulate anti-viral CD8(+) T, cell avidity following HIV-1 recombinant pox viral prime-boost vaccination was investigated. Out of a panel of T cell avidity markers tested, only CD8 expression levels were found to be enhanced on, KdGag197-205 (HIV)-specific CD8(+) T cells obtained from IL-13(-/-), IL-4(-/-) and signal transducer and, activator of transcription of 6 (STAT6)(-/-) mice compared to wild-type (WT) controls following, vaccination. Elevated CD8 expression levels in this instance also correlated with polyfunctionality, (interferon (IFN)-γ, tumour necorsis factor (TNF)-α and IL-2 production) and the avidity of HIVspecific CD8(+) T cells. Furthermore, mucosal vaccination and vaccination with the novel adjuvanted IL-13 inhibitor (i.e. IL-13Rα2) vaccines significantly enhanced CD8 expression levels on HIV-specific CD8(+), T cells, which correlated with avidity. Using anti-CD8 antibodies that blocked CD8 availability on CD8(+), T cells, it was established that CD8 played an important role in increasing HIV-specific CD8(+) T cell avidity and polyfunctionality in IL-4(-/-), IL-13(-/-) and STAT6(-/-) mice compared to WT controls, following vaccination. Collectively, our data demonstrate that IL-4 and IL-13 dampen CD8 expression levels on anti-viral CD8(+) T cells, which can down-regulate anti-viral CD8(+) T cell avidity and, polyfunctionality following HIV-1 recombinant pox viral vaccination. These findings can be exploited to, design more efficacious vaccines not only against HIV-1, but many chronic infections where high, avidity CD8(+) T cells help protection. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Decrease of interleukin (IL)17A gene expression in leucocytes and in the amount of IL-17A protein in CD4+ T cells in children with Down Syndrome.

    PubMed

    Jakubiuk-Tomaszuk, Anna; Sobaniec, Wojciech; Rusak, Małgorzata; Poskrobko, Elżbieta; Nędzi, Agata; Olchowik, Beata; Galicka, Anna

    2015-12-01

    Down Syndrome is by far the most common and best known chromosomal disorder in humans. It expresses multiple systemic complications with both structural and functional defects as part of the clinical manifestation. The mechanisms of immune changes occurring in Down Syndrome are complex and include an extra gene copy of chromosome 21 and secondary dysregulation of numerous intercellular interactions. Recent studies suggest a role of interleukin 17A (IL-17A), a pro-inflammatory cytokine located on 6p12 chromosome, in the pathogenesis of inflammatory and autoimmune diseases. We aimed to analyze IL17A gene expression in peripheral white cells and IL-17A intracellular expression on CD4+ T-cells. The research was carried out on a group of 58 children aged 6-12 years including a group of 30 children with Down Syndrome (simple trisomy of chromosome 21 only) and a reference group of 28 healthy children. We evaluated gene IL17A expression using real-time PCR and intracellular IL-17A analyzed by flow cytometry. We found significantly decreased gene expression in white cells and significantly decreased expression of IL-17A levels on CD4+ T-cells in Down Syndrome. Our data indicate that decreased IL-17A expression may play a significant role in the etiology of infections in Down Syndrome. Moreover, we demonstrated that in Down Syndrome the other gene located outside the extra chromosome 21 is also affected. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  17. Effect of bacterial endotoxin LPS on expression of INF-gamma and IL-5 in T-lymphocytes from asthmatics.

    PubMed

    Koch, Andrea; Knobloch, Jürgen; Dammhayn, Cathrin; Raidl, Maria; Ruppert, Andrea; Hag, Haitham; Rottlaender, Dennis; Müller, Katja; Erdmann, Erland

    2007-11-01

    Epidemiological evidence, in vitro studies and animal models suggest that exposure to the bacterial endotoxin lipopolysaccharide (LPS) can influence the development and severity of asthma. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 and 2 responses, it is unclear whether the LPS ligand TLR 4 is expressed on CD4(+) and CD8(+) T-lymphocytes and if so, whether LPS could modulate the T(H)1 or T(H)2 response in this context. The present authors have, therefore, examined the expression of TLR 4 on peripheral blood CD4(+) and CD8(+) T-lymphocytes using RT-PCR method and FACS analyses. Furthermore, the authors have studied the IL-12-induced expression of the T(H)1-associated cytokine INF-gamma and the IL-4-induced expression of the T(H)2-specific cytokine IL-5 in the presence of LPS using ELISA and compared nine atopic asthmatic subjects and eleven nonatopic normal volunteers. There was an increased anti-CD3/anti-CD28-induced IL-5 expression in T cells of asthmatics compared with normals (p<0.01). In the presence of IL-4 (10 ng/ml), there was an additional increase in IL-5 expression and this additional increase was greater in T cells of normals compared with asthmatics (p<0.05). There was an expression of INF-gamma in anti-CD3/anti-CD28-induced T-lymphocytes without differences between both groups (NS). In the presence of IL-12 (10 ng/ml), there was an increase in INF-gamma release without differences between normals and asthmatics (NS). In the presence of different concentrations of LPS (10 ng/ml, 1 mug/ml), there was a decrease in IL-4-induced IL-5 expression without differences in both groups, indicating an intact T(H)2 response to bacterial endotoxin LPS in asthma. Interestingly, LPS increased the IL-12-induced INF-gamma release in a concentration-dependent manner in T-lymphocytes of normals but this could not be found in T cells of asthmatics, indicating an impaired T(H)1 response to bacterial

  18. [Association of IL-1β-511T gene rs16944 polymorphism with febrile seizures].

    PubMed

    Ren, Xiao-Tun; Sun, Su-Zhen; Liu, Fang; Wang, Xiao-Ming

    2014-02-01

    Despite substantial research efforts worldwide, the role of inflammatory cytokine IL-1β in the onset of febrile seizures (FS) remains controversial. The aim of this study was to assess the relationship between rs16944 polymorphism of the IL-1β-511T gene and occurrence of simple FS in a sample of Han children in northern China. The IL-1β-511T gene rs16944 was genotyped by SNaPshot SNP technique in 141 FS children and 130 healthy control subjects. The genotypic and allelic frequencies in the two groups were comparatively analyzed. There were no significant differences in genotypic and allelic frequencies of rs16944 polymorphism of the IL-1β-511T gene between FS patients and control subjects (P>0.05).When the clinical data on A/A, A/G and G/G genotypes of the rs16944 polymorphism in FS patients, there was statistically significant difference in age of first onset (χ(2)=19.491, P<0.01), temperature of first onset (χ(2)=9.317, P<0.05) and family history of FS (χ(2)=26.798, P<0.01). There is no association between rs16944 polymorphism of the IL-1β-511T gene and the incidence of FS in Han children in Northern China. However, the differences in genotypes of this polymorphism might be associated with pathogenesis and prognosis of simple FS in the population studied.

  19. Intracellular IL-4, IL-5, and IFN-γ as the main characteristic of CD4+CD30+ T cells after allergen stimulation in patients with vernal keratoconjunctivitis

    PubMed Central

    Magaña, Diana; Aguilar, Gustavo; Linares, Marisela; Ayala-Balboa, Julio; Santacruz, Concepción; Chávez, Raúl; Estrada-Parra, Sergio; Garfias, Yonathan; Lascurain, Ricardo; Jiménez-Martínez, Maria C.

    2015-01-01

    Background Vernal keratoconjunctivitis (VKC) is a severe form of allergic conjunctivitis, in which inflammatory infiltrates of the conjunctiva are characterized by CD3+ and CD30+ cells. Until today, the functional involvement of CD30+ T cells in VKC was unclear. Our aim was to evaluate the functional characteristics of CD30+ T cells after allergen stimulation in peripheral blood mononuclear cells obtained from patients with VKC. Methods Seventeen consecutive patients at the Institute of Ophthalmology with active forms of VKC were included. Results After allergen stimulation, we observed the frequency of CD30+ T cells increased compared with non-stimulated cells (p<0.0001). The CD30+ T cells responded to the specific allergen-inducing expression of intracellular interleukin-4 (IL-4), IL-5, and interferon-gamma (IFN-γ) compared with the CD30- T cells (p<0.0001). Increased early secretion of soluble CD30 was observed in the supernatant of the cultured cells from patients with keratoconjunctivitis, compared with healthy controls (p=0.03). Blockage with IL-4 significantly diminished CD30 frequency in the allergen-stimulated cells. Conclusions Our results suggest that after allergenic stimulation, CD4+CD30+ cells are the most important source of IL-4, IL-5, and IFN-γ. IL-4 acts as an activation loop that increases CD30 expression on T cells after specific stimulation. These findings suggest that CD4+CD30+ T cells are effector cells and play a significant role in the immune pathogenic response in patients with vernal keratoconjunctivitis. PMID:25999672

  20. IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis.

    PubMed

    Engelbertsen, Daniel; Rattik, Sara; Wigren, Maria; Vallejo, Jenifer; Marinkovic, Goran; Schiopu, Alexandru; Björkbacka, Harry; Nilsson, Jan; Bengtsson, Eva

    2018-01-01

    The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis. We transferred apoe-/-myd88+/+ or apoe-/-myd88-/- CD4+ T cells to T- and B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88+/+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-γ. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells. We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

  1. p19-targeted ABD-derived protein variants inhibit IL-23 binding and exert suppressive control over IL-23-stimulated expansion of primary human IL-17+ T-cells.

    PubMed

    Křížová, Lucie; Kuchař, Milan; Petroková, Hana; Osička, Radim; Hlavničková, Marie; Pelák, Ondřej; Černý, Jiří; Kalina, Tomáš; Malý, Petr

    2017-03-01

    Interleukin-23 (IL-23), a heterodimeric cytokine of covalently bound p19 and p40 proteins, has recently been closely associated with development of several chronic autoimmune diseases such as psoriasis, psoriatic arthritis or inflammatory bowel disease. Released by activated dendritic cells, IL-23 interacts with IL-23 receptor (IL-23R) on Th17 cells, thus promoting intracellular signaling, a pivotal step in Th17-driven pro-inflammatory axis. Here, we aimed to block the binding of IL-23 cytokine to its cell-surface receptor by novel inhibitory protein binders targeted to the p19 subunit of human IL-23. To this goal, we used a combinatorial library derived from a scaffold of albumin-binding domain (ABD) of streptococcal protein G, and ribosome display selection, to yield a collection of ABD-derived p19-targeted variants, called ILP binders. From 214 clones analyzed by ELISA, Western blot and DNA sequencing, 53 provided 35 different sequence variants that were further characterized. Using in silico docking in combination with cell-surface competition binding assay, we identified a group of inhibitory candidates that substantially diminished binding of recombinant p19 to the IL-23R on human monocytic THP-1 cells. Of these best p19-blockers, ILP030, ILP317 and ILP323 inhibited IL-23-driven expansion of IL-17-producing primary human CD4 +  T-cells. Thus, these novel binders represent unique IL-23-targeted probes useful for IL-23/IL-23R epitope mapping studies and could be used for designing novel p19/IL-23-targeted anti-inflammatory biologics.

  2. IL-12 Influence mTOR to Modulate CD8+ T Cells Differentiation through T-bet and Eomesodermin in Response to Invasive Pulmonary Aspergillosis.

    PubMed

    Wang, Hao; Li, Jingdong; Han, Qiyang; Yang, Fei; Xiao, Yu; Xiao, Meng; Xu, Yingchun; Su, Longxiang; Cui, Na; Liu, Dawei

    2017-01-01

    Objective: To investigate whether mTOR signaling pathway regulate the proliferation and differentiation of CD8 + T cells by transcription factors T-bet and Eomes, and explore the role of IL-12 in this biological procedure. Methods: Aspergillus fumigatus spore suspension nasal inhalation was used to establish the invasive pulmonary aspergillosis (IPA) mouse model. After inoculation, rapamycin (2mg/kg) each day or IL-12 (5ug/kg) every other day was given for 7 days. The blood samples were obtained before the mice sacrificed and lung specimens were taken. Pathological sections were stained with hematoxylin and eosin (HE). The number of CD8 + effective memory T cells (Tem) and the expression of IFN-γ, mTOR, ribosomal protein S6 kinase (S6K), T-bet and EOMES were measured by flow cytometry. The levels of IL-6, IL-10 and Galactomannan (GM) were determined by ELISA. Results: After IL-12 treatment, the number of CD8 + Tem and the expression of IFN-γ increased significantly; while quite the opposite results were observed when the mTOR pathway was blocked by rapamycin. The expression of mTOR and S6K as well as the level of IFN-γ of the IL-12 treatment group were significantly higher than those in IPA and IPA + rapamycin groups. In addition, IL-12 promoted increasing T-bet and down regulating Eomes to make the Tem transformation. The final immune effector was high level of inflammatory cytokines (IL-6) and low level of anti-inflammatory factors (IL-10) and this strengthened immune response to the Aspergillus infection. Conclusions: The biological effects of Tem could significantly affect IPA infection host immune regulation, which depended on the activation of mTOR signaling pathway by IL-12.

  3. Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer.

    PubMed

    Song, Yang; Yang, Jian Ming

    2017-11-04

    Interleukin-17 (IL-17), a pleiotropic proinflammatory cytokine, is reported to be significantly generated by a distinct subset of CD4 + T-cells, upgrading cancer-elicited inflammation and preventing cancer cells from immune surveillance. T-helper (Th)17 cells produced from naive CD4 + T cells have recently been renowned and generally accepted, gaining eminence in cancer studies and playing the effective role in context of cancer. Th17 cells are the main source of IL-17-secreting cells, It was found that other cell types produced this cytokine as well, including Group 3 innate lymphoid cells (ILC3), δγT cells, invariant natural killer T (iNKT) cells, lymphoid-tissue inducer (LTi)-like cells and Natural killer (NK) cells. Th17-associated cytokines give impetus to tumor progression, or inducing angiogenesis and metastasis. This review demonstrates an understanding on how the pro- or antitumor function of Th17 cells and IL-17 may change cancer progression, leading to the appearance of complex and pivotal biologic activities in tumor. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Approche aux soins en milieu communautaire à des adultes ayant une déficience développementale

    PubMed Central

    Osmun, W.E.; Chan, Nelson; Solomon, Robert

    2015-01-01

    Résumé Objectif Passer en revue les obligations d’ordre médical, éthique et juridique dans les soins aux adultes ayant une déficience développementale (DD) qui vivent dans la communauté. Sources des données Des recherches ont été faites dans Google et MEDLINE à l’aide des mots disabled, disability, vulnerable et community. Les lois pertinentes ont fait l’objet d’un examen. Message principal Le traitement d’un patient ayant une DD varie en fonction de facteurs comme la pathogenèse du problème actuel du patient, ses affections concomitantes, la gravité de ses déficiences et ses soutiens sociaux habituels. Bien que l’on s’entende sur les bienfaits du transfert des soins institutionnels vers des soins communautaires pour les patients ayant une DD, il s’est révélé difficile de leur dispenser des soins de grande qualité en milieu communautaire. Par ailleurs, il existe peu de travaux de recherche sur les façons d’offrir efficacement des soins aux adultes ayant une DD. En tant que professionnels des soins primaires, les médecins de famille sont souvent le premier point de contact pour les patients et sont à la fois responsables de la coordination et de la continuité des soins. Compte tenu de l’importance accrue accordée aux soins préventifs et à la détection précoce des maladies, la participation active du patient revêt aussi une grande importance. Les valeurs et les objectifs du patient sont des éléments essentiels à prendre en compte, même s’ils vont à l’encontre de la bonne santé du patient ou des propres valeurs du clinicien. Les lois s’appliquant aux personnes vulnérables varient d’une province à l’autre. Par conséquent, l’obligation de signaler des mauvais traitements suspectés pourrait différer selon que la personne vulnérable habite dans un centre de soins ou la communauté, que la personne qui soupçonne le comportement abusif est un fournisseur de services ou un professionnel de la santé ou

  5. Trajet de soins des personnes âgées à Bobo-Dioulasso, au Burkina Faso: une enquête transversale

    PubMed Central

    Hien, Hervé; Berthé, Abdramane; Konaté, Blahima; Drabo, Maxime koiné; Tou, Fatoumata; Somda, Désiré; Badini-Kinda, Fatoumata; Macq, Jean

    2015-01-01

    Introduction En Afrique, il y n'a pas encore une maitrise du trajet de soins des personnes âgées pour construire des modèles de soins adaptés afin d'améliorer leur prise en charge. L'objectif de cette étude était de décrire le trajet de soins des personnes âgées à Bobo-Dioulasso. Méthodes Nous avons réalisé une étude transversale à prédominance qualitative avec des personnes âgées vivant dans les ménages dans la ville de Bobo-Dioulasso de septembre à novembre 2012. Nous avons sélectionné 30 personnes âgées de manière raisonnée dans 22 secteurs. Des entretiens qualitatifs ont été réalisés. Le recours aux soins formels, informels et mixtes a été analysé. Résultats Le trajet de soins des personnes âgées à Bobo-Dioulasso était à prédominance mixte: elles utilisaient à la fois pour le même épisode de maladie les services publics et privés l'automédication à domicile, la médecine traditionnelle, l'utilisation des médicaments du marche informel de la rue. Les premiers recours aux soins étaient à l'initiative des personnes âgées elles-mêmes. Les recours aux soins formels étaient largement utilisés par les personnes âgées qui avaient un revenu de pension. Conclusion Devant la complexité de la prise en charge des personnes âgées présentant plusieurs pathologies et ayant différents recours des soins il y a une nécessité d'orienter le système d'offre de soins vers une coordination dite « collective ». PMID:26097632

  6. Une version canadienne française du Lower Extremity Functional Scale (LEFS) : L'Échelle fonctionnelle des membres inférieurs (ÉFMI), partie I

    PubMed Central

    René, Frédéric; Casimiro, Lynn; Tremblay, Manon; Lefebvre, Annabelle; Beaudouin, Martine; Belliveau, Véronik; Bergeron, Louis-Philippe

    2011-01-01

    RÉSUMÉ Introduction : Le Rehabilitation Network of Ottawa-Carleton (RENOC) recommande à ses établissements de santé d'utiliser le Lower Extremity Functional Scale (LEFS). Puisque le RENOC dessert une clientèle anglophone et francophone, il s'imposait de traduire le LEFS pour l'évaluation de la clientèle francophone. But : Produire une traduction canadienne-française du LEFS sous l'appellation proposée « Échelle fonctionnelle des membres inférieurs (ÉFMI) » et examiner la validité de son contenu. Méthodologie : Nous avons utilisé une approche modifiée de la méthodologie de validation transculturelle de questionnaires de Vallerand (1989). Une traduction renversée parallèle du LEFS a d'abord été complétée. Ensuite, un comité d'experts a examiné les deux versions préliminaires et a créé la première version expérimentale de l'ÉFMI. Cette version fut évaluée par un deuxième comité d'experts, dont les commentaires menèrent à une deuxième version expérimentale. Finalement, 35 professionnels de la réadaptation évaluèrent la version expérimentale de l'ÉFMI sur une échelle d'ambiguïté et proposèrent les modifications finales. Résultats : Pour les différents énoncés de la version finale de l'ÉFMI, les moyennes sur l'échelle d'ambiguïté démontrent un niveau d'ambiguïté relativement faible puisqu'elles varient entre 1 et 2.54. Conclusion : Les quatre étapes rigoureuses du processus ont permis de produire une version valide du LEFS en français. PMID:22379265

  7. Décision d'amputation dans la prise en charge initiale d'une luxation ouverte grave de la cheville à propos d'un cas observé à l'Hôpital Laquintinie de Douala suite à un accident par moto-taxi

    PubMed Central

    Tsatedem, Faustin Atemkeng; Tsiagadigui, Jean Gustave; Ndando, Richard Polle; Arabo, Mohamadou Saidou; Bayiha, Alphonse; Kenfack, Bruno

    2012-01-01

    La décision d'amputation pour traumatisme grave de membre n'est pas toujours facile à prendre. Les auteurs rapportent le cas d'un traumatisme ouvert de la cheville gauche avec luxation tibiotalienne complète, référé pour amputation. Il s'agit d'une passagère d'une moto-taxi percutée par une voiture. A l'admission, le pouls tibial postérieur était présent et le score dit MESS (Mangled Extremity Severity Score) côté à 5, ce qui a permis et d'éviter l'amputation. Après débridement et réduction, une broche transplantaire a permis d'immobiliser la cheville et de faire les pansements. L'amputation a été évitée. La cicatrisation dirigée de la peau a été suivie par la kinésithérapie. La mobilité de la cheville autorise une marche avec cannes au quatrième mois post-opératoire. Les auteurs recommandent l'utilisation du MESS dans la décision d'amputation après traumatisme grave de membre. PMID:23396997

  8. A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy.

    PubMed

    Alvarez-Fernández, C; Escribà-Garcia, L; Vidal, S; Sierra, J; Briones, J

    2016-07-19

    Immunotherapy based on the adoptive transfer of gene modified T cells is an emerging approach for the induction of tumor-specific immune responses. Memory stem T cells, due to their enhanced antitumor and self-renewal capacity, have become potential candidate for adoptive T cell therapy of cancer. Methods to generate memory stem T cells ex vivo rely on CD3/CD28 costimulation and the use of cytokines such as IL-7 and IL-15 during the entire culture period. However, a strong costimulation may induce differentiation of memory stem T cells to effector memory T cells. Here we show that manipulation of the length of the costimulation and addition of IL-21 enhance the ex vivo expansion of memory stem T cells. Purified naïve T cells from healthy donors were cultured in the presence of anti-CD3/CD28 coated beads, IL-7, IL-15 and/or IL-21 (25 ng/ml). T cells phenotype from the different memory and effector subpopulations were analyzed by multiparametric flow cytometry. A short anti-CD3/CD28 costimulation of naïve T cells, combined with IL-7 and IL-15 significantly increased the frequencies of CD4(+) and CD8(+) memory stem T cells ex vivo, compared to a prolonged costimulation (34.6 ± 4.4 % vs 15.6 ± 4.24 % in CD4(+); p = 0.008, and 20.5 ± 4.00 % vs 7.7 ± 2.53 % in CD8(+); p = 0.02). Moreover, the addition of IL-21 to this condition further enhanced the enrichment and expansion of CD4(+) and CD8(+) memory stem T cells with an increase in the absolute numbers (0.7 × 10(6) ± 0.1 vs 0.26 × 10(6) ± 0.1 cells for CD4(+); p = 0.002 and 1.1 × 10(6) ± 0.1 vs 0.27 × 10(6) ± 0.1 cells for CD8(+); p = 0.0002; short + IL-21 vs long). These new in vitro conditions increase the frequencies and expansion of memory stem T cells and may have relevant clinical implications for the generation of this memory T cell subset for adoptive cell therapy of patients with cancer.

  9. Elevated Plasma Levels of sIL-2R in Complex Regional Pain Syndrome: A Pathogenic Role for T-Lymphocytes?

    PubMed Central

    Stronks, Dirk L.; Dik, Willem A.; Schreurs, Marco W. J.

    2017-01-01

    The immune system has long been thought to be involved in the pathophysiology of complex regional pain syndrome (CRPS). However, not much is known about the role of the immune system and specifically T-cells in the onset and maintenance of this disease. In this study, we aimed to evaluate T-cell activity in CRPS by comparing blood soluble interleukin-2 receptor (sIL-2R) levels between CRPS patients and healthy controls. CRPS patients had statistically significant elevated levels of sIL-2R as compared to healthy controls (median sIL-2R levels: 4151 pg/ml (Q3 − Q1 = 5731 pg/ml − 3546 pg/ml) versus 1907 pg/ml (Q3 − Q1: 2206 pg/ml − 1374 pg/ml), p < 0.001, resp.). Furthermore, sIL-2R level seems to be a good discriminator between CRPS patients and healthy controls with a high sensitivity (90%) and specificity (89.5%). Our finding indicates increased T-cell activity in patients with CRPS. This finding is of considerable relevance as it could point towards a T-cell-mediated inflammatory process in this disease. This could pave the way for new anti-inflammatory therapies in the treatment of CRPS. Furthermore, sIL-2R could be a promising new marker for determining inflammatory disease activity in CRPS. PMID:28634419

  10. Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma

    PubMed Central

    Krenciute, Giedre; Krebs, Simone; Torres, David; Wu, Meng-Fen; Liu, Hao; Dotti, Gianpietro; Li, Xiao-Nan; Lesniak, Maciej S; Balyasnikova, Irina V; Gottschalk, Stephen

    2016-01-01

    Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies. PMID:26514825

  11. L’évaluation et la prise en charge des enfants et des adolescents victimes d’une commotion liée à un sport

    PubMed Central

    Purcell, Laura K

    2012-01-01

    RÉSUMÉ Les commotions sont des blessures sportives fréquentes, et elles sont particulièrement courantes chez les enfants et les adolescents qui participent à des sports organisés ou à des activités récréatives. Les symptômes de commotion peuvent être subtils et négligés par les athlètes, les entraîneurs et les parents. Un enfant ou un adolescent qui est victime d’une commotion devrait être immédiatement retiré du jeu et être évalué par un médecin dans les plus brefs délais. Il devrait éviter les activités physiques et cognitives pour se remettre de la commotion. Une fois les symptômes complètement résorbés au repos, l’athlète peut suivre un protocole d’effort graduel, supervisé par un médecin, avant d’obtenir l’autorisation médicale de retourner au jeu. Il est essentiel que tous ceux qui participent aux activités sportives pour les enfants et les adolescents connaissent les signes et symptômes de commotion afin qu’on puisse poser un diagnostic exact et rapide et amorcer une évaluation et une prise en charge convenables. Le présent document de principes remplace celui qui a été publié en 2006.

  12. Quantitative imaging by pixel-based contrast-enhanced ultrasound reveals a linear relationship between synovial vascular perfusion and the recruitment of pathogenic IL-17A-F+IL-23+ CD161+ CD4+ T helper cells in psoriatic arthritis joints.

    PubMed

    Fiocco, Ugo; Stramare, Roberto; Martini, Veronica; Coran, Alessandro; Caso, Francesco; Costa, Luisa; Felicetti, Mara; Rizzo, Gaia; Tonietto, Matteo; Scanu, Anna; Oliviero, Francesca; Raffeiner, Bernd; Vezzù, Maristella; Lunardi, Francesca; Scarpa, Raffaele; Sacerdoti, David; Rubaltelli, Leopoldo; Punzi, Leonardo; Doria, Andrea; Grisan, Enrico

    2017-02-01

    To develop quantitative imaging biomarkers of synovial tissue perfusion by pixel-based contrast-enhanced ultrasound (CEUS), we studied the relationship between CEUS synovial vascular perfusion and the frequencies of pathogenic T helper (Th)-17 cells in psoriatic arthritis (PsA) joints. Eight consecutive patients with PsA were enrolled in this study. Gray scale CEUS evaluation was performed on the same joint immediately after joint aspiration, by automatic assessment perfusion data, using a new quantification approach of pixel-based analysis and the gamma-variate model. The set of perfusional parameters considered by the time intensity curve includes the maximum value (peak) of the signal intensity curve, the blood volume index or area under the curve, (BVI, AUC) and the contrast mean transit time (MTT). The direct ex vivo analysis of the frequencies of SF IL17A-F + CD161 + IL23 + CD4 + T cells subsets were quantified by fluorescence-activated cell sorter (FACS). In cross-sectional analyses, when tested for multiple comparison setting, a false discovery rate at 10%, a common pattern of correlations between CEUS Peak, AUC (BVI) and MTT parameters with the IL17A-F + IL23 + - IL17A-F + CD161 + - and IL17A-F + CD161 + IL23 + CD4 + T cells subsets, as well as lack of correlation between both peak and AUC values and both CD4 + T and CD4 + IL23 + T cells, was observed. The pixel-based CEUS assessment is a truly measure synovial inflammation, as a useful tool to develop quantitative imaging biomarker for monitoring target therapeutics in PsA.

  13. IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion.

    PubMed

    Correia, Margareta P; Costa, Alexandra V; Uhrberg, Markus; Cardoso, Elsa M; Arosa, Fernando A

    2011-05-01

    During the last years several authors have described a small population of CD8+ T cells expressing NK receptors (NKRs). Although their origin remains largely unknown, we have recently demonstrated that IL-15 is capable of inducing NKR expression in purified human CD8+CD56- T cells. In this study we show that IL-15-driven NKR induction in CD8+ T cells was linked with CD56 de novo acquisition, consistent with an effector-memory phenotype, increased anti-apoptotic levels, high granzyme B/perforin expression and with the ability of displaying in vitro NK-like cytotoxicity. Interestingly, dissection of NKR functional outcome in IL-15-cultured CD8+ T cells revealed: (i) that NKG2D cross-linking was able per se to upregulate degranulation levels and (ii) that KIR and NKG2A cross-linking upregulated secretion of cytokines such as IFN-γ, TNF-α, IL-1β and IL-10. These results suggest that IL-15 is capable of differentiating CD8+ T cells into NK-like T cells displaying a regulatory phenotype. Copyright © 2010 Elsevier GmbH. All rights reserved.

  14. Maladie de Takayasu et polyarthrite rhumatoïde: une association rare - à propos d'une observation

    PubMed Central

    Frikha, Faten; Maazoun, Fatma; Snoussi, Mouna; Abid, Leila; Abid, Hanen; Bouassida, Walid; Kaddour, Neila; Bahloul, Zouhir

    2012-01-01

    L'artérite de Takayasu ou maladie de Takayasu (MT) et la polyarthrite rhumatoïde (PR) et sont deux maladies inflammatoires chroniques et leur association a été rapportée dans la littérature à travers quelques observations de cas sporadiques. Nous rapportons une nouvelle observation d'une telle association. Une patiente âgée de 44 ans, diagnostiquée avec une polyarthrite rhumatoïde à facteur rhumatoïde positif, qui a développé des céphalées avec des vertiges de caractère permanent. L'examen révélait un pouls radial et huméral abolis à droite, un souffle carotidien bilatéral et une tension artérielle imprenable à droite. L'artériographie a confirmé la présence d'une atteinte de l'arc aortique type MT. Le diagnostic d'une maladie de Takayasu associée à une polyarthrite rhumatoïde était retenu. La patiente était traitée par une corticothérapie (prednisone à la dose de 0,5 mg/kg par jour) et un traitement de fond par Méthotrexate avec une bonne réponse initiale. A travers notre observation et une revue de la littérature, les caractéristiques épidémiologiques, étiopathogéniques, cliniques, thérapeutiques et évolutives de cette association seront discutées. PMID:22937201

  15. IL-5 promotes induction of antigen-specific CD4+CD25+ T regulatory cells that suppress autoimmunity.

    PubMed

    Tran, Giang T; Hodgkinson, Suzanne J; Carter, Nicole M; Verma, Nirupama D; Plain, Karren M; Boyd, Rochelle; Robinson, Catherine M; Nomura, Masaru; Killingsworth, Murray; Hall, Bruce M

    2012-05-10

    Immune responses to foreign and self-Ags can be controlled by regulatory T cells (Tregs) expressing CD4 and IL-2Rα chain (CD25). Defects in Tregs lead to autoimmunity, whereas induction of Ag-specific CD4+CD25+ Tregs restores tolerance. Ag-specific CD4+CD25+ FOXP3+Tregs activated by the T helper type 2 (Th2) cytokine, IL-4, and specific alloantigen promote allograft tolerance. These Tregs expressed the specific IL-5Rα and in the presence of IL-5 proliferate to specific but not third-party Ag. These findings suggest that recombinant IL-5 (rIL-5) therapy may promote Ag-specific Tregs to mediate tolerance. This study showed normal CD4+CD25+ Tregs cultured with IL-4 and an autoantigen expressed Il-5rα. Treatment of experimental autoimmune neuritis with rIL-5 markedly reduced clinical paralysis, weight loss, demyelination, and infiltration of CD4+ (Th1 and Th17) CD8+ T cells and macrophages in nerves. Clinical improvement was associated with expansion of CD4+CD25+FOXP3+ Tregs that expressed Il-5rα and proliferated only to specific autoantigen that was enhanced by rIL-5. Depletion of CD25+ Tregs or blocking of IL-4 abolished the benefits of rIL-5. Thus, rIL-5 promoted Ag-specific Tregs, activated by autoantigen and IL-4, to control autoimmunity. These findings may explain how Th2 responses, especially to parasitic infestation, induce immune tolerance. rIL-5 therapy may be able to induce Ag-specific tolerance in autoimmunity.

  16. Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria

    PubMed Central

    Pérez-Mazliah, Damián; Ng, Dorothy Hui Lin; Freitas do Rosário, Ana Paula; McLaughlin, Sarah; Mastelic-Gavillet, Béatris; Sodenkamp, Jan; Kushinga, Garikai; Langhorne, Jean

    2015-01-01

    Interleukin-21 signaling is important for germinal center B-cell responses, isotype switching and generation of memory B cells. However, a role for IL-21 in antibody-mediated protection against pathogens has not been demonstrated. Here we show that IL-21 is produced by T follicular helper cells and co-expressed with IFN-γ during an erythrocytic-stage malaria infection of Plasmodium chabaudi in mice. Mice deficient either in IL-21 or the IL-21 receptor fail to resolve the chronic phase of P. chabaudi infection and P. yoelii infection resulting in sustained high parasitemias, and are not immune to re-infection. This is associated with abrogated P. chabaudi-specific IgG responses, including memory B cells. Mixed bone marrow chimeric mice, with T cells carrying a targeted disruption of the Il21 gene, or B cells with a targeted disruption of the Il21r gene, demonstrate that IL-21 from T cells signaling through the IL-21 receptor on B cells is necessary to control chronic P. chabaudi infection. Our data uncover a mechanism by which CD4+ T cells and B cells control parasitemia during chronic erythrocytic-stage malaria through a single gene, Il21, and demonstrate the importance of this cytokine in the control of pathogens by humoral immune responses. These data are highly pertinent for designing malaria vaccines requiring long-lasting protective B-cell responses. PMID:25763578

  17. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning

    PubMed Central

    Pegram, Hollie J.; Lee, James C.; Hayman, Erik G.; Imperato, Gavin H.; Tedder, Thomas F.; Sadelain, Michel

    2012-01-01

    Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)–modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4+ and CD8+ T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR+ T cells. Importantly, IL-12–secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell–mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients. PMID:22354001

  18. The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking.

    PubMed

    Venkataraman, Chandrasekar; Kuo, Frederick

    2005-11-15

    The orphan G-protein coupled receptor, GPR84 is highly expressed in the bone marrow, and in splenic T cells and B cells. In this study, GPR84-deficient mice were generated to understand the biological function of this orphan receptor. The proliferation of T and B cells in response to various mitogens was normal in GPR84-deficient mice. Interestingly, primary stimulation of T cells with anti-CD3 resulted in increased IL-4 but not IL-2 or IFN-gamma production in GPR84(-/-) mice compared to wild-type mice. Augmented IL-4 production in GPR84-deficient T cells was not related to increased frequency of IL-4-secreting cells in response to anti-CD3 stimulation. In fact, stimulation with anti-CD3 and anti-CD28 resulted in increased levels of IL-4 but not IFN-gamma steady-state mRNA in GPR84(-/-) T cells. In addition, Th2 effector cells generated in vitro from GPR84(-/-) mice produced higher levels of IL-4, IL-5 and IL-13 compared to wild-type mice. However, there was no detectable difference in the extent of IL-4 and IL-5 production between the two groups of mice in response to antigen stimulation of spleen cells, isolated from mice previously immunized with OVA in alum. These studies reveal a novel role for GPR84 in regulating early IL-4 gene expression in activated T cells.

  19. Cutting edge: spontaneous development of IL-17-producing gamma delta T cells in the thymus occurs via a TGF-beta 1-dependent mechanism.

    PubMed

    Do, Jeong-su; Fink, Pamela J; Li, Lily; Spolski, Rosanne; Robinson, Janet; Leonard, Warren J; Letterio, John J; Min, Booki

    2010-02-15

    In naive animals, gammadelta T cells are innate sources of IL-17, a potent proinflammatory cytokine mediating bacterial clearance as well as autoimmunity. However, mechanisms underlying the generation of these cells in vivo remain unclear. In this study, we show that TGF-beta1 plays a key role in the generation of IL-17(+) gammadelta T cells and that it mainly occurs in the thymus particularly during the postnatal period. Interestingly, IL-17(+) gammadelta TCR(+) thymocytes were mainly CD44(high)CD25(low) cells, which seem to derive from double-negative 4 gammadelta TCR(+) cells that acquired CD44 and IL-17 expression. Our findings identify a novel developmental pathway during which IL-17-competent gammadelta T cells arise in the thymus by a TGF-beta1-dependent mechanism.

  20. Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2.

    PubMed

    Condie, R; Herring, A; Koh, W S; Lee, M; Kaminski, N E

    1996-05-31

    Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis toxin-sensitive GTP-binding protein. In the present studies, signaling via the adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T-cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern analysis of genomic DNA digests for the CB2 receptor demonstrated identical banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by inhibiting forskolin-stimulated cAMP accumulation which consequently led to a decrease in protein kinase A activity and the binding of transcription factors to a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which correlated to decreased IL-2 gene transcription, was induced by both cannabinol and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin-induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter. Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings suggest that inhibition of signal transduction via the adenylate cyclase/cAMP pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene transcription.

  1. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.

    PubMed

    Gao, Xin; Wang, Xuefeng; Yang, Qianting; Zhao, Xin; Wen, Wen; Li, Gang; Lu, Junfeng; Qin, Wenxin; Qi, Yuan; Xie, Fang; Jiang, Jingting; Wu, Changping; Zhang, Xueguang; Chen, Xinchun; Turnquist, Heth; Zhu, Yibei; Lu, Binfeng

    2015-01-01

    Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. IL-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a "danger" signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8(+) T cells. In this study, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFN-γ production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor Ag-specific CD8(+) T cells. Furthermore, both NK and CD8(+) T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells worked synergistically with IL-33 expression for tumor elimination. Our studies established "alarmin" IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses. Copyright © 2014 by The American Association of Immunologists, Inc.

  2. Cholesterol negatively regulates IL-9-producing CD8+ T cell differentiation and antitumor activity.

    PubMed

    Ma, Xingzhe; Bi, Enguang; Huang, Chunjian; Lu, Yong; Xue, Gang; Guo, Xing; Wang, Aibo; Yang, Maojie; Qian, Jianfei; Dong, Chen; Yi, Qing

    2018-05-09

    CD8 + T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8 + or CD4 + T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to Il9 promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function. © 2018 Ma et al.

  3. Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression.

    PubMed

    Wang, Yu; Sun, Sheng-Nan; Liu, Qing; Yu, Yang-Yang; Guo, Jian; Wang, Kun; Xing, Bao-Cai; Zheng, Qing-Feng; Campa, Michael J; Patz, Edward F; Li, Shi-You; He, You-Wen

    2016-09-01

    In contrast to its inhibitory effects on many cells, IL10 activates CD8(+) tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8(+) TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell- and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8(+) TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy. Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti-PD-1 to enhance anti-PD-1 efficacy; a targeted IL10 delivery to CD8(+) TILs using anti-PD-1-IL10 or anti-CTLA4-IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022-35. ©2016 AACR.See related commentary by Peng et al., p. 953This article is highlighted in the In This Issue feature, p. 932. ©2016 American Association for Cancer Research.

  4. The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients.

    PubMed

    Di Meglio, Paola; Villanova, Federica; Napolitano, Luca; Tosi, Isabella; Terranova Barberio, Manuela; Mak, Rose K; Nutland, Sarah; Smith, Catherine H; Barker, Jonathan N W N; Todd, John A; Nestle, Frank O

    2013-10-01

    We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.

  5. Modulation of allergy incidence in icelandic horses is associated with a change in IL-4-producing T cells.

    PubMed

    Hamza, E; Doherr, M G; Bertoni, G; Jungi, T W; Marti, E

    2007-01-01

    Equine insect bite hypersensitivity (IBH) is an immediate-type hypersensitivity reaction provoked by insect-derived allergens. Icelandic horses living in Iceland do not have IBH due to absence of relevant insects, but acquire it at high frequency after being imported to mainland Europe. In contrast, their offspring born in mainland Europe has reduced IBH incidence. T helper 1 (Th1) and Th2 cells and cytokines were determined in Icelandic horses born in Iceland and on the continent and which either have IBH or are healthy. Peripheral blood mononuclear cells (PBMC) from these horses were stimulated for 18 h during summer and winter with polyclonal T cell stimuli, IBH allergen(s) or irrelevant allergen(s). Cells were analysed by flow cytometry for interferon-gamma (IFN-gamma) and interleukin-4 (IL-4); RNA was analysed for IFN-gamma, IL-4, IL-5 and IL-13 mRNA. During summer, but not during winter, IBH PBMC stimulated polyclonally showed reduced IFN-gamma mRNA and IFN-gamma-producing cells when compared with those of healthy horses, regardless of origin. PBMC stimulated polyclonally or with IBH allergen showed increased IL-4 mRNA levels and higher numbers of IL-4-producing cells when born in Iceland or showing IBH symptoms. IL-5 and IL-13 mRNA were modulated neither by disease nor by origin. Abrogation of IL-4 production in healthy horses born in mainland Europe may be due, at least in part, to IL-10. There was an increased level of IL-10 in supernatants from PBMC of healthy horses born in mainland Europe and stimulated polyclonally or with IBH allergen. Modulation of IBH incidence is governed by altered Th1/Th2 ratio, which might be influenced by IL-10. Copyright 2007 S. Karger AG, Basel.

  6. T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

    PubMed Central

    Zhu, Jinfang

    2015-01-01

    Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these “type 2 immune response-related” cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. PMID:26044597

  7. Interleukin-7 (IL-7) enhances class switching to IgE and IgG4 in the presence of T cells via IL-9 and sCD23.

    PubMed

    Jeannin, P; Delneste, Y; Lecoanet-Henchoz, S; Gretener, D; Bonnefoy, J Y

    1998-02-15

    Interleukin-7 (IL-7) is a B-cell growth factor produced by both bone marrow stroma cells and follicular dendritic cells (FDCs) located in primary lymphoid follicles and germinal centers. In this study, we have evaluated the role of IL-7 on human Ig class switching. IL-7 was added to peripheral blood mononuclear cells (PBMCs) or tonsillar B cells in the absence or presence of IL-4 and/or anti-CD40 monoclonal antibody (MoAb). Alone, IL-7 did not affect Ig production by PBMCs or by anti-CD40 MoAb-stimulated B cells. Rather, IL-7 potentiated IL-4-induced IgE and IgG4 production by PBMCs. In parallel, IgG3 production was also enhanced but to a lesser extent, whereas the production of the other isotypes was unaltered. The activity of IL-2, IL-9, or IL-15, which share usage of the common gamma chain for signaling, was also assessed. IL-9, like IL-7, potentiated mainly IgE and IgG4 production by IL-4-stimulated PBMCs. IL-15, in contrast, was ineffective, whereas IL-2 enhanced the production of all isotypes. More precisely, IL-7 potentiation of IgE and IgG4 production required the presence of T cells and was accompanied by an increase of the expression of two soluble molecules favoring preferentially IgE and IgG4 synthesis: CD23 (sCD23) and IL-9. Moreover, neutralizing anti-CD23 and anti-IL-9 antibodies partly inhibited the increase of IgE synthesis induced by IL-7. Thus, IL-7 produced locally in the germinal centers by FDCs may interact with T cells and potentiate human IgE and IgG4 switching by favoring IL-9 and sCD23 production.

  8. A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells.

    PubMed

    Kuijpers, Taco W; van Leeuwen, Ester M M; Barendregt, Barbara H; Klarenbeek, Paul; aan de Kerk, Daan J; Baars, Paul A; Jansen, Machiel H; de Vries, Niek; van Lier, René A W; van der Burg, Mirjam

    2013-07-01

    Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8(+) T cells and increased over time. Only the revertant CD8(+) T cells showed normal expression of CD132 and the various CD8(+) T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ(+) T cells and differentiated CD4(+)CD27(-) effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8(+) T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells.

  9. A Novel Sphingomyelinase-Like Enzyme in Ixodes scapularis Tick Saliva Drives Host CD4+ T cells to Express IL-4

    PubMed Central

    Alarcon-Chaidez, F. J.; Boppana, V. D.; Hagymasi, A.T.; Adler, A. J.; Wikel, S. K.

    2009-01-01

    Tick feeding modulates host immune responses. Tick-induced skewing of host CD4+ T cells towards a Th2 cytokine profile facilitates transmission of tick-borne pathogens that would otherwise be neutralized by Th1 cytokines. Tick-derived factors that drive this Th2 response have not previously been characterized. In the current study, we examined an I. scapularis cDNA library prepared at 18-24 hours of feeding and identified and expressed a tick gene with homology to Loxosceles spider venom proteins with sphingomyelinase activity. This I. scapularis sphingomyelinase-like (IsSMase) protein is a Mg+2-dependent, neutral (pH 7.4) form of sphingomyelinase. Significantly, in an in vivo TCR transgenic adoptive transfer assay IsSMase programmed host CD4+ T cells to express the hallmark Th2 effector cytokine IL-4. IsSMase appears to directly program host CD4 T cell IL-4 expression (as opposed to its metabolic by-products) because induced IL-4 expression was not altered when enzymatic activity was neutralized. TCR transgenic CD4 T cell proliferation (CFSE-dilution) was also significantly increased by IsSMase. Furthermore, a Th2 response is superimposed onto a virally-primed Th1 response by IsSMase. Thus, IsSMase is the first identified tick molecule capable of programming host CD4+ T cells to express IL-4. PMID:19292772

  10. Antibody and T cell responses induced in chickens immunized with avian influenza virus N1 and NP DNA vaccine with chicken IL-15 and IL-18.

    PubMed

    Lim, Kian-Lam; Jazayeri, Seyed Davoud; Yeap, Swee Keong; Mohamed Alitheen, Noorjahan Banu; Bejo, Mohd Hair; Ideris, Aini; Omar, Abdul Rahman

    2013-12-01

    We had examined the immunogenicity of a series of plasmid DNAs which include neuraminidase (NA) and nucleoprotein (NP) genes from avian influenza virus (AIV). The interleukin-15 (IL-15) and interleukin-18 (IL-18) as genetic adjuvants were used for immunization in combination with the N1 and NP AIV genes. In the first trial, 8 groups of chickens were established with 10 specific-pathogen-free (SPF) chickens per group while, in the second trial 7 SPF chickens per group were used. The overall N1 enzyme-linked immunosorbent assay (ELISA) titer in chickens immunized with the pDis/N1+pDis/IL-15 was higher compared to the chickens immunized with the pDis/N1 and this suggesting that chicken IL-15 could play a role in enhancing the humoral immune response. Besides that, the chickens that were immunized at 14-day-old (Trial 2) showed a higher N1 antibody titer compared to the chickens that were immunized at 1-day-old (Trial 1). Despite the delayed in NP antibody responses, the chickens co-administrated with IL-15 were able to induce earlier and higher antibody response compared to the pDis/NP and pDis/NP+pDis/IL-18 inoculated groups. The pDis/N1+pDis/IL-15 inoculated chickens also induced higher CD8+ T cells increase than the pDis/N1 group in both trials (P<0.05). The flow cytometry results from both trials demonstrated that the pDis/N1+pDis/IL-18 groups were able to induce CD4+ T cells higher than the pDis/N1 group (P<0.05). Meanwhile, pDis/N1+pDis/IL-18 group was able to induce CD8+ T cells higher than the pDis/N1 group (P<0.05) in Trial 2 only. In the present study, pDis/NP was not significant (P>0.05) in inducing CD4+ and CD8+ T cells when co-administered with the pDis/IL-18 in both trials in comparison to the pDis/NP. Our data suggest that the pDis/N1+pDis/IL-15 combination has the potential to be used as a DNA vaccine against AIV in chickens. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Helminth-conditioned dendritic cells prime CD4+ T cells to IL-4 production in vivo.

    PubMed

    Connor, Lisa M; Tang, Shiau-Choot; Camberis, Mali; Le Gros, Graham; Ronchese, Franca

    2014-09-15

    Dendritic cells (DC) are critical for the initiation of immune responses; however, their role in priming IL-4-producing Th2 cells in vivo is not fully understood. We used a model of intradermal injection with fluorescent-labeled, nonviable larvae from the helminth parasite nonviable Nippostrongylus brasiliensis L3 larvae (Nb), a strong inducer of Th2 responses, together with IL-4-GFP reporter mice that enable a sensitive detection of IL-4 production to examine the contribution of DC to the priming of IL-4-producing CD4(+) T cells in vivo. We found that parasite material is taken up by two distinct DC populations in draining lymph nodes: a mostly CD11c(int)MHC class II (MHCII)(hi)CD11b(+)Ly6C(-) dermal DC population and a CD11c(hi)MHCII(int)CD11b(+)Ly6C(+) monocyte-derived DC population. After Nb treatment, these two DC populations appeared in the draining lymph nodes in comparable numbers and with similar kinetics; however, treatment with pertussis toxin blocked the migration of dermal DC and the priming of IL-4-producing T cells, but only partially affected monocyte-derived DC numbers. In line with this observation, transfer of OVA-loaded CD11c(int)MHCII(hi) DC from Nb-treated mice into naive hosts could sensitize OVA-specific CD4(+) T cells to IL-4 production, whereas transfer of CD11c(int)MHCII(hi) DC from naive mice, or CD11c(hi)MHCII(int) DC from Nb-treated or naive mice, induced CD4(+) T cell expansion but no IL-4 production. Phenotypic analysis of Nb-loaded CD11c(int)MHCII(hi) DC revealed expression of programmed death ligand 2, CD301b, IFN regulatory factor 4, and moderate upregulation of OX40 ligand. However, thymic stromal lymphopoietin and OX40 ligand were not required for Th2 priming. Thus, our data suggest that appropriate stimuli can induce DC to express the unique signals sufficient to direct CD4(+) T cells to Th2 differentiation. Copyright © 2014 by The American Association of Immunologists, Inc.

  12. Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

    PubMed Central

    Chen, Jing; Petrus, Mike; Bryant, Bonita R.; Phuc Nguyen, Vinh; Stamer, Mindy; Goldman, Carolyn K.; Bamford, Richard; Morris, John C.; Janik, John E.

    2008-01-01

    The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-κB motif in its proximal promoter, whereas IL-9 receptor-α (IL-9Rα) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Rα in ATL, a neutralizing monoclonal antibody directed toward IL-9Rα inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Rα on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Rα/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism. PMID:18339896

  13. Exosomes from heat-stressed tumour cells inhibit tumour growth by converting regulatory T cells to Th17 cells via IL-6.

    PubMed

    Guo, Danfeng; Chen, Yinghu; Wang, Shoujie; Yu, Lei; Shen, Yingying; Zhong, Haijun; Yang, Yunshan

    2018-05-01

    Exosomes derived from heat-stressed tumour cells (HS-TEXs), which contain abundant heat shock protein (HSP) 70, strongly induce antitumour immune responses. HSP70-induced interleukin (IL)-6 promotes IL-17 expression and causes rejection of established prostate tumours. However, it remains unclear whether HS-TEXs exhibit antitumour effects by converting regulatory T cells (T regs ) into T helper type 17 (Th17) cells. In this study, we found that compared with TEXs, HS-TEXs were more potent in stimulating secretion of IL-6 from dendritic cells. In vitro, IL-6 blocked tumour cell-derived transforming growth factor beta 1-induced T reg differentiation and promoted Th17 cell differentiation. HS-TEXs exerted strong antitumour effects, converting T regs into Th17 cells with high efficiency, a process that was entirely dependent upon IL-6. Neutralization of IL-17 completely abolished the antitumour effect of TEXs, but only partially inhibited that of HS-TEXs. In addition, we found higher levels of IL-6 and IL-17 in serum from tumour patients treated with hyperthermia, and an increase in Th17 cells and a decrease in T regs was detected in peripheral blood mononuclear cells isolated from these patients after hyperthermia. Therefore, our results demonstrate that HS-TEXs possess a powerful capacity to convert immunosuppressive T regs into Th17 cells via IL-6, which contributes to their potent antitumour effect. © 2017 John Wiley & Sons Ltd.

  14. Pleural mesothelial cells promote expansion of IL-17-producing CD8+ T cells in tuberculous pleural effusion.

    PubMed

    Li, X; Zhou, Q; Yang, W B; Xiong, X Z; Du, R H; Zhang, J C

    2013-05-01

    IL-17-producing CD8(+) T lymphocytes (Tc17 cells) have recently been detected in many cancers and autoimmune diseases. However, the possible implication of Tc17 cells in tuberculous pleural effusion remains unclarified. In this study, distribution and phenotypic features of Tc17 cells in both tuberculous pleural effusion (TPE) and peripheral blood from patients with tuberculosis were determined. The effects of proinflammatory cytokines and local accessory cells (pleural mesothelial cells) on Tc17 cell expansion were also explored. We found that TPE contained more Tc17 cells than the blood. Compared with IFN-γ-producing CD8(+) T cells, Tc17 cells displayed higher expression of chemokine receptors (CCRs) and lower expression of cytotoxic molecules. In particularly, Tc17 cells in TPE exhibited high expression levels of CCR6, which could migrate in response to CCL20. Furthermore, IL-1β, IL-6, IL-23, or their various combinations could promote Tc17 cell expansion from CD8(+) T cells, whereas the proliferative response of Tc17 cells to above cytokines was lower than that of Th17 cells. Pleural mesothelial cells (PMCs) were able to stimulate Tc17 cell expansion via cell contact in an IL-1β/IL-6/IL-23 independent fashion. Thus this study demonstrates that Tc17 cells marks a subset of non-cytotoxic, CCR6(+) CD8(+) T lymphocytes with low proliferative capacity. The overrepresentation of Tc17 cells in TPE may be due to Tc17 cell expansion stimulated by pleural proinflammatory cytokines and to recruitment of Tc17 cells from peripheral blood. Additionally, PMCs may promote the production of IL-17 by CD8(+) T cells at sites of TPE via cell-cell interactions.

  15. Hémothorax spontané révélant une vascularite de Wegener chez une femme enceinte

    PubMed Central

    Serhane, Hind; Yassine, Msougar; Amro, Lamyae

    2016-01-01

    L’hémothorax spontané demeure une pathologie rare. Ses étiologies sont multiples mais restent parfois inconnues. Chez certains patients, la thoracotomie peut être le seul recours pour déterminer son origine. Les vascularites n’ont pas été rapporté comme cause habituelle des hémothorax spontanés. La grossesse ne semble pas avoir d’effet causal, ni aggravant des hémothorax spontanés, ni des vascularites. Nous rapportons une observation assez particulière d’une jeune patiente, présentant au cours de sa grossesse un hémothorax spontané secondaire à une vasularite de type Wegener, diagnostiquée par la biopsie pleurale faite au cours d’une thoracotomie exploratrice et confirmée par le dosage des ANCA. PMID:28154726

  16. A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells.

    PubMed

    Guo, Zhiyong; Khattar, Mithun; Schroder, Paul M; Miyahara, Yoshihiro; Wang, Guohua; He, Xiaoshung; Chen, Wenhao; Stepkowski, Stanislaw M

    2013-04-01

    The molecular mechanism of the extrathymic generation of adaptive, or inducible, CD4(+)Foxp3(+) regulatory T cells (iTregs) remains incompletely defined. We show that exposure of splenic CD4(+)CD25(+)Foxp3(-) cells to IL-2, but not other common γ-chain cytokines, resulted in Stat5 phosphorylation and induced Foxp3 expression in ∼10% of the cells. Thus, IL-2/Stat5 signaling may be critical for Foxp3 induction in peripheral CD4(+)CD25(+)Foxp3(-) iTreg precursors. In this study, to further define the role of IL-2 in the formation of iTreg precursors as well as their subsequent Foxp3 expression, we designed a two-step iTreg differentiation model. During the initial "conditioning" step, CD4(+)CD25(-)Foxp3(-) naive T cells were activated by TCR stimulation. Inhibition of IL-2 signaling via Jak3-Stat5 was required during this step to generate CD4(+)CD25(+)Foxp3(-) cells containing iTreg precursors. During the subsequent Foxp3-induction step driven by cytokines, IL-2 was the most potent cytokine to induce Foxp3 expression in these iTreg precursors. This two-step method generated a large number of iTregs with relatively stable expression of Foxp3, which were able to prevent CD4(+)CD45RB(high) cell-mediated colitis in Rag1(-/-) mice. In consideration of this information, whereas initial inhibition of IL-2 signaling upon T cell priming generates iTreg precursors, subsequent activation of IL-2 signaling in these precursors induces the expression of Foxp3. These findings advance the understanding of iTreg differentiation and may facilitate the therapeutic use of iTregs in immune disorders.

  17. Les agressions sexuelles des jeunes ayant une incapacité ou une maladie chronique

    PubMed Central

    Kaufman, M

    2011-01-01

    Pour diverses raisons, les enfants et les adolescents ayant une incapacité ou une maladie chronique sont plus vulnérables aux agressions sexuelles. Les dispensateurs de soins, de même que les parents et les éducateurs, doivent se méfier davantage de la possibilité d’agression sexuelle au sein de cette population. Les médecins, tout particulièrement, doivent prôner des politiques pour prévenir ou déceler les agressions dans les hôpitaux, les écoles et autres établissements. Ces politiques incluent le dépistage détaillé et la surveillance étroite des employés et des bénévoles, la présence d’un chaperon aux examens physiques et aux interventions thérapeutiques, la supervision des sorties et une culture qui favorise la vie privée du patient en établissement. De plus, les médecins doivent favoriser la conscience de soi et l’habilitation des patients et leur donner très tôt des conseils préventifs au sujet de la sexualité, de l’habilitation personnelle et des risques d’agression. Le présent document de principes remplace celui que la Société canadienne de pédiatrie a publié en 1997.

  18. Atopic dermatitis patients carrying G allele in -1082 G/A IL-10 polymorphism are predisposed to higher serum concentration of IL-10.

    PubMed

    Lesiak, Aleksandra; Zakrzewski, Marcin; Przybyłowska, Karolina; Rogowski-Tylman, Michał; Wozniacka, Anna; Narbutt, Joanna

    2014-12-22

    Atopic dermatitis (AD) is a chronic skin inflammatory disease in which Th2-derived cytokines play an essential role. Aim of the study was to assess interleukin 4, 10 and 13 (IL-4, IL-10 and IL-13) serum concentrations in AD patients and to correlate the values with the occurrence of genotypes of selected polymorphisms in genes encoding these cytokines. Seventy-six AD patients (mean age 11.4 years) and 60 healthy controls were enrolled in the study. Blood samples were analyzed for IL-4, IL-10 and IL-13 concentrations with ELISA assay and genotyping for -590C/T IL-4, -1082A/G IL-10 and -1055C/T IL-13 polymorphisms with PCR-RFLP. The obtained results revealed statistically higher serum concentration of IL-10 and IL-13 in AD patients when compared to healthy controls (10.30 pg/ml vs. 8.51 pg/ml for IL-10 and 5.67 pg/ml vs. 4.98 pg/ml for IL-13). There were no significant differences between AD patients and controls in regard to IL-4 serum level (5.10 pg/ml vs. 7.1 pg/ml). Analyzing the association between level of the examined cytokines and genotype polymorphisms -590 C/T for the IL-4 gene, -1082 A/G for the IL-10 gene and -1055 C/T for the IL-13 gene, we found a statistically higher IL-10 serum level among carriers of the G allele in the -1082 G/A IL-10 polymorphism both in AD and control groups. We did not find any significant differences between serum level of IL-4 and IL-13 in regard to genotype occurrence in examined polymorphisms: -590 C/T for the IL-4 gene and -1055 C/T for the IL-13 gene. The obtained results confirm the genetic background of IL-10 synthesis in the Polish population.

  19. Vγ1+γδT, early cardiac infiltrated innate population dominantly producing IL-4, protect mice against CVB3 myocarditis by modulating IFNγ+ T response.

    PubMed

    Wan, Fangfang; Yan, Kepeng; Xu, Dan; Qian, Qian; Liu, Hui; Li, Min; Xu, Wei

    2017-01-01

    Viral myocarditis (VMC) is an inflammation of the myocardium closely associated with Coxsackievirus B3 (CVB3) infection. Vγ1 + γδT cells, one of early cardiac infiltrated innate population, were reported to protect CVB3 myocarditis while the precise mechanism not fully addressed. To explore cytokine profiles and kinetics of Vγ1 + γδT and mechanism of protection against VMC, flow cytometry was conducted on cardiac Vγ1 cells in C57BL/6 mice following CVB3 infection. The level of cardiac inflammation, transthoracic echocardiography and viral replication were evaluated after monoclonal antibody depletion of Vγ1γδT. We found that Vγ1 + γδT cells infiltration peaked in the heart at day3 post CVB3 infection and constituted a minor source of IFN-γ but major producers for early IL-4. Vγ1γδT cells were activated earlier holding a higher IL-4-producing efficiency than CD4 + Th cells in the heart. Depletion of Vγ1 + γδT resulted in a significantly exacerbated cardiac infiltration, increased T, macrophage and neutrophil population in heart homogenates and worse cardiomyopathy; which was accompanied by a significant expansion of peripheral IFNγ + CD4+ and CD8+T cells. Neutralization of IL-4 in mice resulted in an exacerbated acute myocarditis confirming the IL-4-mediated protective mechanism of Vγ1. Our findings identify a unique property of Vγ1 + γδT cells as one dominant early producers of IL-4 upon CVB3 acute infection which is a key mediator to protect mice against acute myocarditis by modulating IFNγ-secreting T response. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+ T-Cell Activation by Inducing IL-10-Producing Th1 Cells

    PubMed Central

    Selleri, Silvia; Dieng, Mame Massar; Nicoletti, Simon; Louis, Isabelle; Beausejour, Christian; Le Deist, Françoise

    2013-01-01

    The mechanisms by which mesenchymal stromal cells (MSCs) induce immunomodulation are still poorly understood. In the current work, we show by a combination of polymerase chain reaction (PCR) array, flow cytometry, and multiplex cytokine data analysis that during the inhibition of an alloantigen-driven CD4+ T-cell response, MSCs induce a fraction of CD4+ T-cells to coexpress interferon-γ (IFNγ) and interleukin-10 (IL-10). This CD4+ IFNγ+ IL-10+ cell population shares properties with recently described T-cells originating from switched Th1 cells that start producing IL-10 and acquire a regulatory function. Here we report that IL-10-producing Th1 cells accumulated with time during T-cell stimulation in the presence of MSCs. Moreover, MSCs caused stimulated T-cells to downregulate the IFNγ receptor (IFNγR) without affecting IL-10 receptor expression. Further, the inhibitory effect of MSCs could be reversed by an anti-IFNγR-blocking antibody, indicating that IFNγ is one of the major players in MSC-induced T-cell suppression. Stimulated (and, to a lesser extent, resting) CD4+ T-cells treated with MSCs were able to inhibit the proliferation of autologous CD4+ T-cells, demonstrating their acquired regulatory properties. Altogether, our results suggest that the generation of IL-10-producing Th1 cells is one of the mechanisms by which MSCs can downmodulate an immune response. PMID:23167734

  1. Cartographie T

    NASA Astrophysics Data System (ADS)

    Cote, Jean-Charles

    Les cartographies T1 par séquences d'échos stimulés et Look- Locker sont les plus communément utilisées pour mesurer les temps de relaxation T 1 en imagerie par résonance magnétique (IRM). Elles ont des performances d'usage clinique, ne prenant que quelques minutes pour produire une carte des valeurs de T1. Ces séquences demeurent cependant très sensibles à la précision des pulses radiofréquences (RF) qui réorientent l'aimantation pour produire les signaux mesurés. Les pulses RF rectangulaires régulièrement utilisés en IRM produisent un basculement de l'aimantation directement proportionnel à l'intensité du champ magnétique B 1 produit par l'antenne émettrice. Les antennes cliniques ont des distributions de champs B1 qui fluctuent énormément. En exemple, l'antenne servant à produire des images de la tête possède un champ B1 qui est distribué dans son volume utile sur une plage allant de 0,5 à 1,2 relativement à son centre. Cette variation spatiale de B1 entraîne des erreurs systématiques sur les valeurs ajustées de T1 dépassant les 50%. Le développement d'un nouveau concept d'excitation RF à approche tangentielle ayant des propriétés adiabatiques pouvant remplacer les demi-passages adiabatiques (AHP) et son utilisation sous la forme d'un BIR-4-S2 (B1-Insensitive Rotation-4 AHP-Sequentialized 2 steps) dans les séquences de cartographie T1 a permis de réduire à moins de 10% les erreurs systématiques dans le cas mesuré par échos stimulés compensés et à moins de 5% pour le Look-Locker. Le BIR-4-S2 possède une imprécision sur l'angle de basculement de moins de 5° sur une plage relative allant de 0,75 à 1,75 autour d'un champ de référence B1 ref, pour un choix de basculement sur 360°. Et, contrairement aux pulses adiabatiques, il demeure un pulse RF tridimentionnel (3D) à faible puissance pouvant être utilisé à répétition cliniquement sans risque d'échauffement dangereux pour les patients. La séquence d

  2. Interleukin-4 production by Follicular Helper T cells requires the conserved Il4 enhancer HS V

    PubMed Central

    Vijayanand, Pandurangan; Seumois, Grégory; Simpson, Laura J.; Abdul-Wajid, Sarah; Baumjohann, Dirk; Panduro, Marisella; Huang, Xiaozhu; Interlandi, Jeneen; Djuretic, Ivana M.; Brown, Daniel R.; Sharpe, Arlene H.; Rao, Anjana; Ansel, K. Mark

    2012-01-01

    SUMMARY Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that HS V (also known as CNS2), a 3’ enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in Th2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation, and increased accessibility of the Il4 promoter. Thus Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of Th2 mediated allergic diseases. PMID:22326582

  3. Association Between IL-10 Gene Promoter Polymorphisms (-592 A/C, -819 T/C, -1082 A/G) and Susceptibility to HBV Infection in an Iranian Population

    PubMed Central

    Moudi, Bita; Heidari, Zahra; Mahmoudzadeh-Sagheb, Hamidreza; Hashemi, Mohammad; Metanat, Malihe; Khosravi, Soheila; Farrokh, Parisa

    2016-01-01

    Background IL-10 can play a vital role in immune response against HBV. Three biallelic SNPs from the transcription start site control the transcription of the IL-10 gene. An association between susceptibility to HBV and IL-10 polymorphisms has been suggested in patients with HBV infection. Objectives The present study was designed to study the association between polymorphisms in interleukin-10 (-1082 A/G, -819 T/C and -592 A/C) promoter gene and chronic hepatitis B virus (HBV) infection. Patients and Methods 221 chronically infected patients and 200 healthy control subjects were enrolled in the study. Three biallelic (-1082 A/G, -819 T/C and -592 A/C) polymorphisms in the IL-10 promoter gene were determined by PCR-RFLP method. Results Persistent HBV infection was associated with IL-10-1082 AG (P = 0.001) and GG (P = 0.004) genotypes and G (P = 0.000) allele. IL-10-819 T/C and -592 A/C genotype and allele frequencies did not show any correlation with the risk of chronic hepatitis B infection. Conclusions These results suggest that polymorphisms in interleukin-10 gene promoter influence clinical outcome of HBV infection and susceptibility to HBV infection. PMID:27148384

  4. Association Between IL-10 Gene Promoter Polymorphisms (-592 A/C, -819 T/C, -1082 A/G) and Susceptibility to HBV Infection in an Iranian Population.

    PubMed

    Moudi, Bita; Heidari, Zahra; Mahmoudzadeh-Sagheb, Hamidreza; Hashemi, Mohammad; Metanat, Malihe; Khosravi, Soheila; Farrokh, Parisa

    2016-02-01

    IL-10 can play a vital role in immune response against HBV. Three biallelic SNPs from the transcription start site control the transcription of the IL-10 gene. An association between susceptibility to HBV and IL-10 polymorphisms has been suggested in patients with HBV infection. The present study was designed to study the association between polymorphisms in interleukin-10 (-1082 A/G, -819 T/C and -592 A/C) promoter gene and chronic hepatitis B virus (HBV) infection. 221 chronically infected patients and 200 healthy control subjects were enrolled in the study. Three biallelic (-1082 A/G, -819 T/C and -592 A/C) polymorphisms in the IL-10 promoter gene were determined by PCR-RFLP method. Persistent HBV infection was associated with IL-10-1082 AG (P = 0.001) and GG (P = 0.004) genotypes and G (P = 0.000) allele. IL-10-819 T/C and -592 A/C genotype and allele frequencies did not show any correlation with the risk of chronic hepatitis B infection. These results suggest that polymorphisms in interleukin-10 gene promoter influence clinical outcome of HBV infection and susceptibility to HBV infection.

  5. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

    PubMed Central

    Wynn, James Lawrence; Wilson, Chris S.; Hawiger, Jacek; Scumpia, Philip O.; Marshall, Andrew F.; Liu, Jin-Hua; Zharkikh, Irina; Wong, Hector R.; Lahni, Patrick; Benjamin, John T.; Plosa, Erin J.; Weitkamp, Jörn-Hendrik; Sherwood, Edward R.; Moldawer, Lyle L.; Ungaro, Ricardo; Baker, Henry V.; Lopez, M. Cecilia; McElroy, Steven J.; Colliou, Natacha; Mohamadzadeh, Mansour; Moore, Daniel Jensen

    2016-01-01

    Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18–null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G+ myeloid cells, and blocking IL-17A reduced IL-18–potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18–mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis. PMID:27114524

  6. A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

    PubMed Central

    Kuijpers, Taco W.; van Leeuwen, Ester M.M.; Barendregt, Barbara H.; Klarenbeek, Paul; aan de Kerk, Daan J.; Baars, Paul A.; Jansen, Machiel H.; de Vries, Niek; van Lier, René A.W.; van der Burg, Mirjam

    2013-01-01

    Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B+T−NK− X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8+ T cells and increased over time. Only the revertant CD8+ T cells showed normal expression of CD132 and the various CD8+ T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ+ T cells and differentiated CD4+CD27− effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8+ T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells. PMID:23403317

  7. Genetic polymorphism of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer risk.

    PubMed

    Xu, Hua; Ding, Qiang; Jiang, Hao-Wen

    2014-01-01

    We aimed to investigate the associations between polymorphisms of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer (PCa) risk. A comprehensive search for articles of MEDLINE and EMBASE databases and bibliographies of retrieved articles published up to August 3, 2014 was performed. Methodological quality assessment of the trials was based on a standard quality scoring system. The meta-analysis was performed using STATA 12.0. We included 9 studies (1 study for IL-1A, 5 studies for IL-1B, and 3 studies for IL-1RN), and significant association was found between polymorphisms of IL-1B-511 (rs16944) as well as IL-1B-31 (rs1143627) and PCa risk. IL-1B-511 (rs16944) polymorphism was significantly associated with PCa risk in homozygote and recessive models, as well as allele contrast (TT vs CC: OR, 0.74; 95%CI, 0.58-0.94; P=0.012; TT vs TC+CC; OR, 0.79; 95%CI, 0.63-0.98; P=0.033; T vs C: OR, 0.86; 95%CI, 0.77-0.96; P=0.008). The association between IL-1B-31 (rs1143627) polymorphism and PCa risk was weakly significant under a heterozygote model (OR, 1.35; 95%CI, 1.00-1.80; P=0.047). Sequence variants in IL-1B-511 (rs16944) and IL-1B-31 (rs1143627) are significantly associated with PCa risk, which provides additional novel evidence that proinflammatory cytokines and inflammation play an important role in the etiology of PCa.

  8. Intermittent IL-7 Signaling Essential for T cell Homeostasis | Center for Cancer Research

    Cancer.gov

    In order for the immune system to mount an appropriate response to foreign antigens throughout a person’s life, the body must maintain a sufficient population of circulating mature, naïve T cells, a process known as T cell homeostasis. Previous studies revealed that this process depends upon signaling from the cytokine interleukin-7 (IL-7) as well as from the T cell antigen

  9. T Regulatory Cell Induced Foxp3 Binds the IL2, IFNγ, and TNFα Promoters in Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus Infected Cats.

    PubMed

    Wang, Yan; Nag, Mukta; Tuohy, Joanne L; De Paris, Kristina; Fogle, Jonathan E

    2018-03-01

    Polyfunctional CD8 + T cells play a critical role in controlling viremia during AIDS lentiviral infections. However, for most HIV-infected individuals, virus-specific CD8 + T cells exhibit loss of polyfunctionality, including loss of IL2, TNFα, and IFNγ. Using the feline immunodeficiency virus (FIV) model for AIDS lentiviral persistence, our laboratory has demonstrated that FIV-activated Treg cells target CD8 + T cells, leading to a reduction in IL2 and IFNγ production. Furthermore, we have demonstrated that Treg cells induce expression of the repressive transcription factor, Foxp3, in CD8 + T cells. Based upon these findings, we asked if Treg-induced Foxp3 could bind to the IL2, TNFα, and IFNγ promoter regions in virus-specific CD8 + T cells. Following coculture with autologous Treg cells, we demonstrated decreased mRNA levels of IL2 and IFNγ at weeks 4 and 8 postinfection and decreased TNFα at week 4 postinfection in virus-specific CD8 + T cells. We also clearly demonstrated Treg cell-induced Foxp3 expression in virus-specific CD8 + T cells at weeks 1, 4, and 8 postinfection. Finally, we documented Foxp3 binding to the IL2, TNFα, and IFNγ promoters at 8 weeks and 6 months postinfection in virus-specific CD8 + T cells following Treg cell coculture. In summary, the results here clearly demonstrate that Foxp3 inhibits IL2, TNFα, and IFNγ transcription by binding to their promoter regions in lentivirus-specific CD8 + T cells. We believe this is the first description of this process during the course of AIDS lentiviral infection.

  10. IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

    PubMed

    Heon, Elise K; Wulan, Hasi; Macdonald, Loch P; Malek, Adel O; Braunstein, Glenn H; Eaves, Connie G; Schattner, Mark D; Allen, Peter M; Alexander, Michael O; Hawkins, Cynthia A; McGovern, Dermot W; Freeman, Richard L; Amir, Eitan P; Huse, Jason D; Zaltzman, Jeffrey S; Kauff, Noah P; Meyers, Paul G; Gleason, Michelle H; Overholtzer, Michael G; Wiseman, Sam S; Streutker, Catherine D; Asa, Sylvia W; McAlindon, Timothy P; Newcomb, Polly O; Sorensen, Poul M; Press, Oliver A

    2015-08-14

    IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. A single sub-erythematous exposure of solar-simulated radiation on the elicitation phase of contact hypersensitivity induces IL-10-producing T-regulatory cells in human skin.

    PubMed

    Stoebner, Pierre E; Rahmoun, Massilva; Ferrand, Christophe; Meunier, Laurent; Yssel, Hans; Pène, Jérôme

    2006-08-01

    Solar ultraviolet (UV) radiation has hazardous effects on human health that are, in part, associated with its immunosuppressive effects via the induction of interleukin (IL)-10 production. Although IL-10 is produced by both T helper type 2 (Th2) cells and T-regulatory type 1 (Tr1) cells, the relative contribution of either subset in UV radiation-induced immunosuppression has not been established. Here, we show that T cells isolated from non-treated allergic contact dermatitis (ACD) reactions, 48 h following nickel challenge and propagated for 7-10 days in the presence of IL-2, were mainly CD4(+) and produced IL-10, but little interferon-gamma. A single sub-erythematous solar-simulated radiation (SSR) prior to antigen challenge exposure resulted in a clinical attenuation of the intensity of ACD reactions which was associated with a significant increase in both the magnitude of IL-10 production by skin-infiltrating T cells and the frequency of IL-10-producing Tr1 cells. Skin-infiltrating T cells in SSR-exposed, as well as non-exposed, ACD reactions showed a perturbed T-cell receptor (TCR)-Vbeta repertoire, without overexpression of a particular TCR-Vbeta gene product, indicating the presence of high frequencies of nickel non-specific T cells in ACD reactions. These results show that a single sub-erythematous SSR induces immunosuppression via the cutaneous infiltration of IL-10-producing Tr1, and to a lesser extent, Th2 cells.

  12. Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma.

    PubMed

    Brown, Christine E; Badie, Behnam; Barish, Michael E; Weng, Lihong; Ostberg, Julie R; Chang, Wen-Chung; Naranjo, Araceli; Starr, Renate; Wagner, Jamie; Wright, Christine; Zhai, Yubo; Bading, James R; Ressler, Julie A; Portnow, Jana; D'Apuzzo, Massimo; Forman, Stephen J; Jensen, Michael C

    2015-09-15

    A first-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor (CAR)-engineered, autologous primary human CD8(+) cytotoxic T lymphocytes (CTL) targeting IL13Rα2 for the treatment of recurrent glioblastoma (GBM). Three patients with recurrent GBM were treated with IL13(E13Y)-zetakine CD8(+) CTL targeting IL13Rα2. Patients received up to 12 local infusions at a maximum dose of 10(8) CAR-engineered T cells via a catheter/reservoir system. We demonstrate the feasibility of manufacturing sufficient numbers of autologous CTL clones expressing an IL13(E13Y)-zetakine CAR for redirected HLA-independent IL13Rα2-specific effector function for a cohort of patients diagnosed with GBM. Intracranial delivery of the IL13-zetakine(+) CTL clones into the resection cavity of 3 patients with recurrent disease was well-tolerated, with manageable temporary brain inflammation. Following infusion of IL13-zetakine(+) CTLs, evidence for transient anti-glioma responses was observed in 2 of the patients. Analysis of tumor tissue from 1 patient before and after T-cell therapy suggested reduced overall IL13Rα2 expression within the tumor following treatment. MRI analysis of another patient indicated an increase in tumor necrotic volume at the site of IL13-zetakine(+) T-cell administration. These findings provide promising first-in-human clinical experience for intracranial administration of IL13Rα2-specific CAR T cells for the treatment of GBM, establishing a foundation on which future refinements of adoptive CAR T-cell therapies can be applied. ©2015 American Association for Cancer Research.

  13. Secreted protein acidic and rich in cysteine functions in colitis via IL17A regulation in mucosal CD4+ T cells.

    PubMed

    Tanaka, Makoto; Takagi, Tomohisa; Naito, Yuji; Uchiyama, Kazuhiko; Hotta, Yuma; Toyokawa, Yuki; Ushiroda, Chihiro; Hirai, Yasuko; Aoi, Wataru; Higashimura, Yasuki; Mizushima, Katsura; Okayama, Tetsuya; Katada, Kazuhiro; Kamada, Kazuhiro; Ishikawa, Takeshi; Handa, Osamu; Itoh, Yoshito

    2018-03-01

    Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycol that regulates cell proliferation, tissue repair, and tumorigenesis. Despite evidence linking SPARC to inflammation, the mechanisms are unclear. Accordingly, the role of SPARC in intestinal inflammation was investigated. Colitis was induced in wild-type (WT) and SPARC knockout (KO) mice using trinitrobenzene sulfonic acid (TNBS). Colons were assessed for damage; leukocyte infiltration; Tnf, Ifng, Il17a, and Il10 mRNA expression; and histology. Cytokine profiling of colonic lamina propria mononuclear cells (LPMCs) was performed by flow cytometry. Naïve CD4 + T cells were isolated from WT and SPARC KO mouse spleens, and the effect of SPARC on Th17 cell differentiation was examined. Recombination activating gene 1 knockout (RAG1 KO) mice reconstituted with T cells from either WT or SPARC KO mice were investigated. Trinitrobenzene sulfonic acid exposure significantly reduced bodyweight and increased mucosal inflammation, leukocyte infiltration, and Il17a mRNA expression in WT relative to SPARC KO mice. The percentage of IL17A-producing CD4 + T cells among LPMCs from KO mice was lower than that in WT mice when both groups were exposed to TNBS. Th17 cell differentiation was suppressed in cells from SPARC KO mice. In the T cell transfer colitis model, RAG1 KO mice receiving T cells from WT mice were more severely affected than those reconstituted with cells from SPARC KO mice. Secreted protein acidic and rich in cysteine accelerates colonic mucosal inflammation via modulation of IL17A-producing CD4 + T cells. SPARC is a potential therapeutic target for conditions involving intestinal inflammation. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  14. Role of T cells in the B-cell response: glutaraldehyde-fixed T-helper hybridoma cells synergize with the lymphokine IL-4 to induce B-cell activation and proliferation.

    PubMed

    Kubota, E; McKenzie, D T; Dutton, R W; Swain, S L

    1991-01-01

    Antigen-unselected helper T-cell hybridomas (Th) which activate normal resting B cells to RNA synthesis and proliferation in the presence of concanavalin A (Con A) have been developed. The response is completely Th cell dependent, and not restricted by the haplotype of the B-cell major histocompatibility complex (MHC). Culture supernatants from the Con A-stimulated Th hybridomas contain interleukin-4 (IL-4) and IL-2, but undetectable level of IL-5. The supernatant alone, however, does not induce B-cell activation or proliferation. Although the Con A-mediated Th cell-dependent B-cell response occurs in an MHC-unrestricted manner, the response of resting B cells can be blocked by monoclonal Ia antibody specific for the surface class II molecules of the responding B cell. The response is also blocked by monoclonal antibody to L3T4. Significant activation and proliferation of resting B cells can also be triggered by glutaraldehyde-fixed Th hybridomas and Con A when exogenous IL-4 is added. The stimulation with fixed Th hybridomas plus IL-4 can be inhibited by monoclonal anti-L3T4 or anti-Ia. These results suggest that maximal B-cell activation requires a direct helper T cell-B cell interaction which depends on availability of Ia on the B cell and L3T4 on the T cell, even when Con A overcomes the requirement for MHC-restricted T-cell recognition. We suggest that this signal, in conjunction with T-cell produced lymphokine IL-4, is responsible for the activation and subsequent proliferation of the B cells which occurs following interaction with T cells.

  15. A link between osteomyelitis and IL1RN and IL1B polymorphisms—a study in patients from Northeast Brazil

    PubMed Central

    Alves De Souza, Clinio; Queiroz Alves De Souza, Argos; Queiroz Alves De Souza, Maria do Socorro; Dias Leite, José Alberto; Silva De Morais, Maíra; Barem Rabenhorst, Sílvia Helena

    2017-01-01

    Background and purpose Treatment failure of osteomyelitis can result from genetic susceptibility, highlighting polymorphisms of the interleukin-1 (IL-1) family members, central mediators of innate immunity and inflammation. Polymorphisms are DNA sequence variations that are common in the population (1% or more) and represent multiple forms of a single gene. We investigated the association of IL1RNVNTR (rs2234663) and IL1B-511C > T (rs16944) polymorphisms with osteomyelitis development in patients operated on because of bone trauma. Patients and methods 153 patients who fulfilled the inclusion criteria were enrolled from a referral public hospital for trauma. All the patients were followed up daily until hospital discharge and, after this, on an outpatient basis. Patients were treated with prophylactic antimicrobials and surgery according to traumatology service protocol. The IL1RNVNTR and the IL1B-511C > T polymorphisms were determined by PCR and PCR-RFLP, respectively. Results The IL1RN*2/*2 genotype was associated (OR: 7; p < 0.001) with a higher risk of osteomyelitis and was also significantly associated with Staphylococcus aureus infection. The haplotypes (combination of different markers) *2-C and *2-T were also associated with osteomyelitis development. Interpretation IL1B-511C > T and IL1RNVNTR polymorphisms were associated with osteomyelitis development, which may have implications for patients with bone traumas. These data may be relevant for new therapeutic strategies for this disease. PMID:28682145

  16. A link between osteomyelitis and IL1RN and IL1B polymorphisms-a study in patients from Northeast Brazil.

    PubMed

    Alves De Souza, Clinio; Queiroz Alves De Souza, Argos; Queiroz Alves De Souza, Maria do Socorro; Dias Leite, José Alberto; Silva De Morais, Maíra; Barem Rabenhorst, Sílvia Helena

    2017-10-01

    Background and purpose - Treatment failure of osteomyelitis can result from genetic susceptibility, highlighting polymorphisms of the interleukin-1 (IL-1) family members, central mediators of innate immunity and inflammation. Polymorphisms are DNA sequence variations that are common in the population (1% or more) and represent multiple forms of a single gene. We investigated the association of IL1RNVNTR (rs2234663) and IL1B-511C > T (rs16944) polymorphisms with osteomyelitis development in patients operated on because of bone trauma. Patients and methods - 153 patients who fulfilled the inclusion criteria were enrolled from a referral public hospital for trauma. All the patients were followed up daily until hospital discharge and, after this, on an outpatient basis. Patients were treated with prophylactic antimicrobials and surgery according to traumatology service protocol. The IL1RNVNTR and the IL1B-511C > T polymorphisms were determined by PCR and PCR-RFLP, respectively. Results - The IL1RN*2/*2 genotype was associated (OR: 7; p < 0.001) with a higher risk of osteomyelitis and was also significantly associated with Staphylococcus aureus infection. The haplotypes (combination of different markers) *2-C and *2-T were also associated with osteomyelitis development. Interpretation - IL1B-511C > T and IL1RNVNTR polymorphisms were associated with osteomyelitis development, which may have implications for patients with bone traumas. These data may be relevant for new therapeutic strategies for this disease.

  17. MTORC1 EXPANDS TH17 AND IL-4+ DN T CELLS AND CONTRACTS TREGS IN SLE

    PubMed Central

    Kato, Hiroshi; Perl, Andras

    2014-01-01

    The mechanistic target of rapamycin (mTOR) is activated in CD4−CD8− double-negative (DN) T cells and its blockade is therapeutic in systemic lupus erythematosus (SLE) patients. Murine studies showed the involvement of mTOR complex 1 (mTORC1) and 2 (mTORC2) in the differentiation of Th1/Th17 cells and Th2 cells, respectively. Here, we investigated the roles of mTORC1 and mTORC2 in T-cell lineage development in SLE and matched healthy control (HC) subjects. mTORC1 activity was increased while mTORC2 was reduced as assessed by phosphorylation of their substrates pS6K or pS6RP and pAkt, respectively. Rapamycin inhibited mTORC1 and enhanced mTORC2. IL-4 expression was increased in freshly isolated CD8+ lupus T cells (SLE: 8.09±1.93%, HC: 3.61±0.49%; p=0.01). DN T cells had greater IL-4 expression than CD4+ or CD8+ T cells of SLE patients after 3 day in vitro stimulation, which was suppressed by rapamycin (control: 9.26±1.48%, rapamycin: 5.03±0.66%; p<0.001). GATA-3 expression was increased in CD8+ lupus T cells (p<0.01) and insensitive to rapamycin treatment. IFN-γ expression was reduced in all lupus T cell subsets (p=1.0×10−5) and also resisted rapamycin. IL-17 expression was increased in CD4+ lupus T cells (SLE: 3.62±0.66%, HC: 2.29±0.27%; p=0.019), which was suppressed by rapamycin (control: 3.91±0.79%, rapamycin: 2.22±0.60%; p<0.001). Frequency of Tregs was reduced in SLE (SLE: 1.83±0.25%, HC: 2.97±0.27%; p=0.0012). Rapamycin inhibited mTORC1 in Tregs and promoted their expansion. Neutralization of IL-17 but not IL-4 also expanded Tregs in SLE and HC subjects. These results indicate that mTORC1 expands IL-4+ DN T and Th17 cells and contracts Tregs in SLE. PMID:24683191

  18. Interleukin 35 (IL-35) and IL-37: Intestinal and peripheral expression by T and B regulatory cells in patients with Inflammatory Bowel Disease.

    PubMed

    Fonseca-Camarillo, Gabriela; Furuzawa-Carballeda, Janette; Yamamoto-Furusho, Jesús K

    2015-10-01

    The aim of the study was to characterize and to quantify peripheral and tissue. IL-35- and IL-37-producing cells in Inflammatory Bowel Disease (IBD) patients. We studied a total of 38 active UC, 31 inactive UC, 17 active CD, and 13 inactive CD and 50 non-inflamed tissues as control group. Gene expression was measured by real time polymerase chain reaction (RT-PCR) and protein expression was evaluated in tissue by immunohistochemistry and in peripheral blood mononuclear cells by flow cytometry. Higher levels of IL-35 was produced by intestinal regulatory B cells and circulating regulatory CD4(+) and CD8(+) T cells in active vs. inactive disease or healthy donors (P<0.05). The IL-37 was conspicuously synthesized by circulating B cells, active natural killer cells and monocytes. These results suggest that down-regulation of inflammation in active IBD patients might be based on the increased expression of IL-35 and IL-37. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. The presence of IL-8 +781 T/C polymorphism is associated with the parameters of severe Clostridium difficile infection.

    PubMed

    Czepiel, Jacek; Biesiada, Grażyna; Dróżdż, Mirosław; Gdula-Argasińska, Joanna; Żurańska, Justyna; Marchewka, Jakub; Perucki, William; Wołkow, Paweł; Garlicki, Aleksander

    2018-01-01

    There is large variation in the clinical manifestations of Clostridium difficile infection (CDI). We also still can not predict which patients are more susceptible to reinfection with CDI. The aim of our study was to evaluate the effect of gene single nucleotide polymorphisms (SNP) of proinflammatory cytokines, specifically IL-1β, IL-8 on the development, clinical course and recurrence of CDI. We performed a prospective study of adults (130 people ≥ 18 years) including 65 patients with CDI treated in tertiary hospital and 65 healthy persons. The following 3 variants were analyzed for the occurrence of gene polymorphisms in patients with CDI versus the control group: IL-1β +3953 A/G (rs1143634), IL-1β -31 A/G (rs1143627), and IL-8 +781 T/C (rs2227306). Then, we assessed the correlation between these genetic polymorphisms and biochemical parameters important in CDI course, CDI severity as well as CDI recurrence. The presence of genetic polymorphisms of IL-1β +3953 A/G, -31 A/G and IL-8 +781 T/C did not have an effect on the development or recurrence of CDI. The presence of IL-8 +781 T/C polymorphism is associated with the severe CDI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Salivary Concentrations of Interleukin (IL)-1β, IL-17A, and IL-23 Vary in Relation to Periodontal Status.

    PubMed

    Liukkonen, Joonas; Gürsoy, Ulvi K; Pussinen, Pirkko J; Suominen, Anna L; Könönen, Eija

    2016-12-01

    Interleukin (IL)-23-induced T helper (Th) 17 pathway is involved in the pathogenesis of periodontal disease. This study's aim is to determine levels of IL-1β, IL-17A, IL-23, and lipopolysaccharide (LPS) in saliva, and to examine whether their salivary concentrations are associated with periodontal health status. Saliva samples originated from 220 participants; 76 had generalized periodontitis (GP) and 65 had localized periodontitis (LP), whereas 79 without periodontitis were used as controls. Cytokine analyses were performed by a flow cytometry-based technique and LPS analyses from pellet by commercially optimized assay coupled with chromogenic substrate. Salivary concentrations of IL-17A and IL-23 were elevated significantly in patients with LP compared with controls and patients with GP. Salivary IL-1β concentrations were significantly higher in patients with GP than in patients with LP, whereas no difference was found between LP and control groups. Significant correlation was found between concentrations of IL-17A and IL-23 or IL-1β. LPS concentrations did not have significant associations with any of the tested ILs. Elevated salivary IL-1β concentrations are related to GP, whereas distinct elevation and reduction profiles of IL-17A and IL-23 are detected in saliva of patients with LP and GP.

  1. Vitamin D Counteracts an IL-23-Dependent IL-17A+IFN-γ+ Response Driven by Urban Particulate Matter.

    PubMed

    Mann, Elizabeth H; Ho, Tzer-Ren; Pfeffer, Paul E; Matthews, Nick C; Chevretton, Elfy; Mudway, Ian; Kelly, Frank J; Hawrylowicz, Catherine M

    2017-09-01

    Urban particulate matter (UPM) air pollution and vitamin D deficiency are detrimentally associated with respiratory health. This is hypothesized to be due in part to regulation of IL-17A, which UPM is reported to promote. Here, we used a myeloid dendritic cell (DC)-memory CD4 + T cell co-culture system to characterize UPM-driven IL-17A + cells, investigate the mechanism by which UPM-primed DCs promote this phenotype, and address evidence for cross-regulation by vitamin D. CD1c + myeloid DCs were cultured overnight with or without a reference source of UPM and/or active vitamin D (1,25[OH] 2 D 3 ) before they were co-cultured with autologous memory CD4 + T cells. Supernatants were harvested for cytokine analysis on Day 5 of co-culture, and intracellular cytokine staining was performed on Day 7. UPM-primed DCs increased the proportion of memory CD4 + T cells expressing the T helper 17 cell (Th17)-associated cytokines IL-17A, IL-17F, and IL-22, as well as IFN-γ, granulocyte-macrophage colony-stimulating factor, and granzyme B. Notably, a large proportion of the UPM-driven IL-17A + cells co-expressed these cytokines, but not IL-10, indicative of a proinflammatory Th17 profile. UPM-treated DCs expressed elevated levels of il23 mRNA and increased secretion of IL-23p40. Neutralization of IL-23 in culture reduced the frequency of IL-17A + IFN-γ + cells without affecting cell proliferation. 1,25(OH) 2 D 3 counteracted the UPM-driven DC maturation and inhibited the frequency of IL-17A + IFN-γ + cells, most prominently when DCs were co-treated with the corticosteroid dexamethasone, while maintaining antiinflammatory IL-10 synthesis. These data indicate that UPM might promote an inflammatory milieu in part by inducing an IL-23-driven proinflammatory Th17 response. Restoring vitamin D sufficiency may counteract these UPM-driven effects without obliterating important homeostatic immune functions.

  2. High intracytoplasmatic levels of Il-4 and Il-5 in a patient with Gleichs syndrome: case report.

    PubMed

    Novembre, E; Mori, F; Arcangeli, F; Cianferoni, A; Bernardini, R; Pucci, N; Annunziato, F; Parronchi, P; De Martino, M; Vierucci, A

    2006-01-01

    Gleichs syndrome is characterized by recurrent localized angioedema, hypereosinophilia, elevated levels of IgM, rapid weight gain, itchy urticaria and fever. Little is known about the pathogenesis of this disease. Increased serum levels for IL5, IL6 and C5a have been reported before and during clinical exacerbations. In order to better understand the role of the T cells in Gleichs syndrome we analyzed the intracellular cytokine expression in CD3+ cells of a patient affected by the disease. As hypereosinophilia was documented, we asked whether IL-4 and IL-5 levels were increased, and the intracytoplasmatic expression of these Th2-cytokines was determined. The percentage of T lymphocytes (CD3-gated cells) of both CD8- and CD8+ phenotype expressing different cytokines showed an unusually high percentage of Th2-related cytokine (IL-4, IL-5 and IL-13) expressing T lymphocytes. The two new variants (myeloproliferative and lymphoproliferative) seem to account for hypereosinophilia in patients with hypereosinophilic syndrome (HES). In the lymphroliferative variant, the presence of a clonal CD3-CD4+ Th2 like lymphocyte secreting IL-4 and IL-5 in peripheral blood, may explain the hypereosinophilia and the hyper-IgE. In our study we show that the patient had a lymphoproliferative variant and her T cell had a Th2 type phenotype. Moreover, we suggest that Th2 lymphocytes may play a role in the pathogenesis of Gleichs syndrome. Further studies are needed to evaluate the possibility that a polyclonal aspecific activation of Th2 type cells can lead to hypereosinophilia, IgE production and the other manifestations typical of Gleichs syndrome.

  3. An Il12-Il2-Antibody Fusion Protein Targeting Hodgkin's Lymphoma Cells Potentiates Activation Of Nk And T Cells For An Anti-Tumor Attack

    PubMed Central

    Friedrichs, Björn; Heuser, Claudia; Guhlke, Stefan; Abken, Hinrich; Hombach, Andreas A.

    2012-01-01

    Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30+ Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer. PMID:23028547

  4. Evidence for Involvement of IL-9 and IL-22 in Cows' Milk Allergy in Infants.

    PubMed

    Barros, Karina V; Flor Silveira, Vera L; Laranjeira, Marisa S; Wandalsen, Neusa F; Passeti, Susana; de Oliveira, Roberta; Munekata, Regina V; Noakes, Paul S; Miles, Elizabeth A; Calder, Philip C

    2017-09-21

    Although allergic inflammation is characterized by a T helper (Th) 2-dominant immune response, the discovery of a role for new T cell subsets in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogeneses of allergic diseases. We evaluated plasma cytokine profiles in infants with cows' milk allergy (CMA), who were being treated with an elimination diet. In a prospective, randomized and controlled study, infants (aged 8.4 ± 3.9 months) with CMA were treated with an elimination diet for 120 days, which replaced cows' milk with a hydrolysed soy protein formula ( n = 26) or a free amino acid formula ( n = 20). Blood samples were collected before treatment during active disease (T0) and after 120 days, when symptoms were absent (T1). Plasma cytokine concentrations were measured. Infants with CMA had higher plasma concentrations of interleukin (IL)-4 and IL-13 and lower concentrations of IL-9, IL-17A and interferon-γ, compared with healthy breast-fed infants. At T0, there was a positive correlation between blood eosinophil numbers and plasma concentrations of IL-4, IL-9, IL-17A and IL-22. Treatment with a cows' milk elimination diet resulted in a decrease in plasma IL-4, IL-9, IL-13 and IL-22 and an increase in plasma IL-17A. We conclude that IL-4 and IL-13 are elevated in active CMA. The association of IL-9 and IL-22 with eosinophilia, and the decrease in these two cytokines with cows' milk elimination, suggests that they both play a role in the symptoms observed in CMA and may be important targets for future interventions.

  5. Intramuscular delivery of heterodimeric IL-15 DNA in macaques produces systemic levels of bioactive cytokine inducing proliferation of NK and T cells.

    PubMed

    Bergamaschi, C; Kulkarni, V; Rosati, M; Alicea, C; Jalah, R; Chen, S; Bear, J; Sardesai, N Y; Valentin, A; Felber, B K; Pavlakis, G N

    2015-01-01

    Interleukin-15 (IL-15) is a common γ-chain cytokine that has a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha (IL-15Rα) chain, which together form the IL-15 heterodimer. We have generated DNA vectors expressing the heterodimeric IL-15 by optimizing mRNA expression and protein trafficking. Repeated administration of these DNA plasmids by intramuscular injection followed by in vivo electroporation in rhesus macaques resulted in sustained high levels of IL-15 in plasma, with no significant toxicity. Administration of DNAs expressing heterodimeric IL-15 also resulted in an increased frequency of NK and T cells undergoing proliferation in peripheral blood. Heterodimeric IL-15 led to preferential expansion of CD8(+)NK cells, all memory CD8(+) T-cell subsets and effector memory CD4(+) T cells. Expression of heterodimeric IL-15 by DNA delivery to the muscle is an efficient procedure to obtain high systemic levels of bioactive cytokine, without the toxicity linked to the high transient cytokine peak associated with protein injection.

  6. Germinal Center T Follicular Helper Cell IL-4 Production Is Dependent on Signaling Lymphocytic Activation Molecule Receptor (CD150)

    PubMed Central

    Yusuf, Isharat; Kageyama, Robin; Monticelli, Laurel; Johnston, Robert J.; DiToro, Daniel; Hansen, Kyle; Barnett, Burton; Crotty, Shane

    2010-01-01

    CD4 T cell help is critical for the generation and maintenance of germinal centers (GCs), and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP [SH2D1A]) expression in CD4 T cells is essential for GC development. However, SAP-deficient mice have only a moderate defect in TFH differentiation, as defined by common TFH surface markers. CXCR5+ TFH cells are found within the GC, as well as along the boundary regions of T/B cell zones. In this study, we show that GC-associated T follicular helper (GC TFH) cells can be identified by their coexpression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. GC TFH cells are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH cell subset and SAP− TFH cells are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that uses SAP signaling, is specifically required for IL-4 production by GC TFH cells. GC TFH cells require IL-4 and -21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by GC CD4 T cells but not in TFH cell and GC TFH cell differentiation. PMID:20525889

  7. Transcription Factor KLF10 Constrains IL-17-Committed Vγ4+ γδ T Cells

    PubMed Central

    Kim, Girak; Gu, Min Jeong; Kim, Soo Ji; Ko, Kwang Hyun; Kye, Yoon-Chul; Kim, Cheol Gyun; Cho, Jae-Ho; Lee, Woon-Kyu; Song, Ki-Duk; Chu, Hyuk; Park, Yeong-Min; Han, Seung Hyun; Yun, Cheol-Heui

    2018-01-01

    γδ T cells, known to be an important source of innate IL-17 in mice, provide critical contributions to host immune responses. Development and function of γδ T cells are directed by networks of diverse transcription factors (TFs). Here, we examine the role of the zinc finger TFs, Kruppel-like factor 10 (KLF10), in the regulation of IL-17-committed CD27− γδ T (γδ27−-17) cells. We found selective augmentation of Vγ4+ γδ27− cells with higher IL-17 production in KLF10-deficient mice. Surprisingly, KLF10-deficient CD127hi Vγ4+ γδ27−-17 cells expressed higher levels of CD5 than their wild-type counterparts, with hyper-responsiveness to cytokine, but not T-cell receptor, stimuli. Thymic maturation of Vγ4+ γδ27− cells was enhanced in newborn mice deficient in KLF10. Finally, a mixed bone marrow chimera study indicates that intrinsic KLF10 signaling is requisite to limit Vγ4+ γδ27−-17 cells. Collectively, these findings demonstrate that KLF10 regulates thymic development of Vγ4+ γδ27− cells and their peripheral homeostasis at steady state. PMID:29541070

  8. Differential Responsiveness of Innate-like IL-17- and IFN-γ-Producing γδ T Cells to Homeostatic Cytokines.

    PubMed

    Corpuz, Theresa M; Stolp, Jessica; Kim, Hee-Ok; Pinget, Gabriela V; Gray, Daniel H D; Cho, Jae-Ho; Sprent, Jonathan; Webster, Kylie E

    2016-01-15

    γδ T cells respond to molecules upregulated following infection or cellular stress using both TCR and non-TCR molecules. The importance of innate signals versus TCR ligation varies greatly. Both innate-like IL-17-producing γδ T (γδT-17) and IFN-γ-producing γδ T (γδT-IFNγ) subsets tune the sensitivity of their TCR following thymic development, allowing robust responses to inflammatory cytokines in the periphery. The remaining conventional γδ T cells retain high TCR responsiveness. We determined homeostatic mechanisms that govern these various subsets in the peripheral lymphoid tissues. We found that, although innate-like γδT-17 and γδT-IFNγ cells share elements of thymic development, they diverge when it comes to homeostasis. Both exhibit acute sensitivity to cytokines compared with conventional γδ T cells, but they do not monopolize the same cytokine. γδT-17 cells rely exclusively on IL-7 for turnover and survival, aligning them with NKT17 cells; IL-7 ligation triggers proliferation, as well as promotes survival, upregulating Bcl-2 and Bcl-xL. γδT-IFNγ cells instead depend heavily on IL-15. They display traits analogous to memory CD8(+) T cells and upregulate Bcl-xL and Mcl-1 upon cytokine stimulation. The conventional γδ T cells display low sensitivity to cytokine-alone stimulation and favor IL-7 for their turnover, characteristics reminiscent of naive αβ T cells, suggesting that they may also require tonic TCR signaling for population maintenance. These survival constraints suggest that γδ T cell subsets do not directly compete with each other for cytokines, but instead fall into resource niches with other functionally similar lymphocytes. Copyright © 2016 by The American Association of Immunologists, Inc.

  9. CXCL4 is a novel inducer of human Th17 cells and correlates with IL-17 and IL-22 in psoriatic arthritis.

    PubMed

    Affandi, Alsya J; Silva-Cardoso, Sandra C; Garcia, Samuel; Leijten, Emmerik F A; van Kempen, Tessa S; Marut, Wioleta; van Roon, Joel A G; Radstake, Timothy R D J

    2018-03-01

    CXCL4 regulates multiple facets of the immune response and is highly upregulated in various Th17-associated rheumatic diseases. However, whether CXCL4 plays a direct role in the induction of IL-17 production by human CD4 + T cells is currently unclear. Here, we demonstrated that CXCL4 induced human CD4 + T cells to secrete IL-17 that co-expressed IFN-γ and IL-22, and differentiated naïve CD4 + T cells to become Th17-cytokine producing cells. In a co-culture system of human CD4 + T cells with monocytes or myeloid dendritic cells, CXCL4 induced IL-17 production upon triggering by superantigen. Moreover, when monocyte-derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated increased levels of IL-17, IFN-γ, and proliferation by CD4 + T cells. Furthermore, the CXCL4 levels in synovial fluid from psoriatic arthritis patients strongly correlated with IL-17 and IL-22 levels. A similar response to CXCL4 of enhanced IL-17 production by CD4 + T cells was also observed in patients with psoriatic arthritis. Altogether, we demonstrate that CXCL4 boosts pro-inflammatory cytokine production especially IL-17 by human CD4 + T cells, either by acting directly or indirectly via myeloid antigen presenting cells, implicating a role for CXCL4 in PsA pathology. © 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. IL-21 Promotes Late Activator APC-Mediated T Follicular Helper Cell Differentiation in Experimental Pulmonary Virus Infection

    PubMed Central

    Yoo, Jae-Kwang; Braciale, Thomas J.

    2014-01-01

    IL-21 is a type-I cytokine that has pleiotropic immuno-modulatory effects. Primarily produced by activated T cells including NKT and TFH cells, IL-21 plays a pivotal role in promoting TFH differentiation through poorly understood cellular and molecular mechanisms. Here, employing a mouse model of influenza A virus (IAV) infection, we demonstrate that IL-21, initially produced by NKT cells, promotes TFH differentiation by promoting the migration of late activator antigen presenting cell (LAPC), a recently identified TFH inducer, from the infected lungs into the draining lymph nodes (dLN). LAPC migration from IAV-infected lung into the dLN is CXCR3-CXCL9 dependent. IL-21-induced TNF-α production by conventional T cells is critical to stimulate CXCL9 expression by DCs in the dLN, which supports LAPC migration into the dLN and ultimately facilitates TFH differentiation. Our results reveal a previously unappreciated mechanism for IL-21 modulation of TFH responses during respiratory virus infection. PMID:25251568

  11. CCL20, (gamma)(delta) T cells, and IL-22 in corneal epithelial healing

    USDA-ARS?s Scientific Manuscript database

    After corneal epithelial abrasion, leukocytes and platelets rapidly enter the corneal stroma, and CCR6 (+) IL-17(+) gamma delta T cells migrate into the epithelium. Gamma delta T-cell-deficient (TCRd(-/-)) mice have significantly reduced inflammation and epithelial wound healing. Epithelial CCL20 mR...

  12. Diagnostic value of T-Spot TB combined with INF-γ and IL-27 in tuberculous pleurisy

    PubMed Central

    Zhang, Meng; Xiong, Dedong; Li, Hongxia; Wang, Zonglan; Li, Renzhe

    2018-01-01

    The purpose of the present study was to investigate the diagnostic value of T cells spot test (T-Spot TB) combined with interferon-γ (INF-γ) and interleukin-27 (IL-27) in tuberculous pleurisy. Sixty patients with tuberculous pleurisy (observation group) and 60 patients with non-tuberculous pleurisy (control group) were enrolled in this study. T-Spot TB was performed to detect the pleural effusion of two groups of patients. Levels of IFN-γ and IL-27 in serum and pleural effusion were detected by enzyme-linked immunosorbent assay (ELISA). Relative expression of IFN-γ mRNA and IL-27 mRNA in peripheral blood mononuclear cells were detected by RT-PCR. Positive rate of T-Spot TB in observation group was 96.7% (58 cases), which was significantly higher than that in control group (p<0.05). Concentration of INF-γ in pleural effusion of observation group was 468.6±24.8 ng/l, which was significantly higher than that in control group (131.3±18.7 ng/l, p<0.05). Concentration of IL-27 in pleural effusion of observation group was 423.4±37.2 ng/l, which was significantly higher than that in control group (116.2±15.5 ng/l, p<0.05). Concentrations of INF-γ and IL-27 in serum of observation group were 48.2±13.4 and 41.7±10.6 ng/l, respectively, which were significantly higher than those in control group (38.6±11.2 and 35.3±8.4 ng/l, p<0.05). Relative expression levels of INF-γ mRNA and IL-27 mRNA in observation group were significantly higher than those in control group (p<0.05). Therefore, combination of T-Spot TB with INF-γ and IL-27 has significant application value in the clinical diagnosis of tuberculous pleurisy, and should be popularized. PMID:29399137

  13. Diagnostic value of T-Spot TB combined with INF-γ and IL-27 in tuberculous pleurisy.

    PubMed

    Zhang, Meng; Xiong, Dedong; Li, Hongxia; Wang, Zonglan; Li, Renzhe

    2018-02-01

    The purpose of the present study was to investigate the diagnostic value of T cells spot test (T-Spot TB) combined with interferon-γ (INF-γ) and interleukin-27 (IL-27) in tuberculous pleurisy. Sixty patients with tuberculous pleurisy (observation group) and 60 patients with non-tuberculous pleurisy (control group) were enrolled in this study. T-Spot TB was performed to detect the pleural effusion of two groups of patients. Levels of IFN-γ and IL-27 in serum and pleural effusion were detected by enzyme-linked immunosorbent assay (ELISA). Relative expression of IFN-γ mRNA and IL-27 mRNA in peripheral blood mononuclear cells were detected by RT-PCR. Positive rate of T-Spot TB in observation group was 96.7% (58 cases), which was significantly higher than that in control group (p<0.05). Concentration of INF-γ in pleural effusion of observation group was 468.6±24.8 ng/l, which was significantly higher than that in control group (131.3±18.7 ng/l, p<0.05). Concentration of IL-27 in pleural effusion of observation group was 423.4±37.2 ng/l, which was significantly higher than that in control group (116.2±15.5 ng/l, p<0.05). Concentrations of INF-γ and IL-27 in serum of observation group were 48.2±13.4 and 41.7±10.6 ng/l, respectively, which were significantly higher than those in control group (38.6±11.2 and 35.3±8.4 ng/l, p<0.05). Relative expression levels of INF-γ mRNA and IL-27 mRNA in observation group were significantly higher than those in control group (p<0.05). Therefore, combination of T-Spot TB with INF-γ and IL-27 has significant application value in the clinical diagnosis of tuberculous pleurisy, and should be popularized.

  14. Gene polymorphisms of TNF-alpha-308 (G/A), IL-10(-1082) (G/A), IL-6(-174) (G/C) and IL-1Ra (VNTR) in Egyptian cases with type 1 diabetes mellitus.

    PubMed

    Settin, Ahmad; Ismail, Azza; El-Magd, Megahed Abo; El-Baz, Rizk; Kazamel, Amira

    2009-01-01

    Type 1 diabetes (T1D) is a genetically conditioned autoimmune disease in which cytokines play an important role. Objectives. To check for the association of polymorphisms of cytokine genes with type 1 diabetes. Subjects. This work included 50 cases with T1D and 98 healthy individuals from the Nile Delta region of Egypt. Cases included 20 males and 30 females with a median age of 25 and range of 15-50 years. DNA was amplified using PCR with sequence-specific primers for detection of polymorphisms related to tumor necrosis factor (TNF)-alpha(- 308) (G/A), interleukin (IL)-10(- 1082) (G/A), IL-6(- 174) (G/C), and IL-1Ra (VNTR). Cases with T1D showed significant higher frequency of genotypes of TNF-alpha(- 308) AA (p < 0.001, odds ratio (OR) = 7.91), IL-6-17CC (p < 0.05, OR = 3.36) and IL-1Ra A1A1 (p < 0.05, OR = 3.68) with significant lower frequencies of TNF-alpha(- 308) GA, and IL-1Ra A1A2 genotypes (p < 0.001 and < 0.05, respectively). They also showed significant higher frequency of TNF-alpha(- 308) allele A (p < 0.05, OR = 2.0), IL-1Ra allele A1 (p < 0.05, OR = 2.98) with a significant lower frequency of TNF-alpha(- 308) G allele and IL-1Ra A2 allele (p < 0.05). No significant difference was detected among cases in relation to IL-10(- 1082) (G/A) genotypes or alleles nor in relation to age, sex, consanguinity or family history of the disease. Polymorphisms related to TNF-alpha and IL-1Ra genes may be considered genetic markers for T1D among Egyptians with a potential impact on family counseling and management.

  15. Inactive Gingipains from P. gingivalis Selectively Skews T Cells toward a Th17 Phenotype in an IL-6 Dependent Manner

    PubMed Central

    Glowczyk, Izabela; Wong, Alicia; Potempa, Barbara; Babyak, Olena; Lech, Maciej; Lamont, Richard J.; Potempa, Jan; Koziel, Joanna

    2017-01-01

    Gingipain cysteine proteases are considered key virulence factors of Porphyromonas gingivalis. They significantly influence antibacterial and homeostatic functions of macrophages, neutrophils, the complement system, and cytokine networks. Recent data indicate the role of P. gingivalis in T cell differentiation; however, the involvement of gingipains in this process remains elusive. Therefore, the aim of this study was to investigate the contribution of danger signals triggered by the gingipains on the generation of Th17 cells, which play a key role in protection against bacterial diseases but may cause chronic inflammation and bone resorption. To this end we compared the effects of the wild-type strain of P. gingivalis (W83) with its isogenic mutant devoid of gingipain activity (ΔKΔRAB), and bacterial cells pretreated with a highly-specific inhibitor of gingipains activity (KYTs). Antigen presenting cells (APCs), both professional (dendritic cells), and non-professional (gingival keratinocytes), exposed to viable bacteria expressed high amounts of cytokines (IL-6, IL-21, IL-23). These cytokines are reported to either stimulate or balance the Th17-dependent immune response. Surprisingly, cells infected with P. gingivalis devoid of gingipain activity showed increased levels of all tested cytokines compared to bacteria with fully active enzymes. The effect was dependent on both the reduction of cytokine proteolysis and the lack of cross-talk with other bacterial virulence factors, including LPS and fimbriae that induce de novo synthesis of cytokines. The profile of lymphocyte T differentiation from naive T cells showed enhanced generation of Th17 in response to bacteria with inactive gingipains. Moreover, we found that gingipain-dependent induction of Th17 cells was highly specific, since other T cell-subsets remained unchanged. Finally, inhibition of IL-6 signaling in dendritic cells led to a significant depletion of the Th17 population. Cumulatively, this study

  16. Inactive Gingipains from P. gingivalis Selectively Skews T Cells toward a Th17 Phenotype in an IL-6 Dependent Manner.

    PubMed

    Glowczyk, Izabela; Wong, Alicia; Potempa, Barbara; Babyak, Olena; Lech, Maciej; Lamont, Richard J; Potempa, Jan; Koziel, Joanna

    2017-01-01

    Gingipain cysteine proteases are considered key virulence factors of Porphyromonas gingivalis . They significantly influence antibacterial and homeostatic functions of macrophages, neutrophils, the complement system, and cytokine networks. Recent data indicate the role of P. gingivalis in T cell differentiation; however, the involvement of gingipains in this process remains elusive. Therefore, the aim of this study was to investigate the contribution of danger signals triggered by the gingipains on the generation of Th17 cells, which play a key role in protection against bacterial diseases but may cause chronic inflammation and bone resorption. To this end we compared the effects of the wild-type strain of P. gingivalis (W83) with its isogenic mutant devoid of gingipain activity (ΔKΔRAB), and bacterial cells pretreated with a highly-specific inhibitor of gingipains activity (KYTs). Antigen presenting cells (APCs), both professional (dendritic cells), and non-professional (gingival keratinocytes), exposed to viable bacteria expressed high amounts of cytokines (IL-6, IL-21, IL-23). These cytokines are reported to either stimulate or balance the Th17-dependent immune response. Surprisingly, cells infected with P. gingivalis devoid of gingipain activity showed increased levels of all tested cytokines compared to bacteria with fully active enzymes. The effect was dependent on both the reduction of cytokine proteolysis and the lack of cross-talk with other bacterial virulence factors, including LPS and fimbriae that induce de novo synthesis of cytokines. The profile of lymphocyte T differentiation from naive T cells showed enhanced generation of Th17 in response to bacteria with inactive gingipains. Moreover, we found that gingipain-dependent induction of Th17 cells was highly specific, since other T cell-subsets remained unchanged. Finally, inhibition of IL-6 signaling in dendritic cells led to a significant depletion of the Th17 population. Cumulatively, this study

  17. Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

    PubMed Central

    Shinoda, Kenta; Hirahara, Kiyoshi; Iinuma, Tomohisa; Ichikawa, Tomomi; Suzuki, Akane S.; Sugaya, Kaoru; Tumes, Damon J.; Yamamoto, Heizaburo; Hara, Takahiro; Tani-ichi, Shizue; Ikuta, Koichi; Okamoto, Yoshitaka; Nakayama, Toshinori

    2016-01-01

    Memory CD4+ T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1+IL-7–producing lymphatic endothelial cells (LECs). The Thy1+IL-7–producing LECs express IL-33 and T-cell–attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4+ T cells and IL-7+IL-33+ LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1+IL-7–producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells. PMID:27140620

  18. Abnormalities in iNKT cells are associated with impaired ability of monocytes to produce IL-10 and suppress T-cell proliferation in sarcoidosis.

    PubMed

    Crawshaw, Anjali; Kendrick, Yvonne R; McMichael, Andrew J; Ho, Ling-Pei

    2014-07-01

    Sarcoidosis is a multisystem granulomatous disorder characterized by marked T-cell expansion of T helper 1 (Th1) cells. The cause of T-cell overactivity is unknown. We hypothesized that interleukin-10 (IL-10) production by a yet undefined cell type might be defective, resulting in loss of regulation of T-cell activity. Focusing on IL-10-producing monocytes, we first showed that monocytes isolated from the peripheral blood of corticosteroid-naïve sarcoidosis patients (n = 51) produced less IL-10 compared to controls, and were less able to suppress T-cell proliferation. In addition, monocytic IL-10 production correlated negatively with disease activity score. As invariant natural killer T (iNKT) cells are known to both interact with monocytes and be reduced in sarcoidosis patients, we then asked whether iNKT-specific defects might be responsible for this reduced IL-10 production. We found that greater numbers of circulating iNKT cells was associated with higher IL-10 production. Moreover, iNKT cells enhanced monocytic IL-10 production in vitro. Defective IL-10 production and T-cell suppression by sarcoidosis monocytes could be restored following their coculture with iNKT cells, in a CD1d- and cell contact-dependent process. We suggest that reduced iNKT-cell numbers in sarcoidosis may lead to impaired monocytic IL-10 production and unchecked T-cell expansion in sarcoidosis. These findings provide fresh insight into the mechanism of sarcoidosis disease, and interaction between iNKT cells and monocytes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Inhibition of Gαs/cAMP Signaling Decreases TCR-Stimulated IL-2 transcription in CD4(+) T Helper Cells.

    PubMed

    Hynes, Thomas R; Yost, Evan A; Yost, Stacy M; Hartle, Cassandra M; Ott, Braden J; Berlot, Catherine H

    2015-07-06

    The role of cAMP in regulating T cell activation and function has been controversial. cAMP is generally known as an immunosuppressant, but it is also required for generating optimal immune responses. As the effect of cAMP is likely to depend on its cellular context, the current study investigated whether the mechanism of activation of Gαs and adenylyl cyclase influences their effect on T cell receptor (TCR)-stimulated interleukin-2 (IL-2) mRNA levels. The effect of blocking Gs-coupled receptor (GsPCR)-mediated Gs activation on TCR-stimulated IL-2 mRNA levels in CD4(+) T cells was compared with that of knocking down Gαs expression or inhibiting adenylyl cyclase activity. The effect of knocking down Gαs expression on TCR-stimulated cAMP accumulation was compared with that of blocking GsPCR signaling. ZM-241385, an antagonist to the Gs-coupled A2A adenosine receptor (A2AR), enhanced TCR-stimulated IL-2 mRNA levels in primary human CD4(+) T helper cells and in Jurkat T cells. A dominant negative Gαs construct, GαsDN3, also enhanced TCR-stimulated IL-2 mRNA levels. Similar to GsPCR antagonists, GαsDN3 blocked GsPCR-dependent activation of both Gαs and Gβγ. In contrast, Gαs siRNA and 2',5'-dideoxyadenosine (ddA), an adenylyl cyclase inhibitor, decreased TCR-stimulated IL-2 mRNA levels. Gαs siRNA, but not GαsDN3, decreased TCR-stimulated cAMP synthesis. Potentiation of IL-2 mRNA levels by ZM-241385 required at least two days of TCR stimulation, and addition of ddA after three days of TCR stimulation enhanced IL-2 mRNA levels. GsPCRs play an inhibitory role in the regulation of TCR-stimulated IL-2 mRNA levels whereas Gαs and cAMP can play a stimulatory one. Additionally, TCR-dependent activation of Gαs does not appear to involve GsPCRs. These results suggest that the context of Gαs/cAMP activation and the stage of T cell activation and differentiation determine the effect on TCR-stimulated IL-2 mRNA levels.

  20. Toxicité sérotoninergique résultant d’une interaction médicamenteuse entre le bleu de méthylène et les inhibiteurs de la recapture de la sérotonine

    PubMed Central

    Charbonneau, Annie

    2013-01-01

    RÉSUMÉ Contexte : Le bleu de méthylène est employé en pratique pour diverses raisons médicales. Des données récentes ont évoqué une interaction potentielle avec les inhibiteurs de la recapture de la sérotonine, pouvant conduire à une toxicité sérotoninergique. Objectif : Décrire le risque de toxicité sérotoninergique associé à l’interaction entre le bleu de méthylène et les inhibiteurs de la recapture de la sérotonine. Sources de l’information : Les publications pertinentes ont été ciblées systématiquement au moyen des moteurs de recherche MEDLINE (1946 au 21 mars 2013) et Embase (1974 à 2013, semaine 11) en utilisant les mots clés suivants : methylene blue, methylthioninium, monoamine oxidase inhibitors, serotonin reuptake inhibitors et serotonin syndrome. Aucune restriction touchant l’indication du bleu de méthylène ou la langue n’a été appliquée. Les références des publications ont également été analysées. Sélection des études et extraction des données : Dix-huit études de cas et deux séries de cas systématiques ont été sélectionnées. Aucune étude clinique aléatoire n’a encore été publiée. Synthèse des résultats : La première étude de cas à avoir soupçonné une interaction entre le bleu de méthylène et les inhibiteurs de la recapture de la sérotonine est parue en 2003. Dix-sept autres études de cas décrivant le même type d’interaction ont par la suite été rapportées. Les deux séries de cas ont regroupé les données de quelques 325 parathyroïdectomies où le bleu de méthylène avait été employé comme agent colorant. Les 17 patients qui ont présenté une toxicité du système nerveux central prenaient tous en période préopératoire des inhibiteurs de recapture de la sérotonine. Conclusion : Lorsqu’il est administré en concomitance avec des inhibiteurs de recapture de la sérotonine, le bleu de méthylène peut conduire à une toxicité sérotoninergique à une dose aussi

  1. Métastase pleurale et pulmonaire d’une polyadénofibromatose dégénéréé: à propos d’un cas

    PubMed Central

    El Hachimi, Kawtar; Benjelloun, Hanane; Zaghba, Nahid; Yassine, Najiba

    2017-01-01

    La polyadénofibromatose ou l’adénofibromatose est définie par la présence d’au moins 3 adénofibromes, uni ou bilatéraux atteignant une taille importante responsable de troubles trophiques. Nous rapportons une observation colligée au service des maladies respiratoires du Centre Hospitalier Universitaire Ibn Rochd de Casablanca. Il s’agit d’une patiente âgée de 46ans, suivie depuis l’âge de 30 ans pour une adénofibromatose bilatérale opérée à 4 reprises. Suite à un bilan préopératoire d’une mastectomie bilatérale, une radio du thorax a été réalisée objectivant un hémithorax droit opaque avec refoulement des éléments du médiastin. L’examen clinique retrouvait un syndrome d’épanchement liquidien de l’hémithorax droit et une adénopathie cervicale sus claviculaire gauche. La ponction biopsie pleurale confirmait la localisation pleurale d’un carcinome peu différencié et invasif compatible avec une origine mammaire. La bronchoscopie après évacuation pleurale objectivait un aspect infiltré de tout l’arbre bronchique, dont les biopsies concluaient au même résultat anatomopathologique. Le traitement préconisé était une polychimiothérapie. L’évolution était marquée par l’apparition de métastases hépatiques. A travers cette observation, nous concluons que les adénofibromes nécessitent une surveillance régulière vu le risque de dégénérescence vers le cancer du sein qui est une cause fréquente de métastases pleuropulmonaires. PMID:29515733

  2. IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population.

    PubMed

    Nascimento, Daniele C; Melo, Paulo H; Piñeros, Annie R; Ferreira, Raphael G; Colón, David F; Donate, Paula B; Castanheira, Fernanda V; Gozzi, Aline; Czaikoski, Paula G; Niedbala, Wanda; Borges, Marcos C; Zamboni, Dario S; Liew, Foo Y; Cunha, Fernando Q; Alves-Filho, Jose C

    2017-04-04

    Patients who survive sepsis can develop long-term immune dysfunction, with expansion of the regulatory T (Treg) cell population. However, how Treg cells proliferate in these patients is not clear. Here we show that IL-33 has a major function in the induction of this immunosuppression. Mice deficient in ST2 (IL-33R) develop attenuated immunosuppression in cases that survive sepsis, whereas treatment of naive wild-type mice with IL-33 induces immunosuppression. IL-33, released during tissue injury in sepsis, activates type 2 innate lymphoid cells, which promote polarization of M2 macrophages, thereby enhancing expansion of the Treg cell population via IL-10. Moreover, sepsis-surviving patients have more Treg cells, IL-33 and IL-10 in their peripheral blood. Our study suggests that targeting IL-33 may be an effective treatment for sepsis-induced immunosuppression.

  3. IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population

    PubMed Central

    Nascimento, Daniele C.; Melo, Paulo H.; Piñeros, Annie R.; Ferreira, Raphael G.; Colón, David F.; Donate, Paula B.; Castanheira, Fernanda V.; Gozzi, Aline; Czaikoski, Paula G.; Niedbala, Wanda; Borges, Marcos C.; Zamboni, Dario S.; Liew, Foo Y.; Cunha, Fernando Q.; Alves-Filho, Jose C.

    2017-01-01

    Patients who survive sepsis can develop long-term immune dysfunction, with expansion of the regulatory T (Treg) cell population. However, how Treg cells proliferate in these patients is not clear. Here we show that IL-33 has a major function in the induction of this immunosuppression. Mice deficient in ST2 (IL-33R) develop attenuated immunosuppression in cases that survive sepsis, whereas treatment of naive wild-type mice with IL-33 induces immunosuppression. IL-33, released during tissue injury in sepsis, activates type 2 innate lymphoid cells, which promote polarization of M2 macrophages, thereby enhancing expansion of the Treg cell population via IL-10. Moreover, sepsis-surviving patients have more Treg cells, IL-33 and IL-10 in their peripheral blood. Our study suggests that targeting IL-33 may be an effective treatment for sepsis-induced immunosuppression. PMID:28374774

  4. Thymic Stromal-Cell Abnormalities and Dysregulated T-Cell Development in IL-2-Deficient Mice

    PubMed Central

    Reya, Tannishtha; Bassiri, Hamid; Biancaniello, Renée

    1998-01-01

    The role that interleukin-2 (IL-2) plays in T-cell development is not known. To address this issue, we have investigated the nature of the abnormal thymic development and autoimmune disorders that occurs in IL-2-deficient (IL-2–/–) mice. After 4 to 5 weeks of birth, IL-2–/– mice progressively develop a thymic disorder resulting in the disruption of thymocyte maturation. This disorder is characterized by a dramatic reduction in cellularity, the selective loss of immature CD4-8- (double negative; DN) and CD4+8+ (double positive; DP) thymocytes and defects in the thymic stromal-cell compartment. Immunohistochemical staining of sections of thymuses from specific pathogen-free and germ-free IL-2–/– mice of various ages showed a progressive ,loss of cortical epithelial cells, MHC class II-expressing cells, monocytes, and macrophages. Reduced numbers of macrophages were apparent as early as week after birth. Since IL-2–/– thymocyte progenitor populations could mature normally on transfer into a normal thymus, the thymic defect in IL-2–/– mice appears to be due to abnormalities among thymic stromal cells. These results underscore the role of IL-2 in maintaining functional microenvironments that are necessary to support thymocyte growth, development, and selection. PMID:9814585

  5. Syndrome coronarien aigue suite à une injection accidentelle intraveineuse de Bupivacaine

    PubMed Central

    Koita, Siriman Abdoulaye; Bouhabba, Najib; Salaheddine, Fjouji; Bensghir, Mustapha; Charki, Haimeur

    2015-01-01

    Les erreurs médicamenteuses constituent une complication très redoutable en anesthésie. La fréquence des erreurs médicamenteuses par administration serait de l'ordre 1/10 000 à 1/1000. Nous rapportons un cas d'injection accidentelle de bupivacaine en intraveineuse directe. Il s'agissait d'un jeune patient classé ASA I qui était prévu pour cure chirurgicale d'une hydrocèle unilatérale sous rachianesthésie. Une injection de 12,5 mg de bupivacaine et 25 µg de fentanyl étaient injectés après un reflux net du liquide céphalorachidien sans incident. Après installation de la rachianesthésie, le début de l'intervention était autorisé sans incidents. Une sédation de confort était décidée. Juste après apparaissait des troubles de rythme à type tachycardie ventriculaire avec une élévation de taux de troponines en post opératoire. L’évolution était marquée par une normalisation de la troponine au troisième jour post opératoire et sorti de l'hôpital au cinquième jour. PMID:26889325

  6. Deficiency of IL-18 Aggravates Esophageal Carcinoma Through Inhibiting IFN-γ Production by CD8+T Cells and NK Cells.

    PubMed

    Li, Jiantao; Qiu, Gang; Fang, Baoshuan; Dai, Xiaohui; Cai, Jianhui

    2018-03-01

    To investigate the potential role of interleukin-18 (IL-18) in immunomodulation during tumorigenesis of esophageal carcinoma and elucidate the underlying molecular mechanism, we employed IL-18 knockout mice for this purpose. Carcinogen 4-nitroquinoline 1-oxide (4NQO) was administrated in drinking water to induce occurrence of esophageal squamous cell carcinoma (ESCC). T cell activation as indicated by the surface CD molecules was analyzed with flow cytometry. The serous content of interferon-γ (IFN-γ) along with other cytokines was determined by inflammatory human cytokine cytometric bead array. The cytotoxicity assay was performed by co-culture of tumor cells with immune cells and relative cell viability was determined by lactate dehydrogenase (LDH) assay. Apoptotic cells were stained with Annexin-V/propidium iodide (PI) and analyzed by flow cytometry. Cell proliferation was measured with Cell Counting Kit-8 (CCK-8) assay. Our data demonstrated that deficiency of IL-18 promoted the progression and development of 4NQO-induced ESCC. Loss of IL-18 suppressed the activation of T cells in the esophagus. Deficiency of IL-18 inhibited the IFN-γ production by CD8 + T cells and natural killer (NK) cells. Absence of IL-18 inhibited the cytotoxicity of CD8 + T cells and NK cell in vitro. Moreover, deficiency of IL-18 promoted the apoptosis of CD8 + T cells and inhibited the proliferation of CD8 + T cells in vitro. Our data elucidated the immunomodulatory role of IL-18 during tumorigenesis of ESCC, whose deficiency compromised antitumor immunity and contributed to immune escape of esophageal carcinoma. Our results also indicated the therapeutic potential of exogenous IL-18 against ESCC, which warrants further investigations.

  7. Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation.

    PubMed

    Fowler, Daniel H; Odom, Jeanne; Steinberg, Seth M; Chow, Catherine K; Foley, Jason; Kogan, Yelena; Hou, Jeannie; Gea-Banacloche, Juan; Sportes, Claude; Pavletic, Steven; Leitman, Susan; Read, Elizabeth J; Carter, Charles; Kolstad, Arne; Fox, Rebecca; Beatty, Gregory L; Vonderheide, Robert H; Levine, Bruce L; June, Carl H; Gress, Ronald E; Bishop, Michael R

    2006-11-01

    The primary objective of this clinical trial was to evaluate the safety, feasibility, and biologic effects of administering costimulated, interleukin (IL)-4 polarized donor CD4(+) T cells in the setting of HLA-matched sibling, T cell-replete allogeneic hematopoietic cell transplantation (HCT). Forty-seven subjects with hematologic malignancy received granulocyte colony-stimulating factor-mobilized allogeneic hematopoietic cell transplants and cyclosporine graft-versus-host disease (GVHD) prophylaxis after reduced intensity conditioning. Initial subjects received no additional cells (n = 19); subsequent subjects received additional donor CD4(+) T cells generated ex vivo by CD3/CD28 costimulation in medium containing IL-4 and IL-2 (administered day 1 after HCT at 5, 25, or 125 x 10(6) cells/kg). Studies after HCT included measurement of monocyte IL-1alpha and tumor necrosis factor alpha, detection of T cells with antitumor specificity, and characterization of T cell cytokine phenotype. The culture method generated donor CD4(+) T cells that secreted increased T helper 2 (Th2) cytokines and decreased T helper 1 (Th1) cytokines. Such Th2-like cells were administered without infusional or dose-limiting toxicity. The Th2 cohort had accelerated lymphocyte reconstitution; both cohorts had rapid hematopoietic recovery and alloengraftment. Acute GVHD and overall survival were similar in the Th2 and non-Th2 cohorts. Th2 cell recipients tended to have increased monocyte IL-1alpha and had increased tumor necrosis factor alpha secretion. CD8(+) T cells with antitumor specificity were observed in Th2 and non-Th2 cohorts. Post-transplantation T cells from Th2 cell recipients secreted IL-4 and IL-10 (Th2 cytokines) and IL-2 and interferon gamma (Th1 cytokines). Allograft augmentation with costimulated, IL-4-polarized donor CD4(+) T cells resulted in activated Th1, Th2, and inflammatory cytokine pathways without an apparent increase in GVHD.

  8. T-cell activation is enhanced by targeting IL-10 cytokine production in toll-like receptor-stimulated macrophages

    PubMed Central

    Walk, Ryan M; Elliott, Steven T; Blanco, Felix C; Snyder, Jason A; Jacobi, Ashley M; Rose, Scott D; Behlke, Mark A; Salem, Aliasger K; Vukmanovic, Stanislav; Sandler, Anthony D

    2012-01-01

    Toll-like receptor (TLR) agonists represent potentially useful cancer vaccine adjuvants in their ability to stimulate antigen-presenting cells (APCs) and subsequently amplify the cytotoxic T-cell response. The purpose of this study was to characterize APC responses to TLR activation and to determine the subsequent effect on lymphocyte activation. We exposed murine primary bone marrow-derived macrophages to increasing concentrations of agonists to TLRs 2, 3, 4, and 9. This resulted in a dose-dependent increase in production of not only tumor necrosis factor–alpha (TNF-α), a surrogate marker of the proinflammatory response, but also interleukin 10 (IL-10), a well-described inhibitory cytokine. Importantly, IL-10 secretion was not induced by low concentrations of TLR agonists that readily produced TNF-α. We subsequently stimulated lymphocytes with anti-CD3 antibody in the presence of media from macrophages activated with higher doses of TLR agonists and observed suppression of interferon gamma release. Use of both IL-10 knockout macrophages and IL-10 small-interfering RNA (siRNA) ablated this suppressive effect. Finally, IL-10 siRNA was successfully used to suppress CpG-induced IL-10 production in vivo. We conclude that TLR-mediated APC stimulation can induce a paradoxical inhibitory effect on T-cell activation mediated by IL-10. PMID:27471682

  9. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells.

    PubMed

    Gabryšová, Leona; Alvarez-Martinez, Marisol; Luisier, Raphaëlle; Cox, Luke S; Sodenkamp, Jan; Hosking, Caroline; Pérez-Mazliah, Damián; Whicher, Charlotte; Kannan, Yashaswini; Potempa, Krzysztof; Wu, Xuemei; Bhaw, Leena; Wende, Hagen; Sieweke, Michael H; Elgar, Greg; Wilson, Mark; Briscoe, James; Metzis, Vicki; Langhorne, Jean; Luscombe, Nicholas M; O'Garra, Anne

    2018-05-01

    The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4 + T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4 + T cells in disease models involving the T H 1 subset of helper T cells (malaria), T H 2 cells (allergy) and T H 17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in T H 1 and T H 2 responses, T H 17 cell-mediated pathology was reduced in this context, with an accompanying decrease in T H 17 cells and increase in Foxp3 + regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.

  10. Immunosuppressive Effects of Bryoria sp. (Lichen-Forming Fungus) Extracts via Inhibition of CD8+ T-Cell Proliferation and IL-2 Production in CD4+ T Cells.

    PubMed

    Hwang, Yun-Ho; Lee, Sung-Ju; Kang, Kyung-Yun; Hur, Jae-Seoun; Yee, Sung-Tae

    2017-06-28

    Lichen-forming fungi are known to have various biological activities, such as antioxidant, antimicrobial, antitumor, antiviral, anti-inflammation, and anti proliferative effects. However, the immunosuppressive effects of Bryoria sp. extract (BSE) have not previously been investigated. In this study, the inhibitory activity of BSE on the proliferation of CD8 + T cells and the mixed lymphocytes reaction (MLR) was evaluated in vitro. BSE was non-toxic in spleen cells and suppressed the growth of splenocytes induced by anti-CD3. The suppressed cell population in spleen cells consisted of CD8 + T cells and their proliferation was inhibited by the treatment with BSE. This extract significantly suppressed the IL-2 associated with T cell growth and IFN-γ as the CD8 + T cell marker. Furthermore, BSE reduced the expression of the IL-2 receptor alpha chain (IL-2Rα) on CD8 + T cells and CD86 on dendritic cells by acting as antigen-presenting cells. Finally, the MLR produced by the co-culture of C57BL/6 and MMC-treated BALB/c was suppressed by BSE. IL-2, IFN-γ, and CD69 on CD8 + T cells in MLR condition were inhibited by BSE. These results indicate that BSE inhibits the MLR via the suppression of IL-2Rα expression in CD8 + T cells. BSE has the potential to be developed as an anti-immunosuppression agent for organ transplants.

  11. Increased levels of CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells, and associated factors Bcl-6, CXCR5, IL-21 and IL-6 contribute to repeated implantation failure.

    PubMed

    Gong, Qiaoqiao; Zhu, Yuejie; Pang, Nannan; Ai, Haiquan; Gong, Xiaoyun; La, Xiaolin; Ding, Jianbing

    2017-12-01

    In vitro fertilization-embryo transfer (IVF-ET) can be used by infertile couples to assist with reproduction; however, failure of the embryo to implant into the endometrial lining results in failure of the IVF treatment. The present study investigated the expression of chemokine receptor 7 (CCR7)(lo) programmed death-1(PD-1)(hi) chemokine receptor type 5 (CXCR5) + cluster of differentiation 4 (CD4) + T cells and associated factors in patients with repeated implantation failure (RIF). A total of 30 females with RIF and 30 healthy females were enrolled in the current study. Flow cytometry was used to detect the proportion of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells in the peripheral blood. Cytokine bead arrays were performed to detect the levels of interleukin (IL)-6, -4 and -2 in the serum. ELISAs were used to detect the level of IL-21 in the serum. Quantitative real time polymerase chain reaction analysis and immunohistochemistry were used to investigate the expression of B-cell lymphoma 6 (Bcl-6), chemokine receptor type 5 (CXCR5) and IL-21 in the endometrium. The results revealed that the percentage of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells was increased in the RIF group compared with the control group during the mid luteal phase. The mRNA and protein levels of Bcl-6, IL-21 and CXCR5 in the endometrium and the concentrations of IL-21 and IL-6 in the serum were significantly increased in the RIF group; however, no significant difference was observed between the two groups in regards to the expression of IL-4 and IL-2. Furthermore, a significant positive correlation was identified between the percentage of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells and IL-21 and IL-6 levels. The expression of IL-21 also had a positive correlation with Bcl-6 and CXCR5 expression in the RIF group. These results suggest that increased levels of CCR7(lo)PD-1(hi) CXCR5 + CD4 + T cells and associated factors contribute to RIF and could therefore be a potential therapeutic target.

  12. The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells.

    PubMed

    Wang, Jun; Lee, Seungsoo; Teh, Charis En-Yi; Bunting, Karen; Ma, Lina; Shannon, M Frances

    2009-03-01

    Activation of T cells leads to the induction of many cytokine genes that are required for appropriate immune responses, including IL-2, a key cytokine for T cell proliferation and homeostasis. The activating transcription factors such as nuclear factor of activated T cells, nuclear factor kappaB/Rel and activated protein-1 family members that regulate inducible IL-2 gene expression have been well documented. However, negative regulation of the IL-2 gene is less studied. Here we examine the role of zinc finger E-box-binding protein (ZEB) 1, a homeodomain/Zn finger transcription factor, as a repressor of IL-2 gene transcription. We show here that ZEB1 is expressed in non-stimulated and stimulated T cells and using chromatin immunoprecipitation assays we show that ZEB1 binds to the IL-2 promoter. Over-expression of ZEB1 can repress IL-2 promoter activity, as well as endogenous IL-2 mRNA production in EL-4 T cells, and this repression is dependent on the ZEB-binding site at -100. ZEB1 cooperates with the co-repressor C-terminal-binding protein (CtBP) 2 and with histone deacetylase 1 to repress the IL-2 promoter and this cooperation depends on the ZEB-binding site in the promoter as well as the Pro-X-Asp-Leu-Ser protein-protein interaction domain in CtBP2. Thus, ZEB1 may function to recruit a repressor complex to the IL-2 promoter.

  13. Epicubenol and Ferruginol induce DC from human monocytes and differentiate IL-10-producing regulatory T cells in vitro

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Takei, Masao; Umeyama, Akemi; Arihara, Shigenobu

    2005-11-18

    Epicubenol and 19-hydroxyferruginol (Ferruginol) are sesquiterpenes isolated from the black heartwood of Cryptomeria japonica. Dendritic cells (DC) are specialized antigen-presenting cells that monitor the antigenic environment and activate naive T cells. The role of DC is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. In this study, we attempted to investigate the effects of Epicubenol and Ferruginol on the phenotypic and functional maturation of human monocytes-derived DC in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2more » days with Epicubenol or Ferruginol. The expression levels of CD1a, CD83, and HLA-DR as expressed by mean fluorescence intensity (MFI) on Epicubenol-primed DC or Ferruginol-primed DC were enhanced. Allogeneic Epicubenol-primed DC or Ferruginol-primed DC co-cultured with naive T cells at 1:5 ratio, secreted IL-10 and TGF-{beta}, but little IL-4. Moreover, T cells that develop in co-culture of Epicubenol-primed DC or Ferruginol-primed DC and naive T cells at 1:5 ratio suppressed the proliferation of autologous T cells at Treg cells: Ttarget cells and this suppression of proliferation was inhibited by anti-IL-10 mAb. The expression of FoxP3 mRNA on T cells that develop in co-culture of Epicubenol-primed DC or Ferruginol-primed DC and naive T cells was lower. From these results, Epicubenol and Ferruginol may induce IL-10-producing Treg 1 cells from naive T cells by modulating DC function. It seems that Epicubenol and Ferruginol appear to be a target for tolerance after transplantation and in autoimmune diseases.« less

  14. Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

    PubMed Central

    Sojka, Dorothy K.; Fowell, Deborah J.

    2011-01-01

    CD4+CD25+Forkhead box P3 (Foxp3)+ regulatory T cells (Tregs) control immune responses to self and foreign antigens in secondary lymphoid organs and at tissue sites of inflammation. Tregs can modify the function of many immune cells and have been proposed to block early proliferation, differentiation, and effector function. Acute ablation of Tregs has revealed rapid cytokine production immediately after Treg removal, suggesting that Tregs may regulate effector function acutely rather than regulating the programming for immune function. We developed in vitro and in vivo models that enabled the direct test of Treg regulation of T-helper cell type 1 (Th1) differentiation. CD28 signaling is known to abrogate Treg suppression of IL-2 secretion and proliferation, but our studies show that Treg suppression of IFN-γ during Th1 priming proceeds despite enhanced CD28 signaling. Importantly, during Th1 differentiation, Tregs inhibited early IFN-γ transcription without disrupting expression of Th1-specific T-box transcription factor (Tbet) and Th1 programming. Acute shutoff of effector cytokine production by Tregs was selective for IFN-γ but not TNF-α and was independent of TGF-β and Epstein-Barr virus-induced gene 3. In vivo, Tregs potently controlled CD4 IFN-γ and CD4 effector cell expansion in the lymph node (four- to fivefold reduction) but not Th1 programming, independent of IL-10. Tregs additionally reduced CD4 IFN-γ in the inflamed dermis (twofold reduction) dependent on their production of IL-10. We propose a model for Treg inhibition of effector function based on acute cytokine regulation. Interestingly, Tregs used different regulatory mechanisms to regulate IFN-γ (IL-10–dependent or –independent) subject to the target T-cell stage of activation and its tissue location. PMID:22025707

  15. T cell-derived IL-10 and its impact on the regulation of host responses during malaria.

    PubMed

    Freitas do Rosario, Ana Paula; Langhorne, Jean

    2012-05-15

    Despite intense research, malaria still is the one of the most devastating diseases killing more people than any other parasitic infection. In an attempt to control the infection, the host immune system produces a potent pro-inflammatory response. However, this response is also associated with complications, such as severe anaemia, hypoglycaemia and cerebral malaria. This pronounced production of pro-inflammatory cytokines response is a common feature of malaria caused by parasites infecting humans as well as rodents and primates. A balance between pro- and anti-inflammatory responses may be fundamental to the elimination of the parasite without inducing excessive host pathology. IL-10 is a key cytokine that has been shown to have an important regulatory function in establishing this balance in malaria. Here we discuss which cells can produce IL-10 during infection, and present an overview of the evidence showing that T-cell derived IL-10 plays an important role in regulating malaria pathology. Many different subsets of T cells can produce IL-10, however, evidence is accumulating that it is effector Th1 CD4(+) T cells which provide the crucial source that down-regulates inflammatory pathology during blood-stage malaria infections. Copyright © 2012 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  16. Peptide-loaded Langerhans cells, despite increased IL15 secretion and T cell activation in vitro, elicit anti-tumor T cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo

    PubMed Central

    Romano, Emanuela; Rossi, Marco; Ratzinger, Gudrun; de Cos, Maria-Angeles; Chung, David J.; Panageas, Katherine S.; Wolchok, Jedd D.; Houghton, Alan N.; Chapman, Paul B.; Heller, Glenn; Yuan, Jianda; Young, James W.

    2013-01-01

    Purpose We compared the efficacy of human Langerhans cells (LCs) as tumor immunogens in vivo with monocyte-derived DCs (moDCs) and investigated how IL15 supports optimal DC-stimulated antitumor immunity. Experimental Design AJCC stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167,www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity. Results Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than did moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro demonstrating LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-gamma profile even without exogenous IL15. When supplemented by low dose IL15, instead of IL2, moDCs stimulate 5-6 logs more tumor antigen-specific effector memory T-cells (TEMRA) over 3-4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T-cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity. Conclusions MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs. PMID:21355077

  17. Increased IL-27/IL-27R expression in association with the immunopathology of murine ocular toxoplasmosis.

    PubMed

    Tong, Xinxin; Chen, Shengjie; Zheng, Huanqin; Huang, Shiguang; Lu, Fangli

    2018-05-19

    Interleukin 27 (IL-27) is a member of the IL-6/IL-12 family, and IL-27 receptor (IL-27R) consists of WSX-1 (the IL-27Rα subunit) and the signal-transducing subunit gp130. Human and mouse mast cells (MCs) express the IL-27R. To explore the expressions of IL-27/IL-27R subunits (WSX-1 and gp130) during acute ocular toxoplasmosis (OT), we established mouse model by intraocular injection of 500 Toxoplasma gondii RH strain tachyzoites. Histopathological changes were analyzed, MCs were counted by toluidine blue staining, and tryptase + /IL-27 + MCs were examined by immunofluorescence double-staining in the eyes and cervical lymph nodes (CLNs) of T. gondii-infected mice. The mRNA expressions of IL-27p28, WSX-1, gp130, and tachyzoite specific surface antigen 1 (SAG1) in the eyes and CLNs of T. gondii-infected mice, and the expressions of WSX-1 and gp130 in the murine mastocytoma cell line P815 infected with T. gondii tachyzoites in vitro were examined by using quantitative real-time reverse transcription-polymerase chain reaction. Our results showed that, after T. gondii infection, severe histopathological changes, increased numbers of total MCs and degranulated MCs, elevated expressions of IL-27p28, WSX-1, and gp130 were found in the eyes and CLNs, and significant correlations between the levels of IL-27 and SAG1 existed in the eyes and CLNs of T. gondii-infected mice. In addition, increased levels of WSX-1 and gp130 were examined in T. gondii-infected P815 cells. Our data suggested that IL-27/IL-27R expression induced by T. gondii infection may regulate MC-mediated immune response during acute OT in mouse model.

  18. IL-10 and IL-12B gene polymorphisms in a multiethnic Malaysian population.

    PubMed

    Sam, S S; Teoh, B T; AbuBakar, S

    2015-04-13

    Inheritance of polymorphisms in the interleukin (IL)-10 promoter and IL-12B genes, which influence cytokine production and activities, may define the balance in T helper response in infection and autoimmune diseases. In the present study, we investigated the distribution of the IL-10 promoter and IL-12B gene polymorphisms in a multiethnic Malaysian population. Overall, our findings suggest that the IL-12B and IL-10 -592 genotypes were distributed homogenously across all major ethnic groups, including Malays, Chinese, and Indians, except for polymorphisms at IL-10 -1082. At this gene locus, the ethnic Chinese showed a significantly lower allele frequency of -1082G (2.1%) compared to the Malay (12.2%) and Indian (15.3%) populations. Results for the IL-12B and IL-10 gene polymorphisms were consistent with those reported for the Asian population, but markedly different from those of the African and Caucasian populations. Our findings suggest that there are specific genetic variations between different ethnic groups, which should be examined in all gene population-based association studies.

  19. Cell-autonomous CCL5 transcription by memory CD8 T cells is regulated by IL-4.

    PubMed

    Marçais, Antoine; Coupet, Charles-Antoine; Walzer, Thierry; Tomkowiak, Martine; Ghittoni, Raffaella; Marvel, Jacqueline

    2006-10-01

    Immunological memory is associated with the display of improved effector functions. The maintenance by CD8 memory cells of high levels of untranslated CCL5 mRNA allows these cells to immediately secrete this chemokine upon Ag stimulation. Untranslated mRNA storage is a newly described process supporting the immediate display of an effector function by memory lymphocytes. We have tested the capacity of different cytokines to regulate the memorization of CCL5 by memory CD8 T cells. We found that IL-4 treatment of murine CD8 T cells impairs immediate CCL5 secretion capacity by inhibiting CCL5 mRNA transcription through a STAT6-dependent pathway. The inhibition by IL-4 is reversible, as memory CD8 T cells reconstitute their CCL5 mRNA stores and reacquire their immediate CCL5 secretion capacity when IL-4 is withdrawn. This recovery is cell autonomous because it proceeds in culture medium in the absence of exogenous growth factors, suggesting that CCL5 expression by memory CD8 T cells is a default process. Overall, these results indicate that the expression of CCL5 is an intrinsic property acquired by memory CD8 T cells that is regulated by environmental factors.

  20. On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes.

    PubMed

    Ukah, Tobechukwu K; Cattin-Roy, Alexis N; Chen, Weirong; Miller, Mindy M; Barik, Subhasis; Zaghouani, Habib

    2017-08-01

    Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic β cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Rα/IL-13Rα1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R -/- ) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R +/+ ) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R -/- mice. This is likely due to an increase in the frequency of mTGFβ + Foxp3 int regulatory T cells and the persistence of CD206 + macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R +/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D. Copyright © 2017 by The American Association of Immunologists, Inc.

  1. Lait humain provenant d’une banque de dons ou acheté en ligne?

    PubMed Central

    St-Onge, Maude; Chaudhry, Shahnaz; Koren, Gideon

    2015-01-01

    Résumé Question Une de mes patientes m’a demandé si elle pourrait se procurer du lait humain par Internet pour allaiter son nourrisson s’il le fallait. L’usage de lait humain provenant d’une banque de dons est-il plus sécuritaire que son achat en ligne? Réponse L’Organisation mondiale de la Santé et l’American Academy of Pediatrics recommandent d’utiliser des dons de lait humain comme choix à privilégier lorsque le lait maternel n’est pas disponible. Cependant, la Société canadienne de pédiatrie n’approuve pas le partage de lait humain non traité. Le lait humain entreposé dans les banques de lait diffère de celui qu’on peut se procurer par Internet en raison du processus rigoureux de sélection des donneuses, des fréquentes inspections de la qualité, des procédés de transport règlementés et du processus de pasteurisation conforme aux directives établies par l’Agence canadienne d’inspection des aliments. La plupart des échantillons achetés en ligne contiennent des bactéries à gram négatif ou comptent au total plus de 104 unités formant colonies de bactéries aérobiques par millilitre; ils renferment aussi en moyenne au décompte total plus de bactéries aérobiques, de bactéries à gram négatif, de coliformes et de Staphylococcus spp que les échantillons des banques de lait. La croissance de la plupart des espèces de bactéries est associée au nombre de jours en transit, ce qui porte à croire que les conditions de collecte, d’entreposage et de transport sont médiocres pour le lait acheté en ligne.

  2. IL-7 differentially regulates cell cycle progression and HIV-1-based vector infection in neonatal and adult CD4+ T cells.

    PubMed

    Dardalhon, V; Jaleco, S; Kinet, S; Herpers, B; Steinberg, M; Ferrand, C; Froger, D; Leveau, C; Tiberghien, P; Charneau, P; Noraz, N; Taylor, N

    2001-07-31

    Differences in the immunological reactivity of umbilical cord (UC) and adult peripheral blood (APB) T cells are poorly understood. Here, we show that IL-7, a cytokine involved in lymphoid homeostasis, has distinct regulatory effects on APB and UC lymphocytes. Neither naive nor memory APB CD4(+) cells proliferated in response to IL-7, whereas naive UC CD4(+) lymphocytes underwent multiple divisions. Nevertheless, both naive and memory IL-7-treated APB T cells progressed into the G(1b) phase of the cell cycle, albeit at higher levels in the latter subset. The IL-7-treated memory CD4(+) lymphocyte population was significantly more susceptible to infection with an HIV-1-derived vector than dividing CD4(+) UC lymphocytes. However, activation through the T cell receptor rendered UC lymphocytes fully susceptible to HIV-1-based vector infection. These data unveil differences between UC and APB CD4(+) T cells with regard to IL-7-mediated cell cycle progression and HIV-1-based vector infectivity. This evidence indicates that IL-7 differentially regulates lymphoid homeostasis in adults and neonates.

  3. IL-7 differentially regulates cell cycle progression and HIV-1-based vector infection in neonatal and adult CD4+ T cells

    PubMed Central

    Dardalhon, Valérie; Jaleco, Sara; Kinet, Sandrina; Herpers, Bjorn; Steinberg, Marcos; Ferrand, Christophe; Froger, Delphine; Leveau, Christelle; Tiberghien, Pierre; Charneau, Pierre; Noraz, Nelly; Taylor, Naomi

    2001-01-01

    Differences in the immunological reactivity of umbilical cord (UC) and adult peripheral blood (APB) T cells are poorly understood. Here, we show that IL-7, a cytokine involved in lymphoid homeostasis, has distinct regulatory effects on APB and UC lymphocytes. Neither naive nor memory APB CD4+ cells proliferated in response to IL-7, whereas naive UC CD4+ lymphocytes underwent multiple divisions. Nevertheless, both naive and memory IL-7-treated APB T cells progressed into the G1b phase of the cell cycle, albeit at higher levels in the latter subset. The IL-7-treated memory CD4+ lymphocyte population was significantly more susceptible to infection with an HIV-1-derived vector than dividing CD4+ UC lymphocytes. However, activation through the T cell receptor rendered UC lymphocytes fully susceptible to HIV-1-based vector infection. These data unveil differences between UC and APB CD4+ T cells with regard to IL-7-mediated cell cycle progression and HIV-1-based vector infectivity. This evidence indicates that IL-7 differentially regulates lymphoid homeostasis in adults and neonates. PMID:11470908

  4. IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells

    PubMed Central

    Xu, Jiajia; Wang, Yiyun; Li, Jing; Zhang, Xudong; Geng, Yiyun; Huang, Yan; Dai, Kerong; Zhang, Xiaoling

    2016-01-01

    Severe or prolonged inflammatory response caused by infection or biomaterials leads to delayed healing or bone repair failure. This study investigated the important roles of the proinflammatory cytokines of the interleukin-12 (IL-12) family, namely, IL-12 and IL-23, in the inflammation-mediated inhibition of bone formation in vivo. IL-12p40−/− mice lacking IL-12 and IL-23 exhibited enhanced bone formation. IL-12 and IL-23 indirectly inhibited bone marrow mesenchymal stem cell (BMMSC) differentiation by stimulating CD4+ T cells to increase interferon γ (IFN-γ) and IL-17 levels. Mechanistically, IL-17 synergistically enhanced IFN-γ-induced BMMSC apoptosis. Moreover, INF-γ and IL-17 exerted proapoptotic effects by upregulating the expression levels of Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as by activating the caspase cascade in BMMSCs. IL-12p40 depletion in mice could promote ectopic bone formation. Thus, IL-12p40 is an attractive therapeutic target to overcome the inflammation-mediated inhibition of bone formation in vivo. PMID:27472064

  5. Aberrant IL-4 production by SOCS3-over-expressing T cells during infection with Leishmania major exacerbates disease manifestations.

    PubMed

    Nakaya, Mako; Hamano, Shinjiro; Kawasumi, Miyuri; Yoshida, Hiroki; Yoshimura, Akihiko; Kobayashi, Takashi

    2011-03-01

    Suppressor of cytokine signaling (SOCS) 3 is a major negative feedback regulator of signal transducer and activator of transcription 3-activating cytokines. Studies using T-cell-specific SOCS3-deficient mice indicate that the absence of SOCS3 in T cells results in exacerbation of disease progression after infection by Leishmania major due to skewing of the T(h)3 cell phenotype accompanied by hyper-production of IL-10 and transforming growth factor β (TGF-β). Here we show that transgenic mice over-expressing the SOCS3 gene in T cells (Lck-SOCS3 Tg mice) are also susceptible to infection by L. major. Forced expression of SOCS3 in T cells did not affect the production of the anti-inflammatory cytokines IL-10 and TGF-β or that of the protective T(h)1 type cytokine IFN-γ, which is required for parasite clearance. CD4(+) T cells isolated from infected-Lck-SOCS3 Tg mice produced much higher levels of IL-4 when they were re-stimulated with L. major antigen in vitro. Exacerbation of disease progression in Lck-SOCS3 Tg mice was completely reversed by administration of a neutralizing antibody against IL-4. These data suggest that tight regulation of SOCS3 expression in T(h) cells is crucial for disease control during infection by L. major.

  6. IL10A genotypic association with decreased IL-10 circulating levels in malaria infected individuals from endemic area of the Brazilian Amazon.

    PubMed

    Pereira, Virginia A; Sánchez-Arcila, Juan C; Teva, Antonio; Perce-da-Silva, Daiana S; Vasconcelos, Mariana P A; Lima, Cleoni A M; Aprígio, Cesarino J L; Rodrigues-da-Silva, Rodrigo N; Santos, Davi O; Banic, Dalma M; Bonecini-Almeida, Maria G; Lima-Júnior, Josué C; Oliveira-Ferreira, Joseli

    2015-01-28

    Cytokines play an important role in human immune responses to malaria and variation in their production may influence the course of infection and determine the outcome of the disease. The differential production of cytokines has been linked to single nucleotide polymorphisms in gene promoter regions, signal sequences, and gene introns. Although some polymorphisms play significant roles in susceptibility to malaria, gene polymorphism studies in Brazil are scarce. A population of 267 individuals from Brazilian Amazon exposed to malaria was genotyped for five single nucleotide polymorphisms (SNPs), IFNG + 874 T/A, IL10A-1082G/A, IL10A-592A/C, IL10A-819 T/C and NOS2A-954G/C. Specific DNA fragments were amplified by polymerase chain reaction, allowing the detection of the polymorphism genotypes. The polymorphisms IL10A-592A/C and IL10A-819 T/C were estimated by a single analysis due to the complete linkage disequilibrium between the two SNPs with D' = 0.99. Plasma was used to measure the levels of IFN-γ and IL-10 cytokines by Luminex and nitrogen radicals by Griess reaction. No differences were observed in genotype and allelic frequency of IFNG + 874 T/A and NOS2A-954G/C between positive and negative subjects for malaria infection. Interesting, the genotype NOS2A-954C/C was not identified in the study population. Significant differences were found in IL10A-592A/C and IL10A-819 T/C genotypes distribution, carriers of IL10A -592A/-819 T alleles (genotypes AA/TT + AC/TC) were more frequent among subjects with malaria than in negative subjects that presented a higher frequency of the variant C allele (p < 0.0001). The presence of the allele C was associated with low producer of IL-10 and low parasitaemia. In addition, the GTA haplotypes formed from combinations of investigated polymorphisms in IL10A were significantly associated with malaria (+) and the CCA haplotype with malaria (-) groups. The IL10A-1082G/A polymorphism showed high frequency of

  7. Déshumidification de l'air d'une serre par contact direct à courants croisés avec une solution hygroscopique organique

    NASA Astrophysics Data System (ADS)

    Chraibi, A.; Jaffrin, A.; Makhlouf, S.; Bentounes, N.

    1995-07-01

    Greenhouse air can be dehumidified by direct contact with a desicant fluid on a trickle exchanger. The water vapour extraction rate depends on the hygroscopicity of the fluid and on the exchanger efficiency. An organic fluid, the triethylene glycol (TEG) at 90% concentration, has been tested. Cross corrugated cellulosic pads, of the type used in cooling, irrigated with TEG, were placed in a wind channel to dehumidify air at various speeds and temperatures. A semi-analytical model, based on energy and mass conservation, correctly reproduces the water vapor extraction rate and the enthalpy change of both fluids. It is shown that TEG trickling through a ventilated pad of 1 m^2 area and 0.1 m thickness can be used to extract 3 to 5 kg of water vapor per hour in greenhouse climate control applications. Several pads arranged in series can be used to decrease more efficiently the absolute humidity of the air, for other applications like food drying or industrial compressed air. Une technique de déshumidification de l'air des serres consiste à le soumettre au contact d'une solution hygroscopique au sein d'un échangeur ruisselant. Le taux d'extraction de vapeur d'eau dépend à la fois du pouvoir hygroscopique de la solution et de l'efficacité de l'échangeur. Une solution hygroscopique organique, le triéthylène glycol à 90% de concentration, a été expérimentée. Un échangeur ruisselant constitué de parois de cellulose ondulées à corrugations croisées, du type “cooling pad” pour serres agricoles, a été testé pour déshumidifier de l'air dans une soufflerie expérimentale. Un modèle semi-analytique, basé sur les équations de conservation de l'énergie et de masse, permet de rendre compte des échanges et de déduire les paramètres de sortie des deux fluides en contact, à partir des caractéristiques d'entrée. Cette étude permet de chiffrer à environ 3 à 5kg/h la capacité de déshumidification d'un panneau d'un mètre carré et de 10cm d

  8. IL-10 Producing B Cells Ability to Induce Regulatory T Cells Is Maintained in Rheumatoid Arthritis

    PubMed Central

    Mielle, Julie; Audo, Rachel; Hahne, Michael; Macia, Laurence; Combe, Bernard; Morel, Jacques; Daien, Claire

    2018-01-01

    Despite growing evidence highlighting the relevance of increasing IL-10-producing B cells (B10+cells) in autoimmune diseases, their functions in patients are still unknown. The aim of this study was to evaluate the functions of CpG-induced B10+ cells isolated from healthy controls (HC) and rheumatoid arthritis (RA) patients, on naïve T cell differentiation. We demonstrated that CpG-induced B10+ cells from HC drove naïve T cell differentiation toward regulatory T cells (Treg cells) and IL-10-producing T cells (Tr1) through IL-10 secretion and cellular contacts. B10+ cells from HC did not decrease T helper 1 (Th1) nor and tumor necrosis factor α producing T cell (TNFα+ T cell) differentiation. We showed that in RA, B10+ cells could also induce Treg cells and Tr1 from naïve T cells. Contrary to HC, B10+ cells from RA patients increased naïve T cell conversion into Th1. Interestingly, PD-L2, a programmed death-1 (PD-1) ligand that inhibits PD-L1 and promotes Th1 differentiation, was overexpressed on RA B10+ cells compared to HC B10+ cells. Together, our findings showed that CpG-induced B10+ cells may be used to increase Treg cells in patients with RA. However, CpG may not be the most adequate stimuli as CpG-induced B10+ cells also increased inflammatory T cells in those patients. PMID:29774031

  9. Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells*

    PubMed Central

    Tamarit, Blanche; Bugault, Florence; Pillet, Anne-Hélène; Lavergne, Vincent; Bochet, Pascal; Garin, Nathalie; Schwarz, Ulf; Thèze, Jacques; Rose, Thierry

    2013-01-01

    Interleukin (IL)-7 is the main homeostatic regulator of CD4 T-lymphocytes (helper) at both central and peripheral levels. Upon activation by IL-7, several signaling pathways, mainly JAK/STAT, PI3K/Akt and MAPK, induce the expression of genes involved in T-cell differentiation, activation, and proliferation. We have analyzed the early events of CD4 T-cell activation by IL-7. We have shown that IL-7 in the first few min induces the formation of cholesterol-enriched membrane microdomains that compartmentalize its activated receptor and initiate its anchoring to the cytoskeleton, supporting the formation of the signaling complex, the signalosome, on the IL-7 receptor cytoplasmic domains. Here we describe by stimulated emission depletion microscopy the key roles played by membrane microdomains and cytoskeleton transient organization in the IL-7-regulated JAK/STAT signaling pathway. We image phospho-STAT5 and cytoskeleton components along IL-7 activation kinetics using appropriate inhibitors. We show that lipid raft inhibitors delay and reduce IL-7-induced JAK1 and JAK3 phosphorylation. Drug-induced disassembly of the cytoskeleton inhibits phospho-STAT5 formation, transport, and translocation into the nucleus that controls the transcription of genes involved in T-cell activation and proliferation. We fit together the results of these quantitative analyses and propose the following mechanism. Activated IL-7 receptors embedded in membrane microdomains induce actin-microfilament meshwork formation, anchoring microtubules that grow radially from rafted receptors to the nuclear membrane. STAT5 phosphorylated by signalosomes are loaded on kinesins and glide along the microtubules across the cytoplasm to reach the nucleus 2 min after IL-7 stimulation. Radial microtubules disappear 15 min later, while transversal microtubules, independent of phospho-STAT5 transport, begin to bud from the microtubule organization center. PMID:23329834

  10. Reciprocal Regulation of Substance P and IL-12/IL-23 and the Associated Cytokines, IFNγ/IL-17: A Perspective on the Relevance of This Interaction to Multiple Sclerosis.

    PubMed

    Vilisaar, Janek; Kawabe, Kiyokazu; Braitch, Manjit; Aram, Jehan; Furtun, Yasemin; Fahey, Angela J; Chopra, Mark; Tanasescu, Radu; Tighe, Patrick J; Gran, Bruno; Pothoulakis, Charalabos; Constantinescu, Cris S

    2015-09-01

    The neuropeptide substance P (SP) exhibits cytokine-like properties and exerts different effects in autoimmune inflammation. Various immune cells express SP and its neurokinin-1 receptor (NK1R) isoforms. A role for SP has been demonstrated in a number of autoimmune conditions, including multiple sclerosis (MS). In this work, we studied the role of SP and NK1R in human immune cells with a focus on their relationship with IL-12/IL-23 family cytokines and the associated IFN-γ/IL-17. (1) To determine the role of SP mediated effects on induction of various inflammatory cytokines in peripheral blood mononuclear cells (PBMC); (2) to investigate the expression of SP and its receptor in T cells and the effects of stimulation with IL-12 and IL-23. Quantitative real-time PCR, flow cytometry, ELISA, promoter studies on PBMC and primary T cells from healthy volunteers, and Jurkat cell line. Treatment with SP significantly increased the expression of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA in human PBMC. Expression of NK1R and SP in T cells was upregulated by IL-23 but a trend was observed with IL-12. The IL-23 effect likely involves IL-17 production that additionally mediates IL-23 effects. Mutual interactions exist with SP enhancing the cytokines IL-23 and IL-12, and SP and NK1R expression being differentially but potentially synergistically regulated by these cytokines. These findings suggest a proinflammatory role for SP in autoimmune inflammation. We propose a model whereby immunocyte derived SP stimulates Th1 and Th17 autoreactive cells migrating to the central nervous system (CNS), enhances their crossing the blood brain barrier and perpetuates inflammation in the CNS by being released from damaged nerves and activating both resident glia and infiltrating immune cells. SP may be a therapeutic target in MS.

  11. IL-15 Enhances Activation and IGF-1 Production of Dendritic Epidermal T Cells to Promote Wound Healing in Diabetic Mice.

    PubMed

    Wang, Yangping; Bai, Yang; Li, Yashu; Liang, Guangping; Jiang, Yufeng; Liu, Zhongyang; Liu, Meixi; Hao, Jianlei; Zhang, Xiaorong; Hu, Xiaohong; Chen, Jian; Wang, Rupeng; Yin, Zhinan; Wu, Jun; Luo, Gaoxing; He, Weifeng

    2017-01-01

    Altered homeostasis and dysfunction of dendritic epidermal T cells (DETCs) contribute to abnormal diabetic wound healing. IL-15 plays important roles in survival and activation of T lymphocytes. Recently, reduction of epidermal IL-15 has been reported as an important mechanism for abnormal DETC homeostasis in streptozotocin -induced diabetic animals. However, the role of IL-15 in impaired diabetic wound healing remains unknown. Here, we found that, through rescuing the insufficient activation of DETCs, IL-15 increased IGF-1 production by DETCs and thereby promoted diabetic skin wound repair. Regulation of IGF-1 in DETCs by IL-15 was partly dependent on the mTOR pathway. In addition, expression of IL-15 and IGF-1 were positively correlated in wounded epidermis. Together, our data indicated that IL-15 enhanced IGF-1 production by DETCs to promoting diabetic wound repair, suggesting IL-15 as a potential therapeutic agent for managing diabetic wound healing.

  12. Reversal of human allergen-specific CRTH2+ T(H)2 cells by IL-12 or the PS-DSP30 oligodeoxynucleotide.

    PubMed

    Annunziato, F; Cosmi, L; Manetti, R; Brugnolo, F; Parronchi, P; Maggi, E; Nagata, K; Romagnani, S

    2001-11-01

    The chemoattractant receptor homologous molecule expressed on T(H)2 cells (CRTH2) is a receptor for prostaglandin D(2), which among human T cells is selectively expressed by T(H)2 and type 2 cytotoxic effectors. Our purpose was to assess whether the cytokine production profile of T(H)2 effectors could be reversed by exploiting their selective expression of CRTH2. CRTH2(+) T cells were purified from the blood of allergic subjects, stimulated with the specific allergen in the absence or presence of IL-12, and assessed by flow cytometry at the single-cell level for their ability to produce IL-4 and/or IFN-gamma after antigen or polyclonal stimulation. Both IL-12 and the PS-DSP30 oligodeoxynucleotide enabled CRTH2(+) allergen-stimulated T(H)2 cells to produce IFN-gamma. This change in the profile of cytokine production by T(H)2 cells from allergic subjects was related to the upregulation of IL-12 receptor beta2 chain and was associated with the loss of CRTH2. These data demonstrate that the cytokine production pattern of fully differentiated T(H)2 effectors can be changed to a less polarized profile, thus providing the physiologic basis for new immunotherapeutic strategies in allergic disorders.

  13. Nonlytic Fc-fused IL-7 synergizes with Mtb32 DNA vaccine to enhance antigen-specific T cell responses in a therapeutic model of tuberculosis.

    PubMed

    Ahn, So-Shin; Jeon, Bo-Young; Park, Seong-Jeong; Choi, Dong-Hoon; Ku, Sun-Hwa; Cho, Sang-Nae; Sung, Young-Chul

    2013-06-12

    Improvement to the immunogenicity of DNA vaccines was evaluated in a Mycobacterium tuberculosis (MTB) infection mouse model examining the combined effects of nonlytic Fc-fused IL-7 DNA (IL-7-nFc) and Flt3-ligand fused Mtb32 (F-Mtb32) DNA. Mice were treated with conventional chemotherapy for 6 weeks from 4 weeks after aerosol infection of MTB. Following the start of chemotherapy, DNA immunizations were administered five times with 2-week intervals. Coadministration of IL-7-nFc and F-Mtb32 DNA given during chemotherapy synergistically enhanced the magnitude of Mtb32-specific T cell responses and sustained for one-year after the last immunization assessed by IFN-γ ELISPOT assay. After dexamethasone treatment, a significantly reduced MTB reactivation was observed in mice received both IL-7-nFc and F-Mtb32 DNA, compared with F-MTb32 DNA alone or with control mice. In addition, mice treated with IL-7-nFc and F-Mtb32 DNA together showed improved lung pathology and reduced pulmonary inflammation values relative to F-Mtb32 DNA or saline injected mice. Intracellular cytokine staining revealed that the protection levels induced by combination therapy with IL-7-nFc and F-Mtb32 DNA was associated with enhanced Mtb32-specific IFN-γ secreting CD4(+) T cell responses and CD8(+) T cell responses stimulated with CTL epitope peptide in the lungs and spleens. These data suggest that IL-7-nFc as a novel TB adjuvant may facilitate therapeutic TB DNA vaccine to the clinics through significant enhancement of codelivered DNA vaccine-induced T cell immunity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Toxoplasmose oculaire atypique chez une femme congolaise de 72 ans: à propos d'une observation

    PubMed Central

    Bienvenu, Yogolelo Asani; Angel, Musau Nkola; Eric, Kasamba Ilunga; Socrate, Kapalu Mwangala; Sebastien, Mbuyi Musanzayi; Philippe, Cilundika Mulenga; Leon, Kabamba Ngombe; Bruno, Iye Ombamba Kayimba; Gaby, Chenge Borasisi

    2015-01-01

    Les auteurs rapportent un cas de toxoplasmose oculaire binoculaire, rarement décrit dans la littérature, chez une personne âgée de 72 ans, de sexe féminin, à laquelle s'associe une rétinite pigmentaire unilatérale. Cette observation permet d'attirer l'attention de la communauté scientifique sur les autres formes ou variétés de présentation moins courantes, « atypiques », pouvant être rencontrées ou associées à la toxoplasmose oculaire. PMID:26958130

  15. Unique IL-13Rα2-based HIV-1 vaccine strategy to enhance mucosal immunity, CD8(+) T-cell avidity and protective immunity.

    PubMed

    Ranasinghe, C; Trivedi, S; Stambas, J; Jackson, R J

    2013-11-01

    We have established that mucosal immunization can generate high-avidity human immunodeficiency virus (HIV)-specific CD8(+) T cells compared with systemic immunization, and interleukin (IL)-13 is detrimental to the functional avidity of these T cells. We have now constructed two unique recombinant HIV-1 vaccines that co-express soluble or membrane-bound forms of the IL-13 receptor α2 (IL-13Rα2), which can "transiently" block IL-13 activity at the vaccination site causing wild-type animals to behave similar to an IL-13 KO animal. Following intranasal/intramuscular prime-boost immunization, these IL-13Rα2-adjuvanted vaccines have shown to induce (i) enhanced HIV-specific CD8(+) T cells with higher functional avidity, with broader cytokine/chemokine profiles and greater protective immunity using a surrogate mucosal HIV-1 challenge, and also (ii) excellent multifunctional mucosal CD8(+) T-cell responses, in the lung, genito-rectal nodes (GN), and Peyer's patch (PP). Data revealed that intranasal delivery of these IL-13Rα2-adjuvanted HIV vaccines recruited large numbers of unique antigen-presenting cell subsets to the lung mucosae, ultimately promoting the induction of high-avidity CD8(+) T cells. We believe our novel IL-13R cytokine trap vaccine strategy offers great promise for not only HIV-1, but also as a platform technology against range of chronic infections that require strong sustained high-avidity mucosal/systemic immunity for protection.

  16. Forme particulière de Pemphigoide cicatricielle à dépôt unique d'IgA

    PubMed Central

    Aounallah, Amina; Jrad, Mariem; Ksiaa, Mehdi; Mokni, Sana; Saidi, Wafa; Boussofara, Lobna; Sriha, Badreddine; Denguezli, Mohamed; Ghariani, Najet; Belajouza, Colandane; Nouira, Rafia

    2017-01-01

    La Pemphigoide cicatricielle est une dermatose bulleuse sous épithéliale qui atteint essentiellement les muqueuses avec une évolution cicatricielle. Il s'agit d'un homme de 66 ans hospitalisé pour gingivite érosive avec dysphagie, dyspnée et flou visuel. L'examen dermatologique retrouvait des lésions érosives du palais et du pharynx. L'examen ophtalmologique notait des symblépharons, un ectropion et une cataracte bilatérale. La biopsie gingivale avait montré un décollement nécrotique de l'épithélium buccal. L'immunofluorescence directe notait un dépôt linéaire d'Immunoglobuline A à la jonction dermo-épidermique. L'Immunofluorescence indirecte était revenue négative. Le diagnostic de pemphigoide cicatricielle était confirmé. Le Transit oeso-gastro-duodénal a objectivé une double sténose de l'œsophage. L'endoscopie nasale, pharyngée et bronchique retrouvait des ulcérations de l'épiglotte, de l'hypopharynx, du pharynx et de l'arbre bronchique. Le patient a bénéficié d'un bolus de Solumedrol relayé par la Prednisone à la dose de 0.5mg/Kg/j associé à la Disulone à la dose de 100mg/j. L'évolution était favorable au début mais s'est compliquée après 2 mois d'une aggravation de la dysphagie et de la sténose oesophagienne. Notre observation est très particulière par la survenue d'une Pemphigoide cicatricielle chez un sujet de sexe masculin ayant un tableau grave en rapport avec l'extension des lésions à toutes les muqueuses conjonctivale, buccale, nasale, œsophagienne et même bronchique associée à une immunofluorescence directe faite d'un dépôt d'IgA uniquement. PMID:28533859

  17. Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response

    PubMed Central

    Feinerman, Ofer; Jentsch, Garrit; Tkach, Karen E; Coward, Jesse W; Hathorn, Matthew M; Sneddon, Michael W; Emonet, Thierry; Smith, Kendall A; Altan-Bonnet, Grégoire

    2010-01-01

    Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin-2 (IL-2) signaling in a population of T cells during an immune response by combining in silico modeling and single-cell measurements in vitro. We demonstrate that IL-2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL-2 signaling within the population. Our model reveals that at the population level, these heterogeneous cells are engaged in a tug-of-war for IL-2 between regulatory (Treg) and effector (Teff) T cells, whereby access to IL-2 can either increase the survival of Teff cells or the suppressive capacity of Treg cells. This tug-of-war is the mechanism enforcing, at the systems level, a core function of Treg cells, namely the specific suppression of survival signals for weakly activated Teff cells but not for strongly activated cells. Our integrated model yields quantitative, experimentally validated predictions for the manipulation of Treg suppression. PMID:21119631

  18. Regulatory T cells and IL10 suppress pulmonary host defense during early-life exposure to radical containing combustion derived ultrafine particulate matter.

    PubMed

    Jaligama, Sridhar; Saravia, Jordy; You, Dahui; Yadav, Nikki; Lee, Greg I; Shrestha, Bishwas; Cormier, Stephania A

    2017-01-13

    Exposure to elevated levels of particulate matter (PM) is associated with increased risk of morbidity and mortality due to respiratory tract viral infections in infants. Recent identification of environmentally persistent free radicals (EPFRs) in the PM from a variety of combustion sources suggests its role in the enhancement of disease severity of lower respiratory tract infections (LRTI). Our previous studies demonstrated that acute exposure to EPFRs induces pulmonary immunosuppression allowing for enhanced influenza disease severity. Here, we determine the mechanism of EPFR-induced immunosuppression and its impact on the immune response towards influenza infection. Neonatal mice (3 days old) were acutely exposed to DCB (combustion derived PM with chemisorbed EPFR) for seven consecutive days. Four days post-exposure (dpe), mice were infected with influenza virus. Pulmonary T cell phenotypes including regulatory T cells (Tregs) were analyzed by flow cytometry. The role of IL10 in EPFR-induced exacerbation of influenza disease severity was determined by administering recombinant IL10 (rIL10) to wild type mice or by using IL10 deficient (IL10 -/- ) neonatal mice. Mice were assessed for morbidity by measuring percent weight change and pulmonary viral load. Neonatal mice exposed to EPFRs had a significant increase in pulmonary Tregs and the immunosuppressive cytokine IL10 following influenza infection, which coincided with decreased protective T cell responses to influenza infection at 6 dpi. Depletion of Tregs in EPFR-exposed neonatal mice resulted in increased protective, adaptive T cell responses, whereas adoptive transfer of Tregs from EPFR-exposed neonates to air-exposed neonatal mice suppressed adaptive T cell responses towards influenza infection. Further, treatment with rIL10 could recapitulate EPFR-induced exacerbation of morbidity and pulmonary viral load compared to air exposed and influenza infected mice, whereas, EPFR-exposed IL10 -/- neonates exhibited

  19. Bovine Gamma Delta T Cells Contribute to Exacerbated IL-17 Production in Response to Co-Infection with Bovine RSV and Mannheimia haemolytica

    PubMed Central

    McGill, Jodi L.; Rusk, Rachel A.; Guerra-Maupome, Mariana; Briggs, Robert E.; Sacco, Randy E.

    2016-01-01

    Human respiratory syncytial virus (HRSV) is a leading cause of severe lower respiratory tract infection in children under five years of age. IL-17 and Th17 responses are increased in children infected with HRSV and have been implicated in both protective and pathogenic roles during infection. Bovine RSV (BRSV) is genetically closely related to HRSV and is a leading cause of severe respiratory infections in young cattle. While BRSV infection in the calf parallels many aspects of human infection with HRSV, IL-17 and Th17 responses have not been studied in the bovine. Here we demonstrate that calves infected with BRSV express significant levels of IL-17, IL-21 and IL-22; and both CD4 T cells and γδ T cells contribute to this response. In addition to causing significant morbidity from uncomplicated infections, BRSV infection also contributes to the development of bovine respiratory disease complex (BRDC), a leading cause of morbidity in both beef and dairy cattle. BRDC is caused by a primary viral infection, followed by secondary bacterial pneumonia by pathogens such as Mannheimia haemolytica. Here, we demonstrate that in vivo infection with M. haemolytica results in increased expression of IL-17, IL-21 and IL-22. We have also developed an in vitro model of BRDC and show that co-infection of PBMC with BRSV followed by M. haemolytica leads to significantly exacerbated IL-17 production, which is primarily mediated by IL-17-producing γδ T cells. Together, our results demonstrate that calves, like humans, mount a robust IL-17 response during RSV infection; and suggest a previously unrecognized role for IL-17 and γδ T cells in the pathogenesis of BRDC. PMID:26942409

  20. Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1.

    PubMed

    Romano, Emanuela; Cotari, Jesse W; Barreira da Silva, Rosa; Betts, Brian C; Chung, David J; Avogadri, Francesca; Fink, Mitsu J; St Angelo, Erin T; Mehrara, Babak; Heller, Glenn; Münz, Christian; Altan-Bonnet, Gregoire; Young, James W

    2012-05-31

    Human CD34(+) progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-α mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-α/IL-15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1(+) leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against self-differentiation antigens shared by tumors.

  1. CD28 co-stimulation restores T cell responsiveness in NOD mice by overcoming deficiencies in Rac-1/p38 mitogen-activated protein kinase signaling and IL-2 and IL-4 gene transcription.

    PubMed

    Zhang, J; Salojin, K V; Delovitch, T L

    2001-03-01

    Previously, we reported that T cell hyporesponsiveness induced by TCR ligation is causal to autoimmune diabetes in NOD mice. Neonatal CD28 co-stimulation reverses T cell hyporesponsiveness and protects NOD mice from diabetes by an IL-4-mediated mechanism, indicating that a deficiency in TCR signaling may be overcome by CD28/B7-2 co-stimulation in NOD T cells. To investigate which co-stimulation-induced signaling events mediate this protection, we analyzed the activity of Ras, Rac-1, mitogen-activated protein kinases (MAPK) and several transcription factors in TCR-activated NOD T cells in the presence or absence of CD28 co-stimulation. We show that CD28 co-stimulation restores normal TCR-induced activation of Rac-1 and p38 MAPK in NOD T cells. Deficiencies in TCR-induced nuclear expression of activating protein (AP)-1 binding proteins as well as activation of AP-1 and NF-AT in the IL-2 and IL-4 P1 promoters are also corrected by CD28 co-stimulation. Thus, CD28 co-stimulation reverses NOD T cell hyporesponsiveness by restoring TCR signaling leading to the activation of AP-1 and NF-AT during IL-2 and IL-4 gene transcription. Our findings provide additional evidence that CD28 co-stimulation amplifies signals delivered by the TCR and further explain the mechanism by which CD28 co-stimulation may protect against autoimmune diabetes.

  2. IL-25 promotes the function of CD4+CD25+ T regulatory cells and prolongs skin-graft survival in murine models.

    PubMed

    Tang, Jiayou; Zhou, Xiaohui; Liu, Jie; Meng, Qingshu; Han, Yang; Wang, Zhulin; Fan, Huimin; Liu, Zhongmin

    2015-10-01

    Interleukin (IL)-25, also known as IL-17E, belongs to the IL-17 family of cytokines. Unlike other IL-17 family members, IL-25 promotes Th2-type immune responses, stimulating IL-4, IL-5, and IL-13 production. Here, we employed murine models of skin graft to explore the role of IL-25 in suppression of graft rejection. We found that IL-25 expression is increased during allograft rejection, and allograft rejection was enhanced in IL-25 KO mice. IL-25 KO was associated with down-regulation of Foxp3 expression in CD4+ T cells. Further, while adoptive transfer of WT regulatory T cells (Tregs) protected against allograft rejection, adoptive transfer of IL-25 deficient Tregs failed to protect against allograft rejection. Exogenous IL-25 restored Foxp3 expression and Treg function in vitro. Moreover, IL-25 promoted phosphorylation of NFAT2. Thus, IL-25 may enhance Treg function by up-regulating NFAT2 phosphorylation. Our findings suggest that IL-25 can sustain Foxp3 expression, enhance the suppressive function of Tregs, and prolong skin-graft survival. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Reconstruction d’une Carbonisation du Pouce par Lambeau Chinois

    PubMed Central

    Khales, A.; Achbouk, J.A.; Moussaoui, A.; Belmir, R.; Tourabi, K.; Oufkir, A.; Ihrai, H.

    2010-01-01

    Summary La main en tant qu’organe majeur de la préhension peut être le siège de brûlures graves qui compromettent sa fonction. Bien qu’elle ne représente que 2% de la surface corporelle la brûlure de la main est grave et difficile à traiter, vu la vulnérabilité et la complexité de son appareil locomoteur. Nous rapportons dans ce travail le cas d’un patient victime d’une carbonisation de la main. Huit mois après le parage et la couverture par lambeau inguinal, le patient bénéficie d’une reconstruction du pouce par lambeau chinois associé à une greffe osseuse. Le résultat s’est avéré satisfaisant. Le lambeau chinois prouve par son apport vasculaire et par sa facilité technique qu’il est un moyen très intéressant dans la reconstruction du pouce - ou des doigts en général - surtout dans un contexte de brûlure. PMID:21991226

  4. IL-2 Produced by CD8+ Immune T cells Can Augment Their IFN-γ Production Independently from Their Proliferation in the Secondary Response to an Intracellular Pathogen

    PubMed Central

    Sa, Qila; Woodward, Jerold; Suzuki, Yasuhiro

    2013-01-01

    Chronic infection with Toxoplasma gondii induces a potent resistance against re-infection, and IFN-γ production by CD8+ T cells is crucial for the protective immunity. However, the molecular mechanisms that regulate the secondary response remain to be elucidated. In the present study, we examined the role of IL-2 in IFN-γ production by CD8+ immune T cells in their secondary responses using T. gondii-specific CD8+ T cell hybridomas and splenic CD8+ immune T cells from chronically infected mice. The majority (92 %) of CD8+ T cell hybridomas produced large amounts of IFN-γ only when a low amount (0.5 ng/ml) of exogenous IL-2 was provided in combination with T. gondii antigens. Inhibition of cell proliferation by mitomycin C (MMC) did not affect the enhancing effect of IL-2 on the IFN-γ production, and significant increases in transcription factor T-bet expression were associated with the IL-2-mediated IFN-γ amplification. Splenic CD8+ immune T cells produced similar low levels of IL-2 in the secondary response to T. gondii, and a blocking of IL-2 signaling by anti-IL-2Rα antibody or inhibitors of JAK1 and JAK3 significantly reduced IFN-γ production of the T cells. This IL-2-mediated upregulation of IFN-γ production was observed in MMC-treated CD8+ immune T cells, thus independent from their cell division. Therefore, endogenous IL-2 produced by CD8+ immune T cells can play an important autocrine enhancing role on their IFN-γ production in the secondary responses to T. gondii, suggesting an importance of induction of CD8+ immune T cells with an appropriate IL-2 production for vaccine development. PMID:23359502

  5. Association of SNPs from IL1A, IL1B, and IL6 Genes with Human Cytomegalovirus Infection Among Pregnant Women.

    PubMed

    Wujcicka, Wioletta Izabela; Wilczyński, Jan Szczęsny; Nowakowska, Dorota Ewa

    2017-05-01

    The study was aimed to estimate the role and prevalence rates of genotypes, haplotypes, and alleles, located within the single-nucleotide polymorphisms (SNPs) of interleukin (IL) 1A, IL1B, and IL6 genes, in the occurrence and development of human cytomegalovirus (HCMV) infection among pregnant women. A research was conducted in 129 pregnant women, out of whom, 65 were HCMV infected and 64 were age-matched control uninfected individuals. HCMV DNA was quantitated for UL55 gene by the real-time Q PCR in the body fluids. The genotypic statuses within the SNPs were determined by nested PCR-RFLP assays and confirmed, by sequencing for randomly selected representative PCR products. A relationship between the genotypes and alleles, as well as haplotypes and multiple variants in the studied polymorphisms, and the occurrence of HCMV infection in pregnant women, was determined using a logistic regression model. TT genotype within IL1A polymorphism significantly decreased the risk of HCMV infection (OR 0.32, 95% CI 0.09-1.05; p ≤ 0.050). Considering IL6 SNP, the prevalence rate of GC genotype was significantly decreased among the HCMV infected, compared to the uninfected control individuals (OR 0.45, 95% CI 0.21-0.99; p ≤ 0.050). Moreover, CC homozygotic status in IL6 SNP, found in pregnant women, significantly decreased the risk of congenital infection with HCMV in their offsprings (OR 0.12; p ≤ 0.050). In multiple SNP analysis, TC haplotype within the IL1 polymorphisms significantly decreased the risk of the infection in pregnant women (OR 0.38 95% CI 0.15-0.96; p ≤ 0.050). In addition, TTG complex variants for all the studied polymorphisms and TG variants for IL1B and IL6 SNPs were significantly more prevalent among the infected offsprings with symptomatic congenital cytomegaly than among the asymptomatic cases (p ≤ 0.050). In conclusion, the analyzed IL1A -889 C>T, IL1B +3954 C>T, and IL6 -174 G>C polymorphisms may be associated with the

  6. Homeostatic Proliferation and IL-7R Alpha Expression Do Not Correlate with Enhanced T Cell Proliferation and Protection in Chronic Mouse Malaria

    PubMed Central

    Stephens, Robin; Seddon, Benedict; Langhorne, Jean

    2011-01-01

    While chronic infection has been shown to enhance protection from disease caused by several pathogens, the mechanisms are not known. The gamma-c family of cytokines IL-7, IL-2, and IL-15 are implicated in homeostatic proliferation, which is thought to maintain T cell memory. However in chronic infection, prolonged antigen exposure itself may contribute to lymphocyte survival. We have previously observed that chronic malaria infection enhances protection to re-infection, as well as enhancing B cell responses. Here, we show that chronic Plasmodium chabaudi malaria infection in mice enhances the expansion of CD4+ T cells in a second infection, and that this correlates with increased expression of the IL-2/15 Receptor beta (CD122) on memory T cells, as well as increasing IL-2 producers on re-infection. IL-2 has been recently linked to improved secondary proliferation, while the role of IL-7 in maintenance of CD4+ memory cells has been demonstrated in homeostatic proliferation, but its role in protective memory populations in infectious disease protective has not been fully investigated. Increased IL-7Rα (CD127) expression correlated, as previously reported with increased turnover of CD4 memory cells, however, this was not linked to protection or enhanced response to rechallenge, These data support the idea that antigen or IL-2 production resulting from chronic stimulation may play a role in an enhanced secondary T cell response. PMID:22039531

  7. IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts.

    PubMed

    Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki; Kish, Danielle D; Abe, Toyofumi; Su, Charles A; Abe, Ryo; Tanabe, Kazunari; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

    2016-03-15

    Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil, and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor (IL-1R) signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared with complete MHC-mismatched wild-type cardiac allografts, IL-1R(-/-) allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant, whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R(-/-) allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R(-/-) cardiac allografts took 3 wk longer than wild-type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R(-/-)/wild-type chimeric donors indicated that IL-1R signaling on graft nonhematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild-type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli-provoking development and elicitation of optimal alloimmune responses to the grafts. Copyright © 2016 by The American Association of Immunologists, Inc.

  8. Sustained CD4+ T cell-driven lymphopenia without a compensatory IL-7/IL-15 response among high-grade glioma patients treated with radiation and temozolomide

    PubMed Central

    Ellsworth, Susannah; Balmanoukian, Ani; Kos, Ferdynand; Nirschl, Christopher J; Nirschl, Thomas R; Grossman, Stuart A; Luznik, Leo; Drake, Charles G

    2014-01-01

    Prolonged lymphopenia correlating with decreased survival commonly occurs among glioma patients undergoing radiation therapy (RT) and temozolomide (TMZ) treatment. To better understand the pathophysiology of this phenomenon, we prospectively monitored serum cytokine levels and lymphocyte subsets in 15 high-grade glioma patients undergoing combined radiation and TMZ (referred to as RT/TMZ) treatment. Sufficient data for analysis were acquired from 11 of the patients initially enrolled. Lymphocyte phenotyping data were obtained using cytofluorometric analysis and serum cytokine levels were measured using the a multiplex bead-based assays. Total lymphocyte counts (TLCs) were > 1000 cells per μL peripheral blood in 10/11 patients at baseline, but dropped significantly after treatment. Specifically, after RT/TMZ therapy, the TLCs were found to be < 500 cells/μL in 2/11 patients, 500–1000 cells/μL in 7/11 patients, and > 1000 cells/μL in the remaining 2 patients. Among residual mononuclear blood cells, we observed a proportional drop in B and CD4+ T cells but not in CD8+ T lymphocytes. Natural killer cells remained to near-to-baseline levels and there was a transient and slight (insignificant) increase in regulatory T cells (Tregs). The circulating levels of IL-7 and IL-15 remained low despite marked drops in both the total and CD4+ T lymphocyte counts. Thus, patients with malignant glioma undergoing RT/TMZ treatment exhibit a marked decline in TLCs, affecting both CD4+ T cells and B lymphocytes, in the absence of a compensatory increase in interleukin-7 levels. The failure to mount an appropriate homeostatic cytokine response may be responsible for the prolonged lymphopenia frequently observed in these patients. PMID:24790790

  9. IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life.

    PubMed

    Hsu, Peter S; Lai, Catherine L; Hu, Mingjing; Santner-Nanan, Brigitte; Dahlstrom, Jane E; Lee, Cheng Hiang; Ajmal, Ayesha; Bullman, Amanda; Arbuckle, Susan; Al Saedi, Ahmed; Gacis, Lou; Nambiar, Reta; Williams, Andrew; Wong, Melanie; Campbell, Dianne E; Nanan, Ralph

    2018-06-15

    Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant β7 integrin + Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA + ) Treg cells later in life. β7 integrin + Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced β7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development. Copyright © 2018 by The American Association of Immunologists, Inc.

  10. Association between genes encoding components of the IL-4/IL-4 receptor pathway and dermatitis in children.

    PubMed

    Hussein, Yousri M; Shalaby, Sally M; Nassar, Amani; Alzahrani, Saad S; Alharbi, Ayman S; Nouh, Maha

    2014-07-25

    To determine whether IL-4, IL-4Rα and STAT6 polymorphisms are associated with susceptibility to dermatitis in Egyptian children. We genotyped three groups of children, consisting of 106 atopic dermatitis (AD) children, 95 non-AD children, and 100 of healthy controls, for IL-4 (-590 C/T), (-33 C/T), IL-4Rα (I50V), (Q576R) and STAT6 (2964 G/A), (2892 C/T) gene polymorphisms using PCR-RFLP assay. Total serum IgE and serum IL-4 levels were detected by ELISA. There was a non-significant association of IL-4 -590 C/T, -33 C/T polymorphisms in the children with non-AD or those with AD when compared with the controls. We identified a significant association between IL-4Rα I50V, Q576R polymorphisms and dermatitis susceptibility in AD (p=0.002, <0.001 respectively), whereas no such association was observed in non-AD group (p=0.52, 0.99 respectively). A significant association between STAT6 polymorphisms and both types of dermatitis was found. Patients who were carriers of IL4 -590C, IL-4Rα I50V G, STAT6 2964 A and STAT6 2892 T had an increased risk of AD [OR and 95% CI: 3.2 (2.5-4.2), p=0.005]. Furthermore, there was no relation between each polymorphism and serum IL-4 level (p>0.05 for each) while homozygosity for the risk alleles of IL-4, IL-4Rα and STAT6 SNPs were significantly associated with increased total IgE levels in all subjects. In Egyptian children, the IL-4Rα and the STAT6 polymorphism may play a role in susceptibility to AD. In addition, gene-gene interaction between the IL-4, the IL-4Rα and the STAT6 significantly increases an individual's susceptibility to AD. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Effect of intravenous lidocaine combined with amitriptyline on pain intensity, clinical manifestations and the concentrations of IL-1, IL-6 and IL-8 in patients with fibromyalgia: A randomized double-blind study.

    PubMed

    Albertoni Giraldes, Ana Laura; Salomão, Reinaldo; Leal, Plinio da Cunha; Brunialti, Milena Karina Coló; Sakata, Rioko Kimiko

    2016-10-01

    Regarding the use of intravenous lidocaine in fibromyalgia, there are no well-controlled studies. This study aimed to evaluate the effect of intravenous lidocaine on pain intensity, clinical manifestations and plasma levels of interleukin (IL)-1, IL-6, and IL-8 in fibromyalgia patients. In a randomized double-blind study, group 1 patients received 240 mg of lidocaine in 125 mL of saline solution, while group 2 patients received 125 mL of saline, both once a week for 4 weeks (T1, T2, T3 and T4). All patients received amitriptyline. The following were assessed: pain intensity before treatment (T0) and at 1, 2, 3, 4 and 8 weeks after treatment; clinical manifestations; the fibromyalgia impact questionnaire (FIQ) before and at 4 and 8 weeks after; the levels of IL 1, 6 and 8 before and at 4 and 8 weeks after treatment. Lower pain intensity was observed in the lidocaine group at T2, with no difference at the other time points. There was a reduction in pain intensity in both groups. The use of paracetamol and tramadol and plasma levels of IL-1, IL-6 and IL-8 did not differ between the groups. Clinical manifestations and side effects did not differ between groups. The combination of 240 mg of intravenous lidocaine (once a week for 4 weeks) with 25 mg of amitriptyline for 8 weeks had no meaningful impact in fibromyalgia patients. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  12. Leuconychie transversale induite par la manucurie: y a-t-il un apport de la dermoscopie?

    PubMed Central

    Gallouj, Salim; Mernissi, Fatima Zahra

    2014-01-01

    La leuconychie transversale induite par la manucurie est une leuconychie secondaire au microtraumatisme transmis à la matrice unguéale. Nous rapportant une observation où la dermoscopie avait un intérêt considérable pour l'orientation diagnostic. PMID:25368728

  13. IL2RA/CD25 Gene Polymorphisms: Uneven Association with Multiple Sclerosis (MS) and Type 1 Diabetes (T1D)

    PubMed Central

    Alcina, Antonio; Fedetz, María; Ndagire, Dorothy; Fernández, Oscar; Leyva, Laura; Guerrero, Miguel; Abad-Grau, María M.; Arnal, Carmen; Delgado, Concepción; Lucas, Miguel; Izquierdo, Guillermo; Matesanz, Fuencisla

    2009-01-01

    Background IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. Methods and Results Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3′- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. Conclusions These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases. PMID:19125193

  14. IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

    PubMed Central

    Nolz, Jeffrey C.; Harty, John T.

    2014-01-01

    Memory and naive CD8+ T cells exhibit distinct trafficking patterns. Specifically, memory but not naive CD8+ T cells are recruited to inflamed tissues in an antigen-independent manner. However, the molecular mechanisms that regulate memory CD8+ T cell trafficking are largely unknown. Here, using murine models of infection and T cell transfer, we found that memory but not naive CD8+ T cells dynamically regulate expression of core 2 O-glycans, which interact with P- and E-selectins to modulate trafficking to inflamed tissues. Following infection, antigen-specific effector CD8+ T cells strongly expressed core 2 O-glycans, but this glycosylation pattern was lost by most memory CD8+ T cells. After unrelated infection or inflammatory challenge, memory CD8+ T cells synthesized core 2 O-glycans independently of antigen restimulation. The presence of core 2 O-glycans subsequently directed these cells to inflamed tissue. Memory and naive CD8+ T cells exhibited the opposite pattern of epigenetic modifications at the Gcnt1 locus, which encodes the enzyme that initiates core 2 O-glycan synthesis. The open chromatin configuration in memory CD8+ T cells permitted de novo generation of core 2 O-glycans in a TCR-independent, but IL-15–dependent, manner. Thus, IL-15 stimulation promotes antigen-experienced memory CD8+ T cells to generate core 2 O-glycans, which subsequently localize them to inflamed tissues. These findings suggest that CD8+ memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy. PMID:24509081

  15. Production of interleukin-2 (IL-2) and expression of IL-2 receptor in patients with IgA nephropathy.

    PubMed

    Lee, T W; Kim, M J

    1992-01-01

    IL-2 production has been measured in several disease including type I diabetes mellitus, systemic lupus erythematosus, acquired immunodeficiency syndrome and active pulmonary sarcoidosis and its pathogenetic role was suggested. In IgA nephropathy, altered T cell subsets were reported to be associated with increased synthesis of IgA. The altered IL-2 production and the expression of IL-2 receptor might be involved in the pathogenesis of IgA nephropathy. To investigate the role of T cell mediated immunity in the pathogenesis of IgA nephropathy, the immune parameters such as T cell subsets, NK cell activity, interleukin-2 (IL-2) production and IL-2 receptor expression on peripheral blood mononuclear cells (PBMC) were measured before and/or after phytohemagglutinin (PHA) stimulation in 15 patients with IgA nephropathy. Age and sex matched 15 healthy controls and the correlations between the IL-2 production and immune parameters were evaluated. The mean percentages of T helper/inducer cells (CD4), T suppressor/cytotoxic cells (CD8) and the CD4/CD8 ratio of the patients were not different from those of controls and the proportions of CD8 CD11b cell in the patients (21.0 +/- 3.6%) were significantly lower than those in controls (30.5 +/- 5.3%) (p < 0.005). The production of IL-2 by fresh PBMC of both patients and controls was in undetectable ranges. The production of IL-2 by PHA stimulated PBMC of patients was significantly higher than that of controls (140.03 +/- 43.2 U/ml vs 106.5 +/- 42.1 U/ml, p < 0.05). The proportions of lymphocytes expressing the IL-2 receptor (CD25) before the stimulation with PHA in patients were 1.22 +/- 1.00 percent and were not different from those in controls (1.12 +/- 0.78 percent). The correlations between the production of IL-2 and the concentrations of serum IgA, the degrees of histologic alterations and the proportions of CD8 and CD8CD11b cells were not significant. There was a weak tendency of a positive correlation (p < 0.1) between

  16. Une fistule recto-vaginale rentrant dans le cadre d'un syndrome de Currarino

    PubMed Central

    Idrissi, Mounia Lakhdar; Babakhoya, Abdeladim; Bouabdellah, Youssef; Hida, Mostapha

    2011-01-01

    Le syndrome de Currarino (SC) est défini par une triade rassemblant une malformation ano-rectale, une agénésie sacrée et une tumeur pré-sacrée. Nous rapportons le cas d'une fille de 4 ans et demi ayant été admise en consultation de gastro-entérologie pédiatrique pour constipation avec issue de selle à travers un orifice vulvaire. La radiographie du rachis avait montré une agénésie sacrée. Le fistulo-scanner a mis en évidence une fistule recto-vaginale et l'IRM pelvienne a confirmé l'agénésie sacrée et a retrouvé une méningocèle antérieure. La découverte d'une malformation ano-rectale doit faire chercher une autre anomalie de la triade de Currarino. Cette affection, rare, nécessite une prise en charge médico-chirurgicale assez complexe. PMID:22384297

  17. Helminth Infections Coincident with Active Pulmonary Tuberculosis Inhibit Mono- and Multifunctional CD4+ and CD8+ T Cell Responses in a Process Dependent on IL-10

    PubMed Central

    George, Parakkal Jovvian; Anuradha, Rajamanickam; Kumar, Nathella Pavan; Sridhar, Rathinam; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Tissue invasive helminth infections and tuberculosis (TB) are co-endemic in many parts of the world and can trigger immune responses that might antagonize each other. We have previously shown that helminth infections modulate the Th1 and Th17 responses to mycobacterial-antigens in latent TB. To determine whether helminth infections modulate antigen-specific and non-specific immune responses in active pulmonary TB, we examined CD4+ and CD8+ T cell responses as well as the systemic (plasma) cytokine levels in individuals with pulmonary TB with or without two distinct helminth infections—Wuchereria bancrofti and Strongyloides stercoralis infection. By analyzing the frequencies of Th1 and Th17 CD4+ and CD8+ T cells and their component subsets (including multifunctional cells), we report a significant diminution in the mycobacterial–specific frequencies of mono- and multi–functional CD4+ Th1 and (to a lesser extent) Th17 cells when concomitant filarial or Strongyloides infection occurs. The impairment in CD4+ and CD8+ T cell cytokine responses was antigen-specific as polyclonal activated T cell frequencies were equivalent irrespective of helminth infection status. This diminution in T cell responses was also reflected in diminished circulating levels of Th1 (IFN-γ, TNF-α and IL-2)- and Th17 (IL-17A and IL-17F)-associated cytokines. Finally, we demonstrate that for the filarial co-infections at least, this diminished frequency of multifunctional CD4+ T cell responses was partially dependent on IL-10 as IL-10 blockade significantly increased the frequencies of CD4+ Th1 cells. Thus, co-existent helminth infection is associated with an IL-10 mediated (for filarial infection) profound inhibition of antigen-specific CD4+ T cell responses as well as protective systemic cytokine responses in active pulmonary TB. PMID:25211342

  18. Transplantation rénale au Maroc: l'hémodialysé et son entourage sont-ils suffisamment informés?

    PubMed Central

    Noto-Kadou-Kaza, Béfa; Sabi, Kossi Akomola; Imangue, Ghislain; Al-Torayhi, Mays Hadi; Amekoudi, Eyram Yoan Makafui; Tsevi, Claude Mawufemo; Zamd, Mohamed; Medkouri, Ghislaine; Benghanem, Mohamed Gharbi; Ramdani, Benyounes

    2014-01-01

    Introduction La transplantation rénale constitue le traitement idéal de l'insuffisance rénale chronique. Cependant il existe une insuffisance de donneurs contrairement aux receveurs dont le nombre ne cesse de s'accroitre. La méconnaissance de la transplantation par les hémodialysés et leur entourage pourrait être l'une des causes. Notre but était d’évaluer les connaissances et opinions de l'hémodialysé et de son entourage sur la transplantation rénale. Méthodes L'enquête menée en Aout 2013 avait inclus 83 hémodialysés de notre centre et 70 membres de leur entourage. Ils ont été soumis à un questionnaire qui portait sur les thèmes suivants: statut socio-économique, volonté d’être transplanté ou d’être donneur, avantages de la transplantation rénale, point de vue de la religion sur la transplantation. Aucun des individus interrogés n'avait jamais fait l'objet d'une transplantation ou d'un don d'organe. Résultats Parmi 83 hémodialysés on notait 49,4% de femmes avec une moyenne d’âge de 41,4±12 ans. Le niveau socio-économique bas représentait 66,7%. Le manque d'information chez était estimé à 62,7%. Seuls 41% se disaient être candidat à la transplantation rénale mais 12% seulement était inscrit sur la liste d'attente de greffe. La transplantation était estimée plus couteuse que l'hémodialyse par 50,6% des patients et seuls 71,1% estimaient qu'elle offrait une meilleure vie. Pour 20,5%, l'Islam s'opposerait au don cadavérique et pour 10,9% au don vivant. Parmi les 70 membres de l'entourage interrogé il y avait 56,8% de femmes; la moyenne d’âge était de 44,4±10,5 ans. Le niveau économique bas représentait 52,3%. Le manque d'information était estimé à 61,4%. Pour 56,8% la vie serait impossible avec un seul rein. Seuls 13,6% étaient inscrit sur le registre de don. Pour 45,5% l'Islam s'opposerait au don cadavérique. Conclusion Il importe d'intensifier la sensibilisation des hémodialysées et leur famille

  19. Le transfert de connaissances entre les mathematiques et les sciences. Une etude exploratoire aupres d'eleves de 4e secondaire

    NASA Astrophysics Data System (ADS)

    Samson, Ghislain

    2003-06-01

    Au moment ou dans plusieurs pays on travaille a refondre les programmes d'etudes, tant au primaire qu'au secondaire, l'interet pour le transfert renait. Un des concepts fondamentaux en apprentissage consiste en l'habilete a reutiliser de facon consciente et efficace un acquis d'une situation a une autre situation. Cette recherche emane de preoccupations professionnelles au moment ou le chercheur etait enseignant au secondaire. Au cours de ces annees, il lui a ete possible de constater que plusieurs eleves percevaient difficilement les liens presents entre les disciplines mathematiques et scientifiques. Des travaux en psychologie cognitive et plus particulierement selon une perspective du traitement de l'information ont servi de cadre de reference pour evaluer et analyser les capacites de transfert aupres d'eleves de 4e secondaire. Ce cadre de reference permet de formuler le principal objectif qui est de mieux comprendre le processus de transfert chez des eleves en situation de resolution de problemes scientifiques. Cette these s'interesse donc au transfert en tant que phenomene important du processus d'apprentissage au sens de l'integration. La methode de recherche choisie, de nature qualitative, est principalement axee sur l'evaluation de la capacite a transferer des connaissances lors d'une epreuve et d'un entretien. Pour evaluer ce potentiel de transfert, nous avons elabore deux outils: une epreuve en mathematiques et en sciences et un guide d'entretien. Pour la passation de l'epreuve, le chercheur a pu compter sur la collaboration de 130 sujets provenant de deux ecoles. L'entretien complete la prise de donnees avec 13 sujets ayant accepte de poursuivre l'etude. Les donnees recueillies par ces instruments font ensuite l'objet d'une analyse de contenu. En premier lieu, les verbatims de l'epreuve et de l'entretien ont ete transcrits, puis codifies. La correction des reponses fournies pour les problemes resolus s'est faite a partir d'une grille d

  20. Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

    PubMed Central

    Wiedemann, Gabriela Maria; Knott, Max Martin Ludwig; Vetter, Viola Katharina; Rapp, Moritz; Haubner, Sascha; Fesseler, Julia; Kühnemuth, Benjamin; Layritz, Patrick; Thaler, Raffael; Kruger, Stephan; Ormanns, Steffen; Mayr, Doris; Endres, Stefan; Anz, David

    2016-01-01

    ABSTRACT In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1α). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1α as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumor-induced immunosuppression. PMID:27757295

  1. IFN-gamma-mediated inhibition of human IgE synthesis by IL-21 is associated with a polymorphism in the IL-21R gene.

    PubMed

    Pène, Jérôme; Guglielmi, Laurence; Gauchat, Jean-François; Harrer, Nathalie; Woisetschläger, Maximilian; Boulay, Vera; Fabre, Jean-Michel; Demoly, Pascal; Yssel, Hans

    2006-10-15

    IL-21 is a cytokine produced by CD4+ T cells that has been reported to regulate human, as well as, mouse T and NK cell function and to inhibit Ag-induced IgE production by mouse B cells. In the present study, we show that human rIL-21 strongly enhances IgE production by both CD19+ CD27- naive, and CD19+ CD27+ memory B cells, stimulated with anti-CD40 mAb and rIL-4 and that it promotes the proliferative responses of these cells. However, rIL-21 does not significantly affect anti-CD40 mAb and rIL-4-induced Cepsilon promoter activation in a gene reporter assay, nor germline Cepsilon mRNA expression in purified human spleen or peripheral blood B cells. In contrast, rIL-21 inhibits rIL-4-induced IgE production in cultures of PBMC or total splenocytes by an IFN-gamma-dependent mechanism. The presence of a polymorphism (T-83C), in donors heterozygous for this mutation was found to be associated not only with lower rIL-21-induced IFN-gamma production levels, but also with a lower sensitivity to the inhibitory effects of IL-21 on the production of IgE, compared with those in donors expressing the wild-type IL-21R. Taken together, these results show that IL-21 differentially regulates IL-4-induced human IgE production, via its growth- and differentiation-promoting capacities on isotype-, including IgE-, committed B cells, as well as via its ability to induce IFN-gamma production, most likely by T and NK cells, whereas the outcome of these IL-21-mediated effects is dependent on the presence of a polymorphism in the IL-21R.

  2. Lambeau Expanse du Cuir Chevelu dans la Couverture des Alopecies Cicatricielles sur Sequelles de Brulures. A Propos d'une Observation

    PubMed Central

    El Mazouz, S.; Hafidi, J.; Fejjal, N.; Mejjati, H.; Cherkab, L.; Gharib, N.; Abbassi, A.

    2010-01-01

    Summary Les séquelles esthétiques des alopécies cicatricielles sur séquelles de brûlures sont responsables de préjudices empêchant parfois la réinsertion sociale du patient, surtout chez les sujets de sexe féminin. Le cuir chevelu permet la réalisation de lambeaux permettant de couvrir ces alopécies. Les Auteurs décrivent le cas d'une jeune patiente victime d'une alopécie cicatricielle sur séquelles de brûlures chez qui ils ont réalisé un lambeau expansé du cuir chevelu et mettent le point sur la prise en charge de ces lésions à travers ce cas clinique et une revue de littérature. PMID:21991195

  3. Noninvasive monitoring of cancer therapy induced activated T cells using [18F]FB-IL-2 PET imaging.

    PubMed

    Hartimath, S V; Draghiciu, O; van de Wall, S; Manuelli, V; Dierckx, R A J O; Nijman, H W; Daemen, T; de Vries, E F J

    2017-01-01

    Cancer immunotherapy urgently calls for methods to monitor immune responses at the site of the cancer. Since activated T lymphocytes may serve as a hallmark for anticancer responses, we targeted these cells using the radiotracer N-(4-[ 18 F]fluorobenzoyl)-interleukin-2 ([ 18 F]FB-IL-2) for positron emission tomography (PET) imaging. Thus, we noninvasively monitored the effects of local tumor irradiation and/or immunization on tumor-infiltrating and systemic activated lymphocytes in tumor-bearing mice. A 10- and 27-fold higher [ 18 F]FB-IL-2 uptake was observed in tumors of mice receiving tumor irradiation alone or in combination with immunization, respectively. This increased uptake was extended to several non-target tissues. Administration of the CXCR4 antagonist AMD3100 reduced tracer uptake by 2.8-fold, indicating a CXCR4-dependent infiltration of activated T lymphocytes upon cancer treatment. In conclusion, [ 18 F]FB-IL-2 PET can serve as a clinical biomarker to monitor treatment-induced infiltration of activated T lymphocytes and, on that basis, may guide cancer immunotherapies.

  4. IL-21 Therapy Controls Immune Activation and Maintains Antiviral CD8+ T Cell Responses in Acute Simian Immunodeficiency Virus Infection.

    PubMed

    Méndez-Lagares, Gema; Lu, Ding; Merriam, David; Baker, Christopher A; Villinger, François; Van Rompay, Koen K A; McCune, Joseph M; Hartigan-O'Connor, Dennis J

    2017-11-01

    Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replicate during acute infection in lymphocytes of the gastrointestinal tract, before disseminating systemically. Localized replication and associated loss of gut-resident CD4 + T cells occur regardless of the portal of entry of the virus (e.g., intravenous vs. rectal). Thus, HIV and SIV are tropic for gut tissue, and their pathogenesis requires the special environment of the intestine. T helper 17 (Th17) cells are important contributors to microbial defense in the gut that are vulnerable to HIV infection and whose loss is associated with translocation of microbial products to the systemic circulation, leading to chronic immune activation and disease progression. Interleukin (IL)-21 promotes differentiation and survival of Th17 cells and stimulates CD8 + T cell function. By promoting Th17 cell survival, IL-21 could limit bacterial translocation and immune activation in the setting of acute or rebounding HIV/SIV disease. In this study, we tested the effect of recombinant IL-21-IgFc treatment, given at the time of infection, on SIV mac251 infection. We found that rIL-21-IgFc decreases immune activation and maintains effective antiviral responses by CD8 + T cells in blood, but this maintenance is not associated with lower viral loads. rIL-21-IgFc treatment also did not generally support Th17 cell populations, but Th17 cells remained strongly and independently associated with control of plasma viremia. For example, the single animal exhibiting greatest control over viremia in our study also manifested the highest levels of IL-21 in plasma, Th17 cell maintenance in blood, and Th17 cells in intestinal tissue. These findings provide rationale for further exploration of IL-21 treatment as a support for host CD8 + T cell responses in HIV cure strategies.

  5. Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

    PubMed

    Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D; Lombardi, Giovanna; Nestle, Frank O

    2012-01-01

    The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null)), notably the NOD-scid IL-2Rγ(null) (NSG) and BALB/c-Rag2(null) IL-2Rγ(null) (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+) compartment and higher engraftment levels of CD3(+) T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM)) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM)-cell driven GvHD.

  6. IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection

    PubMed Central

    Davies, Jessica; Hansi, Navjyot; Easom, Nicholas J.W.; Burton, Alice R.; Stegmann, Kerstin A.; Schurich, Anna; Swadling, Leo; Male, Victoria; Luong, TuVinh; Davidson, Brian R.; Kennedy, Patrick T.F.

    2017-01-01

    The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)–infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-betloEomesloBlimp-1hiHobitlo T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69+CD103+ CXCR6+CXCR3+). These tissue-resident memory T cells (TRM) are preferentially expanded in patients with partial immune control of HBV infection and can remain in the liver after the resolution of infection, including compartmentalized responses against epitopes within all major HBV proteins. Sequential IL-15 or antigen exposure followed by TGFβ induces liver-adapted TRM, including their signature high expression of exhaustion markers PD-1 and CD39. We suggest that these inhibitory molecules, together with paradoxically robust, rapid, cell-autonomous IL-2 and IFNγ production, equip liver CD8 TRM to survive while exerting local noncytolytic hepatic immunosurveillance. PMID:28526759

  7. IL-15 Deficient Tax Mice Reveal a Role for IL-1α in Tumor Immunity

    PubMed Central

    Rauch, Daniel A.; Harding, John C.; Ratner, Lee

    2014-01-01

    IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia/lymphoma (ATL) and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15−/− TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra) were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma. PMID:24416335

  8. Dendritic Cells Induce a Subpopulation of IL-12Rβ2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses

    PubMed Central

    Sela, Uri; Park, Chae Gyu; Park, Andrew; Olds, Peter; Wang, Shu; Fischetti, Vincent A.

    2016-01-01

    Cytokines secreted from dendritic cells (DCs) play an important role in the regulation of T helper (Th) cell differentiation and activation into effector cells. Therefore, controlling cytokine secretion from DCs may potentially regulate Th differentiation/activation. DCs also induce de-novo generation of regulatory T cells (Treg) that modulate the immune response. In the current study we used the mixed leukocyte reaction (MLR) to investigate the effect of allospecific Treg on IL-12, TNFα and IL-6 secretion by DCs. Treg cells were found to markedly down-regulate IL-12 secretion from DCs following stimulation with TLR7/8 agonist. This down-regulation of IL-12 was neither due to a direct suppression of its production by the DCs nor a result of marked DC death. We found that IL-12 was rather actively consumed by Treg cells. IL-12 consumption was mediated by a subpopulation of IL-12Rβ2-expressing Treg cells and was dependent on MHC class-II expressed on dendritic cells. Furthermore, IL-12 consumption by Tregs increased their suppressive effect on T cell proliferation and Th1 activation. These results provide a new pathway of Th1 response regulation where IL-12 secreted by DCs is consumed by a sub-population of IL-12Rβ2-expressing Treg cells. Consumption of IL-12 by Tregs not only reduces the availability of IL-12 to Th effector cells but also enhances the Treg immunosuppressive effect. This DC-induced IL-12Rβ2-expressing Treg subpopulation may have a therapeutic advantage in suppressing Th1 mediated autoimmunity. PMID:26745371

  9. Polymorphic variations in IL-1β, IL-6 and IL-10 genes, their circulating serum levels and breast cancer risk in Indian women.

    PubMed

    Pooja, Singh; Chaudhary, Preeti; Nayak, Lakshma V; Rajender, Singh; Saini, Karan Singh; Deol, Debashish; Kumar, Sandeep; Bid, Hemant Kumar; Konwar, Rituraj

    2012-10-01

    Cytokines are known as important regulators of the entire gamut of cancer from initiation, invasion and metastasis. This fact and plethora of gene polymorphism data prompted us to investigate cytokine gene polymorphisms in breast cancer (BC) patients. Selected polymorphisms in the IL-1β [-511 T>C (rs16944) and +3954 C>T (rs1143634)]; IL-6 [-174 G>C (rs1800795)]; IL-10 [-1082 A>G (rs1800896), -819 T>C (rs1800871) and -592 A>C (rs1800872)] genes were genotyped in 200 BC patients and 200 healthy volunteers in a case-control study using PCR-RFLP and direct DNA sequencing techniques. Peripheral cytokine levels were measured using ELISA. Allele and genotype data were analyzed for significance of differences between cases and controls using Chi-Square [χ(2)] test. Two sided P-values of less than 0.05 were considered to be statistically significant. Peripheral level of all three cytokines did not show any significant difference between cases and controls. Allele and genotype frequency of IL-1β [-511 T>C (rs16944)] did not show any difference between cases and controls. On the other hand mutant allele and genotype at IL-1β [+3954 C>T (rs1143634)] associated with increased risk of BC. This was also true for pre-menopausal cases and for mutant genotype in post-menopausal cases. Mutant allele and genotypes at IL-6 [-174 G>C (rs1800795)] appeared to be protective in nature such that controls had a higher frequency of both mutant alleles and genotypes. None of the three SNPs in IL-10 gene associated with risk of BC, except significant association of mutant allele and genotypes of -1082 A>G (rs1800896) polymorphism with postmenopausal BC. Mutant allele and genotype at IL-1β [+3954 C>T (rs1143634)] site associated with increased BC risk, while mutant allele and genotypes at IL-6 [-174 G>C (rs1800795)] polymorphism appeared to be protective. Also, there was significant association of mutant allele and genotypes of IL-10 [-1082 A>G (rs1800896)] with postmenopausal BC. None of

  10. Listériose humaine : Expériences cliniques avec cette zoonose chez 12 patients en Estrie, Québec sur une période de 19 ans (1976 à 1995)

    PubMed Central

    Maziade, Pierre-Jean; Marcoux, J André

    1997-01-01

    Une étude rétrospective a été faite dans le but de réviser l’épidémiologie, les facteurs de risque, les manifestations cliniques et l’évolution des cas d’infection à Listeria monocytogenes en Estrie, Québec de 1976–1995. Les patients ont été repérés à partir des cultures positives et du diagnostic donné par le Service des maladies infectieuses du Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Québec. Un total de 12 patients ont fait partie de l’étude. La septicémie non reliée à la grossesse (4/12) et la méningite (6/12) ont été les deux présentations cliniques majeures. Il y avait 1 cas de listériose de grossesse et 1 cas de granulomatosis infanti septica. Dix patients avaient au moins une condition prédisposante. Un seul décès a été attribué à l’infection à L monocytogenes. Des séquelles neurologiques ont été observées chez la moitié des patients avec méningite tandis qu’aucune séquelle a été notée chez ceux avec septicémie. En conclusion, la listériose est une maladie de patients âgés et immunocompromis. La présentation clinique et l’évolution ne sont pas différentes de ce qui a déjà été rapporté dans d’autres régions industrialisées. PMID:22514474

  11. Adoptive Transfer of IL13Rα2-Specific Chimeric Antigen Receptor T Cells Creates a Pro-inflammatory Environment in Glioblastoma.

    PubMed

    Pituch, Katarzyna C; Miska, Jason; Krenciute, Giedre; Panek, Wojciech K; Li, Gina; Rodriguez-Cruz, Tania; Wu, Meijing; Han, Yu; Lesniak, Maciej S; Gottschalk, Stephen; Balyasnikova, Irina V

    2018-04-04

    In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13Rα2 (IL13Rα2-CARs) in immunocompetent MG models. Murine T cells expressing IL13Rα2-CARs with a CD28.ζ (IL13Rα2-CAR.CD28.ζ) or truncated signaling domain (IL13Rα2-CAR.Δ) were generated by retroviral transduction, and their effector function was evaluated both in vitro and in vivo. IL13Rα2-CAR.CD28.ζ T cells' specificity toward IL13Rα2 was confirmed through cytokine production and cytolytic activity. In vivo, a single intratumoral injection of IL13Rα2-CAR.CD28.ζ T cells significantly extended the survival of IL13Rα2-expressing GL261 and SMA560 glioma-bearing mice; long-term survivors were resistant to re-challenge with IL13Rα2-negative and IL13Rα2-positive tumors. IL13Rα2-CAR.CD28.ζ T cells proliferated, produced cytokines (IFNγ, TNF-α), and promoted a phenotypically pro-inflammatory glioma microenvironment by inducing a significant increase in the number of CD4 + and CD8 + T cells and CD8α + dendritic cells and a decrease in Ly6G + myeloid-derived suppressor cells (MDSCs). Our data underline the significance of CAR T cell studies in immunocompetent hosts and further validate IL13Rα2-CAR T cells as an efficacious therapeutic strategy for MG. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  12. Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene

    PubMed Central

    Hsu, Cary; Jones, Stephanie A.; Cohen, Cyrille J.; Zheng, Zhili; Kerstann, Keith; Zhou, Juhua; Robbins, Paul F.; Peng, Peter D.; Shen, Xinglei; Gomes, Theotonius J.; Dunbar, Cynthia E.; Munroe, David J.; Stewart, Claudia; Cornetta, Kenneth; Wangsa, Danny; Ried, Thomas; Rosenberg, Steven A.

    2007-01-01

    Malignancies arising from retrovirally transduced hematopoietic stem cells have been reported in animal models and human gene therapy trials. Whether mature lymphocytes are susceptible to insertional mutagenesis is unknown. We have characterized a primary human CD8+ T-cell clone, which exhibited logarithmic ex vivo growth in the absence of exogenous cytokine support for more than 1 year after transduction with a murine leukemia virus–based vector encoding the T-cell growth factor IL-15. Phenotypically, the clone was CD28−, CD45RA−, CD45RO+, and CD62L−, a profile consistent with effector memory T lymphocytes. After gene transfer with tumor-antigen–specific T-cell receptors, the clone secreted IFN-γ upon encountering tumor targets, providing further evidence that they derived from mature lymphocytes. Gene-expression analyses revealed no evidence of insertional activation of genes flanking the retroviral insertion sites. The clone exhibited constitutive telomerase activity, and the presence of autocrine loop was suggested by impaired cell proliferation following knockdown of IL-15Rα expression. The generation of this cell line suggests that nonphysiologic expression of IL-15 can result in the long-term in vitro growth of mature human T lymphocytes. The cytokine-independent growth of this line was a rare event that has not been observed in other IL-15 vector transduction experiments or with any other integrating vector system. It does not appear that the retroviral vector integration sites played a role in the continuous growth of this cell clone, but this remains under investigation. PMID:17353346

  13. Genetic characterization of interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18) with relevant biological roles in lagomorphs

    PubMed Central

    Neves, Fabiana; Abrantes, Joana; Almeida, Tereza; de Matos, Ana Lemos; Costa, Paulo P

    2015-01-01

    ILs, as essential innate immune modulators, are involved in an array of biological processes. In the European rabbit (Oryctolagus cuniculus) IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18 have been implicated in inflammatory processes and in the immune response against rabbit hemorrhagic disease virus and myxoma virus infections. In this study we characterized these ILs in six Lagomorpha species (European rabbit, pygmy rabbit, two cottontail rabbit species, European brown hare and American pika). Overall, these ILs are conserved between lagomorphs, including in their exon/intron structure. Most differences were observed between leporids and American pika. Indeed, when comparing both, some relevant differences were observed in American pika, such as the location of the stop codon in IL-1α and IL-2, the existence of a different transcript in IL8 and the number of cysteine residues in IL-1β. Changes at N-glycosylation motifs were also detected in IL-1, IL-10, IL-12B and IL-15. IL-1α is the protein that presents the highest evolutionary distances, which is in contrast to IL-12A where the distances between lagomorphs are the lowest. For all these ILs, sequences of human and European rabbit are more closely related than between human and mouse or European rabbit and mouse. PMID:26395994

  14. IL-15 regulates Bcl-2 family members Bim and Mcl-1 through JAK/STAT and PI3K/AKT pathways in T cells.

    PubMed

    Shenoy, Aparna R; Kirschnek, Susanne; Häcker, Georg

    2014-08-01

    Maintenance of T cells is determined by their survival capacity, which is regulated by Bcl-2 proteins. Cytokines signalling through the common gamma chains such as IL-2, IL-7 and IL-15 are important for T-cell survival but how these cytokines determine the expression of Bcl-2-family proteins is not clear. We report signalling events of cytokines that regulate expression of two key Bcl-2 proteins, pro-apoptotic Bim and anti-apoptotic Mcl-1, in resting C57BL/6 mouse T cells. IL-2, IL-7 and IL-15 inhibited apoptosis but paradoxically induced the expression of Bim, countered by concomitant induction of Mcl-1. Bim induction by IL-15 was found at the mRNA and protein levels and depended on both JAK/STAT and PI3K signals. A new STAT5-binding site was identified in the Bim promoter, which was occupied by STAT5 upon IL-15 stimulation. Although it also depended on JAK/STAT- and PI3K signalling, Mcl-1 regulation was independent of Mcl-1 mRNA levels and of regulation of protein stability, suggesting translational regulation. Concurrent CD3 signals inhibited some of the IL-7 effect but not the IL-15 effect on Bcl-2 proteins. The data suggest that cytokines induce Bim and prime T cells for apoptosis, but also inhibit apoptosis by stabilising Mcl-1. Later downregulation of short-lived Mcl-1 may induce efficient, Bim-dependent apoptosis. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Effects of overexpression of IL-1 receptor-associated kinase on NFkappaB activation, IL-2 production and stress-activated protein kinases in the murine T cell line EL4.

    PubMed

    Knop, J; Wesche, H; Lang, D; Martin, M U

    1998-10-01

    The association and activation of the IL-1 receptor-associated protein kinase (IRAK) to the IL-1 receptor complex is one of the earliest events detectable in IL-1 signal transduction. We generated permanent clones of the murine T cell line EL4 6.1 overexpressing human (h)IRAK to evaluate the role of this kinase in IL-1 signaling. Overexpression of hIRAK enhanced IL-1-stimulated activation of the transcription factor NFkappaB, whereas a truncated form (N-IRAK) specifically inhibited IL-1-dependent NFkappaB activity. In clones stably overexpressing hIRAK a weak constitutive activation of NFkappaB correlated with a low basal IL-2 production which was enhanced in an IL-1-dependent manner. Compared to the parental cell line the dose-response curve of IL-1-induced IL-2 production was shifted in both potency and efficacy. These results demonstrate that IRAK directly triggers NFkappaB-mediated gene expression in EL4 cells. Qualitatively different effects were observed for the IL-1-induced activation of stress-activated protein (SAP) kinases: permanent overexpression of IRAK did not affect the dose dependence but prolonged the kinetics of IL-1-induced activation of SAP kinases, suggesting that this signaling branch may be regulated by distinct mechanisms.

  16. Genetic characterization of interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18) with relevant biological roles in lagomorphs.

    PubMed

    Neves, Fabiana; Abrantes, Joana; Almeida, Tereza; de Matos, Ana Lemos; Costa, Paulo P; Esteves, Pedro J

    2015-11-01

    ILs, as essential innate immune modulators, are involved in an array of biological processes. In the European rabbit (Oryctolagus cuniculus) IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18 have been implicated in inflammatory processes and in the immune response against rabbit hemorrhagic disease virus and myxoma virus infections. In this study we characterized these ILs in six Lagomorpha species (European rabbit, pygmy rabbit, two cottontail rabbit species, European brown hare and American pika). Overall, these ILs are conserved between lagomorphs, including in their exon/intron structure. Most differences were observed between leporids and American pika. Indeed, when comparing both, some relevant differences were observed in American pika, such as the location of the stop codon in IL-1α and IL-2, the existence of a different transcript in IL8 and the number of cysteine residues in IL-1β. Changes at N-glycosylation motifs were also detected in IL-1, IL-10, IL-12B and IL-15. IL-1α is the protein that presents the highest evolutionary distances, which is in contrast to IL-12A where the distances between lagomorphs are the lowest. For all these ILs, sequences of human and European rabbit are more closely related than between human and mouse or European rabbit and mouse. © The Author(s) 2015.

  17. NK cells modulate the cytotoxic activity generated by Mycobacterium leprae-hsp65 in leprosy patients: role of IL-18 and IL-13

    PubMed Central

    DE LA BARRERA, S; FINIASZ, M; FINK, S; ILARREGUI, J; ALEMÁN, M; OLIVARES, L; FRANCO, M C; PIZZARIELLO, G; DEL CARMEN SASIAIN, M

    2004-01-01

    Protection against intracellular pathogens such as Mycobacterium leprae is critically dependent on the function of NK cells at early stages of the immune response and on Th1 cells at later stages. In the present report we evaluated the role of IL-18 and IL-13, two cytokines that can influence NK cell activity, in the generation of M. leprae-derived hsp65-cytotoxic T lymphocytes (CTL) from peripheral blood mononuclear cells (PBMC) of leprosy patients. We demonstrated that IL-18 modulates hsp65-induced CTL generation and collaborates with IL-12 for this effect. In paucibacillary (PB) patients and normal controls (N) depletion of NK cells reduces the cytolytic activity. Under these conditions, IL-12 cannot up-regulate this CTL generation, while, in contrast, IL-18 increases the cytotoxic activity both in the presence or absence of NK cells. IL-13 down-regulates the hsp65-induced CTL generation and counteracts the positive effect of IL-18. The negative effect of IL-13 is observed in the early stages of the response, suggesting that this cytokine affects IFNγ production by NK cells. mRNA coding for IFNγ is induced by IL-18 and reduced in the presence of IL-13, when PBMC from N or PB patients are stimulated with hsp65. Neutralization of IL-13 in PBMC from multibacillary (MB) leprosy patients induces the production of IFNγ protein by lymphocytes. A modulatory role on the generation of hsp65 induced CTL is demonstrated for IL-18 and IL-13 and this effect takes place through the production of IFNγ. PMID:14678270

  18. Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy.

    PubMed

    Maddur, Mohan S; Stephen-Victor, Emmanuel; Das, Mrinmoy; Prakhar, Praveen; Sharma, Varun K; Singh, Vikas; Rabin, Magalie; Trinath, Jamma; Balaji, Kithiganahalli N; Bolgert, Francis; Vallat, Jean-Michel; Magy, Laurent; Kaveri, Srini V; Bayry, Jagadeesh

    2017-03-20

    Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (T reg ) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking. Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4-5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA. The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with T reg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and T reg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. T reg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α. T reg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. T reg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.

  19. Quand la biopsie cutanée peut étiqueter une épilepsie

    PubMed Central

    Harmouch, Taoufiq; Gallouj, Salim; Znati, Kaoutar; Sennou, Aicha Slassi; Belahcen, Faouzi; Amarti, Afaf

    2011-01-01

    La maladie de Lafora (ML) représente une forme rare et grave d’épilepsie myoclonique progressive. C'est une affection à transmission autosomique récessive, hétérogène sur le plan génétique. Nous rapportons le cas d'une adolescente de 16 ans, issue de parents consanguins de premier degré, qui présente depuis l’âge de 14 ans des crises d’épilepsie et des myoclonies. L'examen neurologique a montré un syndrome cérébelleux et unetérioration intellectuelle. La biopsie cutanée était indispensable pour orienter le diagnostic. La ML a un pronostic constamment fatal. L’étude histologique confirme le diagnostic et l’étude moléculaire peut aider à établir un conseil génétique. PMID:22187608

  20. Une alternative au cobalt pour la synthese de nanotubes de carbone monoparoi par plasma inductif thermique

    NASA Astrophysics Data System (ADS)

    Carrier, Jean-Francois

    Les nanotubes de carbone de type monoparoi (C-SWNT) sont une classe recente de nanomateriaux qui ont fait leur apparition en 1991. L'interet qu'on leur accorde provient des nombreuses proprietes d'avant-plan qu'ils possedent. Leur resistance mecanique serait des plus rigide, tout comme ils peuvent conduire l'electricite et la chaleur d'une maniere inegalee. Non moins, les C-SWNT promettent de devenir une nouvelle classe de plateforme moleculaire, en servant de site d'attache pour des groupements reactifs. Les promesses de ce type particulier de nanomateriau sont nombreuses, la question aujourd'hui est de comment les realiser. La technologie de synthese par plasma inductif thermique se situe avantageusement pour la qualite de ses produits, sa productivite et les faibles couts d'operation. Par contre, des recherches recentes ont permis de mettre en lumiere des risques d'expositions reliees a l'utilisation du cobalt, comme catalyseur de synthese; son elimination ou bien son remplacement est devenu une preoccupation importante. Quatre recettes alternatives ont ete mises a l'essai afin de trouver une alternative plus securitaire a la recette de base; un melange catalytique ternaire, compose de nickel, de cobalt et d'oxyde d'yttrium. La premiere consiste essentiellement a remplacer la proportion massique de cobalt par du nickel, qui etait deja present dans la recette de base. Les trois options suivantes contiennent de nouveaux catalyseurs, en remplacement au Co, qui sont apparus dans plusieurs recherches scientifiques au courant des dernieres annees: le dioxyde de zircone (ZrO2), dioxyde de manganese (MnO2) et le molybdene (Mo). La methode utilisee consiste a vaporiser la matiere premiere, sous forme solide, dans un reacteur plasma a haute frequence (3 MHz) a paroi refroidi. Apres le passage dans le plasma, le systeme traverse une section dite de "croissance", isolee thermiquement a l'aide de graphite, afin de maintenir une certaine plage de temperature favorable a la

  1. [Traffic-related PM2.5 regulates IL-2 releasing in Jurkat T cells by calcium signaling pathway].

    PubMed

    Tong, Guoqiang; Zhang, Zhihong; Han, Jianbiao; Qiu, Yong; Xu, Jianjun

    2013-09-01

    To explore the effects of traffic-related PM2.5 on interleukin-2 (IL-2) in Jurkat T cells and the regulatory action of calcium signaling pathway. The cells were exposed to 100 microg/ml of PM2.5 for 3, 6 and 24 h. Normal saline group, blank filter group, calcium chelating agent EGTA group and the calcineurin antagonist cyclosporine A (CSA) group were as parallel control. The level of IL-2 was detected by ELISA kits, the mRNA expression of CaN, NFAT were determined by QRT-PCR. The nuclear distribution of NFAT was observed by immunofluorescence microscopy. The level of IL-2 in Jurkat T cells exposed to 100 microg/ml PM2.5 was significantly lower than parallel groups, but higher than PM2.5 + CSA group and PM2.5 + EGTA group (P < 0.05). With the increase of time, the releasing level of IL-2 appeared reducing trend in 100 microg/ml of PM2.5 group. The mRNA expression level of NFAT and CaN were higher than parallel groups, PM2.5 + CSA group and PM2.5 + EGTA group (P < 0.05). PM2.5 can induce NFAT protein with dephosphorylation and be activated, and NFAT protein can shift into nuclear. The level of IL-2 was negatively associated with the expression level of NFAT and CaN gene (P < 0.05). Traffic-related PM2.5 may inhibit the releasing of IL-2, Ca(2+)-CaN-NFAT signal pathway may involve in the regulation of IL-2.

  2. Development of an antibody to bovine IL-2 reveals multifunctional CD4 T(EM) cells in cattle naturally infected with bovine tuberculosis.

    PubMed

    Whelan, Adam O; Villarreal-Ramos, Bernardo; Vordermeier, H Martin; Hogarth, Philip J

    2011-01-01

    Gaining a better understanding of the T cell mechanisms underlying natural immunity to bovine tuberculosis would help to identify immune correlates of disease progression and facilitate the rational design of improved vaccine and diagnostic strategies. CD4 T cells play an established central role in immunity to TB, and recent interest has focussed on the potential role of multifunctional CD4 T cells expressing IFN-γ, IL-2 and TNF-α. Until now, it has not been possible to assess the contribution of these multifunctional CD4 T cells in cattle due to the lack of reagents to detect bovine IL-2 (bIL-2). Using recombinant phage display technology, we have identified an antibody that recognises biologically active bIL-2. Using this antibody, we have developed a polychromatic flow cytometric staining panel that has allowed the investigation of multifunctional CD4 T-cells responses in cattle naturally infected with M. bovis. Assessment of the frequency of antigen specific CD4 T cell subsets reveals a dominant IFN-γ(+)IL-2(+)TNF-α(+) and IFN-γ(+) TNF-α(+) response in naturally infected cattle. These multifunctional CD4 T cells express a CD44(hi)CD45RO(+)CD62L(lo) T-effector memory (T(EM)) phenotype and display higher cytokine median fluorescence intensities than single cytokine producers, consistent with an enhanced 'quality of response' as reported for multifunctional cells in human and murine systems. Through our development of these novel immunological bovine tools, we provide the first description of multifunctional T(EM) cells in cattle. Application of these tools will improve our understanding of protective immunity in bovine TB and allow more direct comparisons of the complex T cell mediated immune responses between murine models, human clinical studies and bovine TB models in the future. © 2011 Whelan et al.

  3. IL-2 and Beyond in Cancer Immunotherapy.

    PubMed

    Wrangle, John M; Patterson, Alicia; Johnson, C Bryce; Neitzke, Daniel J; Mehrotra, Shikhar; Denlinger, Chadrick E; Paulos, Chrystal M; Li, Zihai; Cole, David J; Rubinstein, Mark P

    2018-02-01

    The development of the T- and natural killer (NK) cell growth factor IL-2 has been a sentinel force ushering in the era of immunotherapy in cancer. With the advent of clinical grade recombinant IL-2 in the mid-1980s, oncologists could for the first time directly manipulate lymphocyte populations with systemic therapy. By itself, recombinant IL-2 can induce clinical responses in up to 15% of patients with metastatic cancer or renal cell carcinoma. When administered with adoptively transferred tumor-reactive lymphocytes, IL-2 promotes T cell engraftment and response rates of up to 50% in metastatic melanoma patients. Importantly, these IL-2-driven responses can yield complete and durable responses in a subset of patients. However, the use of IL-2 is limited by toxicity and concern of the expansion of T regulatory cells. To overcome these limitations and improve response rates, other T cell growth factors, including IL-15 and modified forms of IL-2, are in clinical development. Administering T cell growth factors in combination with other agents, such as immune checkpoint pathway inhibitors, may also improve efficacy. In this study, we review the development of T- and NK cell growth factors and highlight current combinatorial approaches based on these reagents.

  4. Anti-IL-23 receptor monoclonal antibody prevents CD4+ T cell-mediated colitis in association with decreased systemic Th1 and Th17 responses.

    PubMed

    Imamura, Emiko; Taguchi, Katsunari; Sasaki-Iwaoka, Haruna; Kubo, Satoshi; Furukawa, Shigetada; Morokata, Tatsuaki

    2018-04-05

    Experimental colitis studies, including T cell-mediated colitis, indicate that IL-23 rather than IL-12 orchestrates intestinal inflammation in inflammatory bowel disease (IBD). Previous studies have identified the roles of IL-12 and IL-23 using mice deficient for their specific subunits, p35 and p19, respectively. However, these studies do not completely reflect the difference in roles between IL-12 and IL-23, especially since the discovery of novel IL-12 family cytokines, which also include p35 or p19 subunits. Here, to clarify the contribution of IL-12 and IL-23 in T cell-mediated colitis, we compared the efficacy of a monoclonal antibody (mAb) to an IL-23-specific receptor subunit with that of an anti-IL-12/23p40 mAb in a naive CD4 + T cell transfer model of experimental colitis, which is associated with enhanced Th1 and Th17 responses. Both antibodies almost completely prevented the development of colitis and showed reduced associated histological changes, including mucosal hyperplasia, infiltration of inflammatory cells and loss of goblet cells. The anti-IL-23 receptor mAb inhibited not only the systemic Th17-response but also the Th1-response, both of which were up-regulated in this model. These results suggest that IL-23, but not IL-12, signaling is critical for the development of colitis. Blockade of IL-23 signaling is a promising therapeutic approach for IBD. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-γ+IL-17+coproducing CD4+ T cells in active inflammatory bowel disease.

    PubMed

    Globig, Anna-Maria; Hennecke, Nadine; Martin, Bianca; Seidl, Maximilian; Ruf, Günther; Hasselblatt, Peter; Thimme, Robert; Bengsch, Bertram

    2014-12-01

    Skewed T helper (TH) cell responses and specific functions of TH1, TH2, TH17, and Treg cells have been implicated in the pathogenesis of inflammatory bowel disease (IBD) that led to the establishment of the pathogenic TH1/TH2 and TH17/Treg cell imbalance paradigms. However, the relevant TH cell population driving mucosal inflammation is still unknown. We performed a comprehensive TH cell profiling of circulating and intestinal lymphocytes isolated from patients with Crohn's disease (CD; n = 69) and ulcerative colitis (UC; n = 41) undergoing endoscopy or surgical resection and compared them with healthy controls (n = 45). Mucosal inflammation was assessed endoscopically and histologically. TH cells were analyzed by flow cytometric evaluation of cytokine production and differentiation marker expression. Specialized TH cell populations were enriched in the intestinal mucosa compared with peripheral blood. Specifically, we observed a concomitant upregulation of TH17 cells and Tregs in active inflammatory lesions in patients with both CD and UC compared with quiescent/mildly inflamed lesions and healthy tissue. Of note, interferon γ+ interleukin (IL)-17+coproducing CD4+ T cells with high expression of T-bet, CD26, and IL-22 resembling recently described pathogenic TH17 cells were specifically enriched in the inflamed mucosal tissue. Our results argue against the controversial TH1/TH2 or TH17/Treg paradigms. In contrast, they suggest that a subpopulation of TH17 cells sharing a TH1 signature may be specifically involved in intestinal inflammation in CD and UC. These findings provide a better understanding of IBD pathogenesis and may help explain the efficacy of anti-IL-12p40/IL-23 and failure of anti-IL-17A therapies despite the enrichment of TH17 cells.

  6. IL-12 and IL-23 modulate plasticity of FoxP3+ regulatory T cells in human Leprosy.

    PubMed

    Tarique, Mohd; Saini, Chaman; Naqvi, Raza Ali; Khanna, Neena; Sharma, Alpana; Rao, D N

    2017-03-01

    Leprosy is a bacterial disease caused by M. leprae. Its clinical spectrum reflects the host's immune response to the M. leprae and provide an ideal model to investigate the host pathogen interaction and immunological dysregulation. Tregs are high in leprosy patients and responsible for immune suppression of the host by producing IL-10 and TGF-β cytokines. In leprosy, plasticity of Tregs remain unstudied. This is the first study describing the conversion of Tregs into Th1-like and Th17-like cells using in vitro cytokine therapy in leprosy patients. Peripheral blood mononuclear cells from leprosy patients were isolated and stimulated with M. leprae antigen (MLCwA), rIL-12 and rIL-23 for 48h. Expression of FoxP3 in CD4 + CD25 + Tregs, intracellular cytokines IFN-γ, TGF-β, IL-10 and IL-17 in Tregs cells were evaluated by flow cytometry (FACS) after stimulation. rIL-12 treatment increases the levels of pStat4 in Tregs and IFN-γ production. In the presence of rIL-23, pStat3 + and IL-17A + cells increase. rIL-12 and r-IL-23 treatment downregulated the FoxP3 expression, IL-10 and TGF-β production by Tregs and enhances the expression of co-stimulatory molecules (CD80, CD86). In conclusion rIL-12 converts Tregs into IFN-γ producing cells through STAT-4 signaling while rIL-23 converts Tregs into IL-17 producing cells through STAT-3 signaling in leprosy patients. This study may helpful to provide a new avenue to overcome the immunosuprression in leprosy patients using in vitro cytokine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Autoreactive T cells from patients with myasthenia gravis are characterized by elevated IL-17, IFN-γ and GM-CSF and diminished IL-10 production

    PubMed Central

    Cao, Yonghao; Amezquita, Robert A.; Kleinstein, Steven H.; Stathopoulos, Panos; Nowak, Richard J.; O’Connor, Kevin C.

    2016-01-01

    Myasthenia gravis (MG) is a prototypical autoimmune disease that is among the few for which the target antigen and the pathogenic autoantibodies are clearly defined. The pathology of the disease is affected by autoantibodies directed toward the acetylcholine receptor (AChR). Mature, antigen-experienced B cells rely on the action of helper T cells to produce these pathogenic antibodies. The phenotype of the MG antigen-reactive T cell compartment is not well defined, thus we sought to determine whether such cells exhibit both a pro-inflammatory and pathogenic phenotype. A novel T cell library assay that affords multi-parameter interrogation of rare antigen-reactive CD4+ T cells was applied. Proliferation and cytokine production in response to both AChR and control antigens were measured from 3,120 T cell libraries derived from eleven MG subjects and paired healthy controls. The frequency of CCR6+ memory T cells from MG subjects proliferating in response to AChR-derived peptides was significantly higher than that of healthy controls. Production of both IFN-γ and IL-17, in response to AChR was also restricted to the CCR6+ memory T cell compartment in the MG cohort indicating a pro-inflammatory phenotype. These T cells also included an elevated expression of GM-CSF and absence of IL-10 expression, indicating a pro-inflammatory and pathogenic phenotype. This component of the autoimmune response in MG is of particular importance when considering the durability of MG treatment strategies that eliminate B cells, as the autoreactive T cells could renew autoimmunity in the reconstituted B cell compartment with ensuing clinical manifestations. PMID:26826242

  8. IL-17A acts via p38 MAPK to increase stability of TNF-alpha-induced IL-8 mRNA in human ASM.

    PubMed

    Henness, Sheridan; van Thoor, Eveline; Ge, Qi; Armour, Carol L; Hughes, J Margaret; Ammit, Alaina J

    2006-06-01

    Human airway smooth muscle (ASM) plays an immunomodulatory role in asthma. Recently, IL-17A has become of increasing interest in asthma, being found at elevated levels in asthmatic airways and emerging as playing an important role in airway neutrophilia. IL-17A predominantly exerts its neutrophil orchestrating role indirectly via the induction of cytokines by resident airway structural cells. Here, we perform an in vitro study to show that although IL-17A did not induce secretion of the CXC chemokine IL-8 from ASM cells, IL-17A significantly potentiates TNF-alpha-induced IL-8 protein secretion and gene expression in a concentration- and time-dependent manner (P < 0.05). Levels of IL-8 protein produced after 24 h of incubation with TNF-alpha were enhanced 2.7-fold in the presence of IL-17A, and conditioned media significantly enhanced neutrophil chemotaxis in vitro. As IL-17A had no effect on the activity of NF-kappaB, a key transcriptional regulator of IL-8 gene expression, we then examined whether IL-17A acts at the posttranscriptional level. We found that IL-17A significantly augmented TNF-alpha-induced IL-8 mRNA stability. Interestingly, this enhanced stability occurred via a p38 MAPK-dependent pathway. The decay of IL-8 mRNA transcripts proceeded at a significantly faster rate when cells were pretreated with the p38 MAPK inhibitor SB-203580 (-0.05763 +/- 0.01964, t(1/2) = 12.0 h), compared with vehicle (-0.01030 +/- 0.007963, t(1/2) = 67.3 h) [results are expressed as decay constant (means +/- SE) and half-life (t(1/2) in h): P < 0.05]. Collectively, these results demonstrate that IL-17A amplifies the synthetic function of ASM cells, acting via a p38 MAPK-dependent posttranscriptional pathway to augment TNF-alpha-induced secretion of the potent neutrophil chemoattractant IL-8 from ASM cells.

  9. Interaction of IL1B and IL1RN polymorphisms, smoking habit, gender, and ethnicity with aggressive and chronic periodontitis susceptibility.

    PubMed

    Ribeiro, Magali Silveira Monteiro; Pacheco, Renata Botelho Antunes; Fischer, Ricardo Guimarães; Macedo, Jacyara Maria Brito

    2016-01-01

    Although the interleukin-1 (IL-1) plays a critical role in the pathogenesis of periodontitis, associations between IL1 gene cluster polymorphisms and the disease remains unclear. To investigate the importance of IL1B-511C>T (rs16944), IL1B +3954C>T (rs1143634), and IL1RN intron 2 variable number tandem repeat (VNTR) (rs2234663) polymorphisms, individually or in combination, as the risk factors of periodontitis in a Southeastern Brazilian population with a high degree of miscegenation. A total of 145 individuals, with aggressive (aggressive periodontitis [AgP], n = 43) and chronic (chronic periodontitis [CP], n = 52) periodontitis, and controls (n = 50) were genotyped by polymerase chain reaction (PCR) (IL1RN intron 2 VNTR) or PCR-restriction fragment length polymorphism (PCR-RFLP) (IL1B-511 C>T and IL1B + 3954C>T) techniques. The independent t-test, Chi-square, and Fisher's exact tests were used. The SNPStats program was used for haplotype estimation and multiplicative interaction analyses. The IL1B +3954T allele represented risk for CP (odds ratio [OR] = 2.84), particularly in smokers (OR = 4.43) and females (OR = 6.00). The minor alleles IL1RN*2 and *3 increased the risk of AgP (OR = 2.18), especially the IL1RN*2*2 genotype among  white Brazilians (OR = 7.80). Individuals with the combinations of the IL1B + 3954T and IL1RN*2 or *3-containing genotypes were at increased risk of developing CP (OR = 4.50). Considering the three polymorphisms (rs16944, rs1143634, and rs2234663), the haplotypes TC2 and CT1 represented risk for AgP (OR = 3.41) and CP (OR = 6.39), respectively. Our data suggest that the IL1B +3954C>T and IL1RN intron 2 VNTR polymorphisms are potential candidates for genetic biomarkers of periodontitis, particularly in specific groups of individuals.

  10. Common polymorphisms in interleukin genes (IL4, IL6, IL8 and IL12) are not associated with alcoholic liver disease or alcoholism in Spanish men.

    PubMed

    Marcos, Miguel; Pastor, Isabel; González-Sarmiento, Rogelio; Laso, Francisco-Javier

    2009-03-01

    Preliminary data suggest that polymorphisms in cytokine genes may be involved in the genetic predisposition to alcoholic liver cirrhosis or alcohol use disorders. We thus analyze the association between these diseases and the following polymorphisms: -33T>C IL4, -174 G>C IL6, -251 T>A IL8 and 1188 A>C IL12B. 258 male alcoholics (161 without liver disease and 97 with liver cirrhosis) and 101 healthy controls were genotyped for the above mentioned polymorphisms. We examined the relationship between genotype and allele frequencies and the presence of disease, as well as the correlation with combinations of putative pro-inflammatory genotypes. Haplotypes were inferred using the expectation-maximization algorithm and haplotype frequencies were compared. We found no statistically significant association between any of these polymorphisms or the combinations of pro-inflammatory polymorphisms and the risk of alcoholic liver cirrhosis or alcohol abuse or dependence. Haplotype analysis of the IL4 and IL12B polymorphisms did not show any statistical relationship either. Our results do not support the hypothesis that the analyzed polymorphisms confer differences in alcoholic liver cirrhosis or alcohol use disorders susceptibility.

  11. Profil épidémiologique de l'infection à VIH au cours d'une campagne de sensibilisation à Yaoundé au Cameroun

    PubMed Central

    Mbopi-Keou, Francois-Xavier; Nguefack-Tsague, Georges; Kalla, Ginette Claude Mireille; Viche, Lade; Noubom, Michel

    2013-01-01

    Introduction L'objectif de ce travail était de déterminer le profil épidémiologique de l'infection à VIH/SIDA au cours d'une campagne de sensibilisation à Yaoundé au Cameroun. Méthodes Après avoir obtenu le consentement éclairé des participants, le dépistage de l'infection par le VIH a été effectué selon l'algorithme de dépistage en série de l'Organisation Mondiale de la Santé (OMS). En outre, un questionnaire socio-comportemental a été proposé à chaque participant. Résultats Au total, 911 personnes ont été dépistées. La prévalence de l'infection par le VIH était de 2.6%. Elle était 3 fois plus élevée parmi les femmes (RC = 3.22, IC (1.26 - 8.18). Les prévalences les plus élevées ont été observées chez les personnes de plus de 45 ans (p = 0.01), les personnes sans emploi (p < 0.001) et les veufs/veuves (p = 0.02). Plus de 80% des participants trouvaient le test de dépistage nécessaire et 76,2% l'avaient déjà effectué au moins une fois auparavant. Il s'agissait principalement de femmes (p = 0.02), d'étudiants (p < 0.001) et des personnes âgées de 25 à 34 ans (p < 0.001). Les personnes séropositives avaient moins tendance à retirer leur résultat (p = 0.01). Conclusion Il apparait urgent d'intensifier les campagnes de dépistage de l'infection par le VIH en ciblant davantage des groupes particuliers tels que les élèves, les personnes âgées et les veufs/veuves, tout en recherchant les facteurs pouvant favoriser la propagation de l'infection dans ces groupes. PMID:24255725

  12. Oral Escherichia coli Colonization Factor Antigen I (CFA/I) Fimbriae Ameliorate Arthritis via IL-35, not IL-27

    PubMed Central

    Kochetkova, Irina; Thornburg, Theresa; Callis, Gayle; Holderness, Kathryn; Maddaloni, Massimo; Pascual, David W.

    2014-01-01

    A Salmonella therapeutic expressing enterotoxigenic E. coli colonization factor antigen I (CFA/I) fimbriae protects against collagen-induced arthritis (CIA) by eliciting two regulatory T cell (Treg) subsets: TGF-β-producing Foxp3−CD39+CD4+ and IL-10-producing Foxp3+CD39+CD4+ T cells. However, it is unclear if CFA/I fimbriae alone are protective, and if other regulatory cytokines are involved especially in the context for the EBI3-sharing cytokines, Treg-derived IL-35 and APC-derived IL-27, both capable of suppressing Th17 cells and regulating autoimmune diseases. Subsequent evaluation revealed that a single oral dose of purified, soluble CFA/I fimbriae protected against CIA as effectively as Salmonella-CFA/I, and found Foxp3+CD39+CD4+ T cells as the source of secreted IL-35, whereas IL-27 production by CD11c+ cells was inhibited. Inquiring into their relevance, CFA/I fimbriae-treated IL-27 receptor-deficient (WSX-1−/−) mice were equally protected against CIA as wild-type mice suggesting a limited role for IL-27. In contrast, CFA/I fimbriae-mediated protection was abated in EBI3−/− mice accompanied by the loss of TGF-β- and IL-10-producing Tregs. Adoptive transfer of B6 CD39+CD4+ T cells to EBI3−/− mice with concurrent CFA/I plus IL-35 treatment effectively stimulated Tregs suppressing proinflammatory CII-specific Th cells. Opposingly, recipients co-transferred with B6 and EBI3−/− CD39+CD4+ T cells and treated with CFA/I plus IL-35 failed in protecting mice implicating the importance for endogenous IL-35 to confer CFA/I-mediated protection. Thus, CFA/I fimbriae stimulate IL-35 required for the co-induction of TGF-β and IL-10. PMID:24337375

  13. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway

    PubMed Central

    Anipindi, Varun C.; Dizzell, Sara E.; Nguyen, Philip V.; Shaler, Christopher R.; Chu, Derek K.; Jiménez-Saiz, Rodrigo; Liang, Hong; Swift, Stephanie; Nazli, Aisha; Kafka, Jessica K.; Bramson, Jonathan; Xing, Zhou; Jordana, Manel; Wan, Yonghong; Snider, Denis P.; Stampfli, Martin R.; Kaushic, Charu

    2016-01-01

    Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway. PMID:27148737

  14. Infiltration of γ⁢δ T cells, IL-17+ T cells and FoxP3+ T cells in human breast cancer

    PubMed Central

    Allaoui, Roni; Hagerling, Catharina; Desmond, Eva; Warfvinge, Carl-Fredrik; Jirström, Karin; Leandersson, Karin

    2017-01-01

    BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have a strong prognostic value in various forms of cancers. These data often refer to use of the pan-T cell marker CD3, or the cytotoxic T lymphocyte marker CD8α. However, T cells are a heterogeneous group of cells with a wide array of effector mechanisms ranging from immunosuppression to cytotoxicity. OBJECTIVE: In this study we have investigated the prognostic effects of some unconventional T cell subtypes in breast cancer; γ⁢δ T cells, IL-17+ T cells and FoxP3+ T cells (Tregs) in relation to the conventional CD3 and CD8α T cell markers. METHODS: This was done using immunohistochemistry on a human breast cancer tissue microarray consisting of 498 consecutive cases of primary breast cancer. RESULTS: Infiltration of γ⁢δ T cells and T cell infiltration in general (CD3), correlated with a good prognosis, while Treg infiltration with a worse. Infiltration of γ⁢δ T cells was associated with a significantly improved clinical outcome in all breast cancer subtypes except triple negative tumors. Only infiltration of either CD3+ or CD8α+ cells was independently associated with better prognosis for all breast cancer patients. CONCLUSIONS: This study sheds further light on the prognostic impact of various T cell subtypes in breast cancer. PMID:29060923

  15. Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 T and B cell immunity with greater protective efficacy.

    PubMed

    Jackson, Ronald J; Worley, Matthew; Trivedi, Shubhanshi; Ranasinghe, Charani

    2014-09-29

    We have established that the efficacy of a heterologous poxvirus vectored HIV vaccine, fowlpox virus (FPV)-HIV gag/pol prime followed by attenuated vaccinia virus (VV)-HIV gag/pol booster immunisation, is strongly influenced by the cytokine milieu at the priming vaccination site, with endogenous IL-13 detrimental to the quality of the HIV specific CD8+ T cell response induced. We have now developed a novel HIV vaccine that co-expresses a C-terminal deletion mutant of the mouse IL-4, deleted for the essential tyrosine (Y119) required for signalling. In our vaccine system, the mutant IL-4C118 can bind to IL-4 type I and II receptors with high affinity, and transiently prevent the signalling of both IL-4 and IL-13 at the vaccination site. When this IL-4C118 adjuvanted vaccine was used in an intranasal rFPV/intramuscular rVV prime-boost immunisation strategy, greatly enhanced mucosal/systemic HIV specific CD8+ T cells with higher functional avidity, expressing IFN-γ, TNF-α and IL-2 and greater protective efficacy were detected. Surprisingly, the IL-4C118 adjuvanted vaccines also induced robust long-lived HIV gag-specific serum antibody responses, specifically IgG1 and IgG2a. The p55-gag IgG2a responses induced were of a higher magnitude relative to the IL-13Rα2 adjuvant vaccine. More interestingly, our recently tested IL-13Rα2 adjuvanted vaccine which only inhibited IL-13 activity, even though induced excellent high avidity HIV-specific CD8+ T cells, had a detrimental impact on the induction of gag-specific IgG2a antibody immunity. Our observations suggest that (i) IL-4 cell-signalling in the absence of IL-13 retarded gag-specific antibody isotype class switching, or (ii) IL-13Rα2 signalling was involved in inducing good gag-specific B cell immunity. Thus, we believe our novel IL-4R antagonist adjuvant strategy offers great promise not only for HIV-1 vaccines, but also against a range of chronic infections where sustained high quality mucosal and systemic T and B

  16. Acetylcholine released from T cells regulates intracellular Ca2+, IL-2 secretion and T cell proliferation through nicotinic acetylcholine receptor.

    PubMed

    Mashimo, Masato; Iwasaki, Yukari; Inoue, Shoko; Saito, Shoko; Kawashima, Koichiro; Fujii, Takeshi

    2017-03-01

    T lymphocytes synthesize acetylcholine (ACh) and express muscarinic and nicotinic ACh receptors (mAChR and nAChR, respectively) responsible for increases in the intracellular Ca 2+ concentration ([Ca 2+ ] i ). Our aim in the present study was to assess whether autocrine ACh released from T lymphocytes regulates their physiological functions. MOLT-3 human leukemic cell line and murine splenocytes were loaded with fura-2 to monitor [Ca 2+ ] i changes in the absence or presence of several AChR antagonists, including mecamylamine, methyllycaconitine and scopolamine. Real-time PCR and ELISA were performed to measure interleukin-2 (IL-2) mRNA and protein levels. T lymphocytes constitutively produce sufficient amounts of ACh to elicit autocrine changes in [Ca 2+ ] i . These autocrine ACh-evoked [Ca 2+ ] i transients were mediated by nAChRs and then influx of extracellular Ca 2+ . Mecamylamine, a nAChR inhibitor, suppressed not only these [Ca 2+ ] i transients, but also IL-2 release and T cell proliferation. Here, we confirmed that T lymphocytes utilize ACh as a tool to interact with each other and that autocrine ACh-activated nAChRs are involved in cytokine release and cell proliferation. These findings suggest the possibility that nAChR agonists and antagonists and smoking are able to modulate immune function, which in turn suggests the therapeutic potential of immune activation or suppression using nAChR agonists or antagonists. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. In Vivo Expansion of Activated Foxp3+ Regulatory T Cells and Establishment of a Type 2 Immune Response upon IL-33 Treatment Protect against Experimental Arthritis.

    PubMed

    Biton, Jérôme; Khaleghparast Athari, Sara; Thiolat, Allan; Santinon, François; Lemeiter, Delphine; Hervé, Roxane; Delavallée, Laure; Levescot, Anais; Roga, Stéphane; Decker, Patrice; Girard, Jean-Philippe; Herbelin, André; Boissier, Marie-Christophe; Bessis, Natacha

    2016-09-01

    IL-33 is strongly involved in several inflammatory and autoimmune disorders with both pro- and anti-inflammatory properties. However, its contribution to chronic autoimmune inflammation, such as rheumatoid arthritis, is ill defined and probably requires tight regulation. In this study, we aimed at deciphering the complex role of IL-33 in a model of rheumatoid arthritis, namely, collagen-induced arthritis (CIA). We report that repeated injections of IL-33 during induction (early) and during development (late) of CIA strongly suppressed clinical and histological signs of arthritis. In contrast, a late IL-33 injection had no effect. The cellular mechanism involved in protection was related to an enhanced type 2 immune response, including the expansion of eosinophils, Th2 cells, and type 2 innate lymphoid cells, associated with an increase in type 2 cytokine levels in the serum of IL-33-treated mice. Moreover, our work strongly highlights the interplay between IL-33 and regulatory T cells (Tregs), demonstrated by the dramatic in vivo increase in Treg frequencies after IL-33 treatment of CIA. More importantly, Tregs from IL-33-treated mice displayed enhanced capacities to suppress IFN-γ production by effector T cells, suggesting that IL-33 not only favors Treg proliferation but also enhances their immunosuppressive properties. In concordance with these observations, we found that IL-33 induced the emergence of a CD39(high) Treg population in a ST2L-dependent manner. Our findings reveal a powerful anti-inflammatory mechanism by which IL-33 administration inhibits arthritis development. Copyright © 2016 by The American Association of Immunologists, Inc.

  18. Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming

    PubMed Central

    Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin; Wang, Hong Y.; Cheng, Mangeng; Baldwin, Donald; Tobias, John W.; Schuster, Stephen J.; Woetmann, Anders; Zhang, Qian; Turner, Suzanne D.; Odum, Niels; Wasik, Mariusz A.

    2013-01-01

    Anaplastic lymphoma kinase (ALK) physiologically expressed only by nervous system cells displays remarkable capacity to transform CD4+ T lymphocytes and other types of non-neural cells. Here we report that activity of nucleophosphmin (NPM)/ALK chimeric protein, the dominant form of ALK expressed in T-cell lymphomas (ALK+TCL), closely resembles cell activation induced by interleukin 2 (IL-2), the key cytokine supporting growth and survival of normal CD4+ T lymphocytes. Direct comparison of gene expression by ALK+TCL cells treated with an ALK inhibitor and IL-2-dependent ALK-TCL cells stimulated with the cytokine revealed a very similar, albeit inverse, gene regulation pattern. Depending on the analysis method, up to 67% of the modulated genes could be defined as modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT and IL-2 signaling pathways topped the list of pathways identified as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes: CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4 was confirmed at the protein level. In both ALK+TCL and IL-2-stimulated ALK-TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly by the STAT5 and STAT3 transcription factors, while transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms the target CD4+ T lymphocytes, at least in part, by utilizing the pre-existing, IL-2-dependent signaling pathways. PMID:24218456

  19. Propriétés électriques d'hétérostructures a-GaAs/c-GaAs(n) et de structures de type MIS a-GaAsN/c-GaAs(n)

    NASA Astrophysics Data System (ADS)

    Aguir, K.; Fennouh, A.; Carchano, H.; Lollman, D.

    1995-10-01

    Heterojunctions were fabricated by deposit of amorphous GaAs and GaAsN on c-GaAs. I(V) and C(V) measurements were performed to determine electrical properties of these structures. The a-GaAs/c-GaAs(n) heterojunctions present a p-n junction like behaviour. The characteristics of the a-GaAsN/c-GaAs(n) heterojunctions present a MIS like structure behaviour with some imperfections. A fixed positive charge was detected and a density of interface states of about 10^{11} eV^{-1}cm^{-2} was evaluated. L'étude porte sur des couches minces de GaAs et de GaAsN amorphes déposées par pulvérisation cathodique RF réactive sur des substrats de GaAs cristallin. Les caractéristiques électriques I(V) et C(V) ont été mesurées. Les hétérojonctions a-GaAs/c-GaAs(n) présentent un effet redresseur. Cet effet laisse place à une caractéristique symétrique avec une forte atténuation de l'intensité du courant pour les structures a-GaAsN/cGaAs(n). Les structures réalisées ont alors un comportement semblable à celui d'une structure MIS imparfaite. L'existence d'une charge positive fixe dans le a-GaAsN a été mise en évidence. La densité des états d'interface au milieu de la bande interdite est évaluée à quelques 10^{11} cm^{-2}eV^{-1}.

  20. Interleukin-12 (IL-12)-driven alloimmune responses in vitro and in vivo: requirement for beta1 subunit of the IL-12 receptor.

    PubMed

    Piccotti, J R; Li, K; Chan, S Y; Eichwald, E J; Bishop, D K

    1999-06-15

    Interleukin-12 (IL-12) mediates its biologic activities via binding high-affinity receptors on T and natural killer cells. Although emphasis has been placed on the requirement for IL-12Rbeta2 in IL-12 bioactivity, the role of IL-12Rbeta1 is less well defined. The current study evaluated the effects of exogenous IL-12 on alloantigen-specific immune responses and determined the requirement for IL-12Rbeta1 in IL-12-mediated alloimmunity. The mouse heterotopic cardiac transplant model was employed to evaluate the effects of IL-12 on alloantigen-specific immune responses in vivo. In addition, IFN-gamma production in mixed lymphocyte cultures (MLC) supplemented with IL-12 was measured to assess the effects of IL-12 on Th1 function in vitro. Mice deficient in IL-12Rbeta1 (IL-12Rbeta1-/-) were used to determine the requirement for this receptor component in IL-12-driven alloimmune responses. Addition of IL-12 to MLC consisting of wild-type splenocytes enhanced alloantigen-specific proliferative responses and Th1 development. In contrast, IL-12 did not alter these in vitro immune parameters in IL-12Rbeta1-/- MLC. Treatment of wild-type cardiac allograft recipients with IL-12 resulted in high concentrations of serum interferon-gamma (IFN-gamma) and a 10-fold increase in IFN-gamma production by recipient splenocytes after restimulation in vitro. However, this fulminate Th1 response did not accelerate allograft rejection. Importantly, IL-12 had no effect on serum IFN-gamma or in vivo priming of Thl in IL-12Rbeta1-/- recipients. Finally, administration of IL-12 to WT allograft recipients resulted in a bimodal alloantibody response: antibody production was suppressed at high doses of IL-12, and enhanced at lower doses. IL-12 markedly enhances alloantigen-specific immune function; however, these exaggerated Th1-driven responses do not culminate in accelerated allograft rejection. Further, these data indicate that IL-12Rbeta1 is essential for the enhancement of both in vitro and

  1. Intestinal IFN-γ-producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease.

    PubMed

    Alfen, Johanna Sophie; Larghi, Paola; Facciotti, Federica; Gagliani, Nicola; Bosotti, Roberto; Paroni, Moira; Maglie, Stefano; Gruarin, Paola; Vasco, Chiara Maria; Ranzani, Valeria; Frusteri, Cristina; Iseppon, Andrea; Moro, Monica; Crosti, Maria Cristina; Gatti, Stefano; Pagani, Massimiliano; Caprioli, Flavio; Abrignani, Sergio; Flavell, Richard A; Geginat, Jens

    2018-01-31

    IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (T R 1) cells but is also produced by CD25 + regulatory T (Treg) cells. We aimed to identify and characterize human intestinal T R 1 cells and to investigate whether they are a relevant cellular source of IL-10 in patients with inflammatory bowel diseases (IBDs). CD4 + T cells isolated from the intestinal lamina propria of human subjects and mice were analyzed for phenotype, cytokine production, and suppressive capacities. Intracellular IL-10 expression by CD4 + T-cell subsets in the inflamed guts of patients with IBD (Crohn disease or ulcerative colitis) was compared with that in cells from noninflamed control subjects. Finally, the effects of proinflammatory cytokines on T-cell IL-10 expression were analyzed, and IL-1β and IL-23 responsiveness was assessed. Intestinal T R 1 cells could be identified by coexpression of CCR5 and programmed cell death protein 1 (PD-1) in human subjects and mice. CCR5 + PD-1 + T R 1 cells expressed IFN-γ and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-γ + T R 1 cells, but not IL-7 receptor-positive T H cells or CD25 + Treg cells, showed lower IL-10 expression in patients with IBDs. T R 1 cells were responsive to IL-23, and IFN-γ + T R 1 cells downregulated IL-10 with IL-1β and IL-23. Conversely, CD25 + Treg cells expressed higher levels of IL-1 receptor but showed stable IL-10 expression. We provide the first ex vivo characterization of human intestinal T R 1 cells. Selective downregulation of IL-10 by IFN-γ + T R 1 cells in response to proinflammatory cytokines is likely to drive excessive intestinal inflammation in patients with IBDs. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  2. Association between -1082G/A, -819C/T, and -592C/A genetic polymorphisms in IL-10 and risk of type 2 diabetes mellitus in a Chinese population.

    PubMed

    Dong, Q Y; Liu, X M; Liang, C G; Du, W H; Wang, Y L; Li, W X; Gao, G Q

    2016-08-29

    Type 2 diabetes mellitus is the most common form of endocrine disease in humans; genetic factors are known to contribute to the development of this disease. In this case-control study, we investigated the relationship between the -1082G/A, -819C/T, and -592C/A polymorphisms in interleukin 10 (IL-10) and the pathogenesis of type 2 diabetes mellitus in a Chinese population. Patients with type 2 diabetes mellitus (N = 228) and control subjects (N = 240) were recruited from the Department of Endocrinology at the People's Hospital of Linyi City, between September 2013 and April 2015. The IL-10 -1082G/A, -819C/T, and -592C/A polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Multivariate logistic regression analyses revealed that patients carrying the AA genotype of IL-10 -592C/A were at a higher risk of developing type 2 diabetes mellitus compared to those carrying the CC genotype [adjusted odds ratio (OR) = 1.74; 95% confidence interval (CI) = 1.03-2.95]. In addition, individuals carrying the A allele of IL-10 -592C/A showed a 1.34-fold higher risk of developing type 2 diabetes mellitus compared to those carrying the C allele (adjusted OR = 1.34; 95%CI = 1.03- 1.75). There was no significant correlation between the IL-10 -1082G/ A and -819C/T polymorphisms and risk of type 2 diabetes mellitus. In conclusion, this study shows that the -1082G/A polymorphism of IL-10 contributes to the onset of type 2 diabetes mellitus, and may be considered a biomarker for early screening of type 2 diabetes mellitus in the Chinese population studied here.

  3. Place de la splénectomie dans la prise en charge de l’hypertension portale non cirrhotique: à propos de 3 cas

    PubMed Central

    Belhamidi, Mohamed Said; Hammi, Salah Eddine; Bouzroud, Mohamed; Benmoussa, Mustapha; ali, Abdelmounaim Ait; Bounaim, Ahmed

    2017-01-01

    L’hypertension portale non cirrhotique est une affection décrite pour la première fois par Guido BANTI en 1898 comme une affection associant une hypertension portale avec splénomégalie et anémie sur foie sain. Le diagnostic repose sur l’échographie abdominale, la splénoportographie et la biopsie hépatique. Le but de notre travail est d’évaluer la place de la splénectomie dans l’hypertension portale non cirrhotique à travers une étude rétrospective portant sur 3 malades dont 2 femmes et un homme pris en charge dans notre formation entre Janvier 2010 et Septembre 2016. Le diagnostic de l’hypertension portale idiopathique a été basé sur les critères suivants : une hypertension portale, la présence des varices oesophagiènnes avec une splénomégalie, l’absence de cirrhose ou d’autres affections hépatiques responsables de l’hypertension portale. La splénectomie a été réalisée chez les 3 malades. L’évolution après la splénectomie était marquée par la normalisation des signes cliniques, radiologiques et biologiques de cette affection, avec absence de récidive des varices œsophagiennes. La splénectomie associée à la ligature des varices œsophagiennes pourraient être suffisantes pour traiter ce syndrome et surtout ses conséquences sans avoir recours à une dérivation spléno-rénale. PMID:29255554

  4. [Proliferation and IFN-gamma secretion of autologous T lymphocytes stimulated by myeloid leukemia cells induced with rhGM-CSF and rhIL-4].

    PubMed

    Xie, Yan-Hui; Chen, Qin-Fen; Xie, Yi; Xie, Hong

    2002-12-01

    To observe the proliferation of T lymphocytes stimulated by CML and AML cells which were induced by rhGM-CSF and rhIL-4, and the secretion of IFN-gamma from proliferated T lymphocytes, the expression of CD80, CD86 and HLA-DR on CML and AML cells induced by GM-CSF and IL-4 was assayed by flow cytometry in vitro. Then one-way mixed lymphocyte reaction was carried out, with induced leukemia cells as stimulating cells and auto-T lymphocytes as reactive cells. The secretion of IFN-gamma from T lymphocytes was determined by double antibody sandwich ELISA. The results showed that GM-CSF and IL-4 significantly upregulated the expression of CD80, CD86 and HLA-DR on CML cells and CD80 and CD86 on AML cells, which could stimulate the T lymphocyte proliferation and high secretion of IFN-gamma (in CML group) of autologous T lymphocytes. It is concluded that the CML and AML cells induced by GM-CSF and IL-4 have the ability to present tumor specific antigen to auto-T lymphocyte.

  5. Association of IL-17A and IL-17F polymorphisms with gastric cancer risk in Asians: a meta-analysis.

    PubMed

    Liu, Jingwei; Xu, Qian; Yuan, Quan; Wang, Zhenning; Xing, Chengzhong; Yuan, Yuan

    2015-01-01

    Increasing number of studies focused on the association of IL-17A rs2275913 and IL-17F rs763780 polymorphisms with gastric cancer (GC) risk. However, the results were inconsistent. To elucidate the exact association, we performed the present meta-analysis. Databases including PubMed, Web of knowledge and Chinese National Knowledge Infrastructure (CNKI) were systematically searched for potentially eligible literatures. Odds ratios (OR) and their 95% confidence interval (CI) were used to evaluate the strength of association. Eight studies for IL-17A rs2275913 (3345 cases and 4427 controls) and five studies for IL-17F rs763780 (1784 cases and 2592 controls) were finally included. The results indicated that individuals with AA genotype of IL-17A rs2275913 polymorphism were associated with increased GC risk compared with wild-type GG (OR=1.61, 95% CI=1.17-2.23, P=0.004); A allele was significantly associated with increased GC risk compared with G allele (OR=1.22, 95% CI=1.06-1.41, P=0.007). IL-17F rs763780 polymorphism was also significantly associated with increased GC risk (CC vs. CT: OR=1.40, 95% CI=1.04-1.88, P=0.025; CT vs. TT: OR=1.35, 95% CI=1.16-1.58, P<0.001; C allele vs. T allele: OR=1.30, 95% CI=1.15-1.47, P<0.001). In summary, IL-17A rs2275913 A/G polymorphism and IL-17F rs763780 C/T polymorphism might be associated with increased GC risk in Asians. Further large-scale studies are still required to confirm the results of this meta-analysis. Copyright © 2014. Published by Elsevier Inc.

  6. Filarial infection modulates the immune response to Mycobacterium tuberculosis through expansion of CD4+ IL-4 memory T cells

    PubMed Central

    Chatterjee, Soumya; Clark, Carolyn E.; Lugli, Enrico; Roederer, Mario; Nutman, Thomas B.

    2015-01-01

    Exaggerated CD4+T helper 2-specific cytokine producing memory T cell responses developing concomitantly with a T helper1 response might have a detrimental role in immunity to infection caused by Mycobacterium tuberculosis (Mtb). To assess the dynamics of antigen (Ag)-specific memory T cell compartments in the context of filarial infection we used multiparameter flow cytometry on PBMCs from 25 microfilaremic filarial -infected (Inf) and 14 filarial-uninfected (Uninf) subjects following stimulation with filarial (BmA) or with the Mycobacterium tuberculosis (Mtb)-specific Ag CFP10. Our data demonstrated that the Inf group not only had a marked increase in BmA-specific CD4+IL-4+ cells (Median net frequency compared to baseline (Fo)=0.09% vs. 0.01%, p=0.038) but also to CFP10 (Fo =0.16% vs. 0.007%, p=0.04) and Staphylococcal Enterotoxin B (SEB) (Fo =0.49% vs. 0.26%, p=0.04). The Inf subjects showed a BmA-specific expansion of CD4+CD45RO+IL-4+ producing central memory (TCM, CD45RO+CCR7+CD27+) (Fo =1.1% vs. 0.5%, p=0.04) as well as effector memory (TEM CD45RO+CCR7-CD27-) (Fo =1.5% vs. 0.2%, p=0.03) with a similar but non-significant response to CFP10. In addition, there was expansion of CD4+ IL-4+ CD45RA+ CCR7+CD27+ (naïve-like) in Inf individuals compared to Uninf subjects. Among Inf subjects with definitive latent tuberculosis , there were no differences in frequencies of IL-4 producing cells within any of the memory compartments compared to the Uninf group. Our data suggest that filarial infection induces antigen-specific, exaggerated IL-4 responses in distinct T cell memory compartments to Mtb-specific antigens, which are attenuated in subjects who are able to mount a delayed type hypersensitivity reaction to Mtb. PMID:25667413

  7. Increased IL-15 Production and Accumulation of Highly Differentiated CD8+ Effector/Memory T Cells in the Bone Marrow of Persons with Cytomegalovirus

    PubMed Central

    Pangrazzi, Luca; Naismith, Erin; Meryk, Andreas; Keller, Michael; Jenewein, Brigitte; Trieb, Klemens; Grubeck-Loebenstein, Beatrix

    2017-01-01

    Cytomegalovirus (CMV) has been described as a contributor to immunosenescence, thus exacerbating age-related diseases. In persons with latent CMV infection, the CD8+ T cell compartment is irreversibly changed, leading to the accumulation of highly differentiated virus-specific CD8+ T cells in the peripheral blood. The bone marrow (BM) has been shown to play a major role in the long-term survival of antigen-experienced T cells. Effector CD8+ T cells are preferentially maintained by the cytokine IL-15, the expression of which increases in old age. However, the impact of CMV on the phenotype of effector CD8+ T cells and on the production of T cell survival molecules in the BM is not yet known. We now show, using BM samples obtained from persons who underwent hip replacement surgery because of osteoarthrosis, that senescent CD8+ TEMRA cells with a bright expression of CD45RA and a high responsiveness to IL-15 accumulate in the BM of CMV-infected persons. A negative correlation was found between CMV antibody (Ab) titers in the serum and the expression of CD28 and IL-7Rα in CD8+ TEMRAbright cells. Increased IL-15 mRNA levels were observed in the BM of CMV+ compared to CMV− persons, being particularly high in old seropositive individuals. In summary, our results indicate that a BM environment rich in IL-15 may play an important role in the maintenance of highly differentiated CD8+ T cells generated after CMV infection. PMID:28674537

  8. Trichomonas vaginalis α-Actinin 2 Modulates Host Immune Responses by Inducing Tolerogenic Dendritic Cells via IL-10 Production from Regulatory T Cells.

    PubMed

    Lee, Hye-Yeon; Kim, Juri; Ryu, Jae-Sook; Park, Soon-Jung

    2017-08-01

    Trichomonas vaginalis is a pathogen that triggers severe immune responses in hosts. T. vaginalis α-actinin 2, Tvα-actinin 2, has been used to diagnose trichomoniasis. This study was undertaken to examine the role of Tvα-actinin 2 as an antigenic molecule to induce immune responses from humans. Western blot analysis using anti-Tvα-actinin 2 antibodies indicated its presence in the secreted proteins of T. vaginalis. ELISA was employed to measure cytokine production by vaginal epithelial cells, prostate cells, mouse dendritic cells (DCs), or T cells stimulated with T. vaginalis or Tvα-actinin 2 protein. Both T. vaginalis and rTvα-actinin 2 induced cytokine production from epithelial cell lines, including IL-10. Moreover, CD4+CD25- regulatory T cells (Treg cells) incubated with rTvα-actinin 2-treated DCs produced high levels of IL-10. These data indicate that Tvα-actinin 2 modulates immune responses via IL-10 production by Treg cells.

  9. Helminth Infection and Commensal Microbiota Drive Early IL-10 Production in the Skin by CD4+ T Cells That Are Functionally Suppressive

    PubMed Central

    Bourke, Claire D.; Mountford, Adrian P.

    2015-01-01

    The skin provides an important first line of defence and immunological barrier to invasive pathogens, but immune responses must also be regulated to maintain barrier function and ensure tolerance of skin surface commensal organisms. In schistosomiasis-endemic regions, populations can experience repeated percutaneous exposure to schistosome larvae, however little is known about how repeated exposure to pathogens affects immune regulation in the skin. Here, using a murine model of repeated infection with Schistosoma mansoni larvae, we show that the skin infection site becomes rich in regulatory IL-10, whilst in its absence, inflammation, neutrophil recruitment, and local lymphocyte proliferation is increased. Whilst CD4+ T cells are the primary cellular source of regulatory IL-10, they expressed none of the markers conventionally associated with T regulatory (Treg) cells (i.e. FoxP3, Helios, Nrp1, CD223, or CD49b). Nevertheless, these IL-10+ CD4+ T cells in the skin from repeatedly infected mice are functionally suppressive as they reduced proliferation of responsive CD4+ T cells from the skin draining lymph node. Moreover, the skin of infected Rag-/- mice had impaired IL-10 production and increased neutrophil recruitment. Finally, we show that the mechanism behind IL-10 production by CD4+ T cells in the skin is due to a combination of an initial (day 1) response specific to skin commensal bacteria, and then over the following days schistosome-specific CD4+ T cell responses, which together contribute towards limiting inflammation and tissue damage following schistosome infection. We propose CD4+ T cells in the skin that do not express markers of conventional T regulatory cell populations have a significant role in immune regulation after repeated pathogen exposure and speculate that these cells may also help to maintain skin barrier function in the context of repeated percutaneous insult by other skin pathogens. PMID:25974019

  10. Interleukin (IL)-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts1

    PubMed Central

    Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki; Kish, Danielle D.; Abe, Toyofumi; Su, Charles A.; Abe, Ryo; Tanabe, Kazunari; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

    2016-01-01

    Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared to complete MHC-mismatched wild type cardiac allografts, IL-1R−/− allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R−/− allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R−/− cardiac allografts took 3 weeks longer than wild type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R−/−/wild type chimeric donors indicated that IL-1R signaling on graft non-hematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli provoking development and elicitation of optimal alloimmune responses to the grafts. PMID:26856697

  11. La prévention des blessures chez les enfants et les adolescents : une démarche de santé publique

    PubMed Central

    Yanchar, Natalie L; Warda, Lynne J; Fuselli, Pamela

    2012-01-01

    RÉSUMÉ La majorité des blessures dont sont victimes les enfants et les adolescents sont évitables. Le présent document de principes contient des renseignements généraux, des conseils et une déclaration d’engagement à l’égard de la prévention des blessures au Canada. Il sert de base sur laquelle construire en s’attardant d’abord aux définitions, à l’étendue et aux priorités en matière de prévention des blessures. Il contient également une description du fardeau et du profil des blessures non intentionnelles, de même que les principes d’interventions de prévention efficaces. La version intégrale renferme une liste de ressources en vue d’obtenir des données et de l’information probante (www.cps.ca). Enfin, le présent document de principes peut être utilisé pour la défense généralisée de la prévention des blessures.

  12. Meprin A and meprin {alpha} generate biologically functional IL-1{beta} from pro-IL-1{beta}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Herzog, Christian; University of Arkansas for Medical Sciences, Department of Medicine, Little Rock, AR 72205; Haun, Randy S.

    The present study demonstrates that both oligomeric metalloendopeptidase meprin A purified from kidney cortex and recombinant meprin {alpha} are capable of generating biologically active IL-1{beta} from its precursor pro-IL-1{beta}. Amino-acid sequencing analysis reveals that meprin A and meprin {alpha} cleave pro-IL-1{beta} at the His{sup 115}-Asp{sup 116} bond, which is one amino acid N-terminal to the caspase-1 cleavage site and five amino acids C-terminal to the meprin {beta} site. The biological activity of the pro-IL-1{beta} cleaved product produced by meprin A, determined by proliferative response of helper T-cells, was 3-fold higher to that of the IL-1{beta} product produced by meprin {beta}more » or caspase-1. In a mouse model of sepsis induced by cecal ligation puncture that results in elevated levels of serum IL-1{beta}, meprin inhibitor actinonin significantly reduces levels of serum IL-1{beta}. Meprin A and meprin {alpha} may therefore play a critical role in the production of active IL-1{beta} during inflammation and tissue injury.« less

  13. Systemic IL-2/anti-IL-2Ab complex combined with sublingual immunotherapy suppresses experimental food allergy in mice through induction of mucosal regulatory T cells.

    PubMed

    Smaldini, P L; Trejo, F; Cohen, J L; Piaggio, E; Docena, G H

    2018-04-01

    Therapeutic tolerance restoration has been proven to modify food allergy in patients and animal models and although sublingual immunotherapy (SLIT) has showed promise, combined therapy may be necessary to achieve a strong and long-term tolerance. In this work, we combined SLIT with systemic administration of IL-2 associated with an anti-IL-2 monoclonal antibody (IL-2/anti-IL-2Ab complex or IL-2C) to reverse the IgE-mediated experimental allergy. Balb/c mice were sensitized with cholera toxin and milk proteins and orally challenged with allergen to elicit hypersensitivity reactions. Then, allergic mice were treated with a sublingual administration of very low amounts of milk proteins combined with intraperitoneal injection of low doses of IL-2C. The animals were next re-exposed to allergens and mucosal as well as systemic immunological parameters were assessed in vivo and in vitro. The treatment reduced serum specific IgE, IL-5 secretion by spleen cells and increased IL-10 and TGF-β in the lamina propria of buccal and duodenal mucosa. We found an augmented frequency of IL-10-secreting CD4 + CD25 + Foxp3 + regulatory T cells (Treg) in the submaxilar lymph nodes and buccal lamina propria. Tregs were sorted, characterized and adoptively transferred to naïve mice, which were subsequently sensitized. No allergy was experienced in these mice and we encouragingly discovered a faster and more efficient tolerance induction with the combined therapy compared with SLIT. The combination of two therapeutic strategies rendered Treg-mediated tolerance more efficient compared to individual treatments and reversed the established IgE-mediated food allergy. This approach highlights the ability of IL-2C to expand Tregs, and it may represent a promising disease-modifying therapy for managing food allergy. © 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  14. Interaction effects among IFN-γ+874, IL-2-330, IL-10-1082, IL-10-592 and IL-4-589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus: a retrospective nested case-control study.

    PubMed

    Gao, Qiu-Ju; Xie, Jia-Xin; Wang, Li-Min; Zhou, Qiang; Zhang, Shi-Yong

    2017-08-23

    The natural outcomes of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections vary considerably among individuals The infection may heal naturally, or patients may succumb to chronic liver diseases, including chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The mechanism is not fully understood. To evaluate the interaction among four single nucleotide polymorphisms (SNPs) and their influence on different clinical outcomes. 277 individuals infected with HBV and/or HCV, including 81 patients with chronic hepatitis B and C, 122 asymptomatic HBV and/or HCV carriers and 74 controls who cleared HBV and HCV spontaneously, were involved in this study. The SNPs of four genes ( rs2069762/-330 G/T of IL-2 , rs2430561/+874A>T of IFN-γ, rs1800896/-1082G>A  and rs1800872/-592C>A of IL-10 and rs2243250/ -589 C>T of IL-4 ) were analysed using restriction fragment length polymorphism-polymerase chain reaction or sequence-specific primer PCR. The gene-gene interactions were assessed using the multifactor-dimensionality reduction method. Interleukin (IL)-10-592 AC and IL-4-589 CC/CT showed a synergistic effect on liver inflammatory injury (p<0.01), whereas interferon (IFN)-γ+874  AA and IL-2-330 TT had a synergistic impact (p<0.05). IFN-γ+874  AA and IL-10-1082 AA had an antagonistic effect (p<0.01) on the clinical progression, including asymptomatic HBV and HCV carriers and chronic hepatitis. IL-2-330 TT and IL-10-1082 AA synergistically influenced the clinical outcome (p<0.05). IFN-γ+874 AA, IL-2-330 TT and IL-10-1082 AA interactively affected the clinical outcome including asymptomatic HBV and HCV carriers and chronic hepatitis (p<0.05). Interactions among polymorphisms of IFN-γ+874 AA, IL-2-330 TT, IL-10-1082 AA, IL10--592 AC and IL-4-589 CC/CT significantly influenced the clinical progression of the subjects with HBV and/or HCV infection. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article

  15. Interleukin (IL)-33 and the IL-1 Family of Cytokines-Regulators of Inflammation and Tissue Homeostasis.

    PubMed

    Vasanthakumar, Ajithkumar; Kallies, Axel

    2017-11-03

    Cytokines play an integral role in shaping innate and adaptive immune responses. Members of the interleukin (IL)-1 family regulate a plethora of immune-cell-mediated processes, which include pathogen defense and tissue homeostasis. Notably, the IL-1 family cytokine IL-33 promotes adaptive and innate type 2 immune responses, confers viral protection and facilitates glucose metabolism and tissue repair. At the cellular level, IL-33 stimulates differentiation, maintenance, and function of various immune cell types, including regulatory T cells, effector CD4 + and CD8 + T cells, macrophages, and type 2 innate lymphoid cells (ILC2s). Other IL-1 family members, such as IL-1β and IL-18 promote type 1 responses, while IL-37 limits immune activation. Although IL-1 cytokines play critical roles in immunity and tissue repair, their deregulated expression is often linked to autoimmune and inflammatory diseases. Therefore, IL-1 cytokines are regulated tightly by posttranscriptional mechanisms and decoy receptors. In this review, we discuss the biology and function of IL-1 family cytokines, with a specific focus on regulation and function of IL-33 in immune and tissue homeostasis. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  16. Influence of In Vitro IL-2 or IL-15 Alone or in Combination with Hsp 70 Derived 14-Mer Peptide (TKD) on the Expression of NK Cell Activatory and Inhibitory Receptors on Peripheral Blood T Cells, B Cells and NKT Cells.

    PubMed

    Hromadnikova, Ilona; Li, Shuang; Kotlabova, Katerina; Dickinson, Anne M

    2016-01-01

    Previous studies from Multhoff and colleagues reported that plasma membrane Hsp70 acts as a tumour-specific recognition structure for activated NK cells, and that the incubation of NK cells with Hsp70 and/or a 14-mer peptide derived from the N-terminal sequence of Hsp70 (TKDNNLLGRFELSG, TKD, aa 450-463) plus a low dose of IL-2 triggers NK cell proliferation and migration, and their capacity to kill cancer cells expressing membrane Hsp70. Herein, we have used flow cytometry to determine the influence of in vitro stimulation of peripheral blood mononuclear cells from healthy individuals with IL-2 or IL-15, either alone or in combination with TKD peptide on the cell surface expression of CD94, NK cell activatory receptors (CD16, NK2D, NKG2C, NKp30, NKp44, NKp46, NKp80, KIR2DL4, DNAM-1 and LAMP1) and NK cell inhibitory receptors (NKG2A, KIR2DL2/L3, LIR1/ILT-2 and NKR-P1A) by CD3+CD56+ (NKT), CD3+CD4+, CD3+CD8+ and CD19+ populations. NKG2D, DNAM-1, LAMP1 and NKR-P1A expression was upregulated after the stimulation with IL-2 or IL-15 alone or in combination with TKD in NKT, CD8+ T cells and B cells. CD94 was upregulated in NKT and CD8+ T cells. Concurrently, an increase in a number of CD8+ T cells expressing LIR1/ILT-2 and CD4+ T cells positive for NKR-P1A was observed. The proportion of CD8+ T cells that expressed NKG2D was higher after IL-2/TKD treatment, when compared with IL-2 treatment alone. In comparison with IL-15 alone, IL-15/TKD treatment increased the proportion of NKT cells that were positive for CD94, LAMP1 and NKRP-1A. The more potent effect of IL-15/TKD on cell surface expression of NKG2D, LIR1/ILT-2 and NKRP-1A was observed in B cells compared with IL-15 alone. However, this increase was not of statistical significance. IL-2/TKD induced significant upregulation of LAMP1 in CD8+ T cells compared with IL-2 alone. Besides NK cells, other immunocompetent cells present within the fraction of peripheral blood mononuclear cells were influenced by the treatment

  17. Interaction effects among IFN-γ+874, IL-2-330, IL-10-1082, IL-10-592 and IL-4-589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus: a retrospective nested case–control study

    PubMed Central

    Gao, Qiu-Ju; Xie, Jia-Xin; Wang, Li-Min; Zhou, Qiang; Zhang, Shi-Yong

    2017-01-01

    Background The natural outcomes of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections vary considerably among individuals The infection may heal naturally, or patients may succumb to chronic liver diseases, including chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The mechanism is not fully understood. Objectives To evaluate the interaction among four single nucleotide polymorphisms (SNPs) and their influence on different clinical outcomes. Methods 277 individuals infected with HBV and/or HCV, including 81 patients with chronic hepatitis B and C, 122 asymptomatic HBV and/or HCV carriers and 74 controls who cleared HBV and HCV spontaneously, were involved in this study. The SNPs of four genes (rs2069762/−330 G/T of IL-2, rs2430561/+874A>T of IFN-γ, rs1800896/−1082G>A and rs1800872/−592C>A of IL-10 and rs2243250/−589C>T of IL-4) were analysed using restriction fragment length polymorphism-polymerase chain reaction or sequence-specific primer PCR. The gene–gene interactions were assessed using the multifactor-dimensionality reduction method. Results Interleukin (IL)-10-592 AC and IL-4-589 CC/CT showed a synergistic effect on liver inflammatory injury (p<0.01), whereas interferon (IFN)-γ+874  AA and IL-2-330 TT had a synergistic impact (p<0.05). IFN-γ+874  AA and IL-10-1082 AA had an antagonistic effect (p<0.01) on the clinical progression, including asymptomatic HBV and HCV carriers and chronic hepatitis. IL-2-330 TT and IL-10-1082 AA synergistically influenced the clinical outcome (p<0.05). IFN-γ+874 AA, IL-2-330 TT and IL-10-1082 AA interactively affected the clinical outcome including asymptomatic HBV and HCV carriers and chronic hepatitis (p<0.05). Conclusions Interactions among polymorphisms of IFN-γ+874 AA, IL-2-330 TT, IL-10-1082 AA, IL10-−592 AC and IL-4-589 CC/CT significantly influenced the clinical progression of the subjects with HBV and/or HCV infection. PMID:28838891

  18. A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response.

    PubMed

    Ikebuchi, Ryoyo; Teraguchi, Shunsuke; Vandenbon, Alexis; Honda, Tetsuya; Shand, Francis H W; Nakanishi, Yasutaka; Watanabe, Takeshi; Tomura, Michio

    2016-10-19

    Foxp3 + regulatory T cells (Tregs) migrating from the skin to the draining lymph node (dLN) have a strong immunosuppressive effect on the cutaneous immune response. However, the subpopulations responsible for their inhibitory function remain unclear. We investigated single-cell gene expression heterogeneity in Tregs from the dLN of inflamed skin in a contact hypersensitivity model. The immunosuppressive genes Ctla4 and Tgfb1 were expressed in the majority of Tregs. Although Il10-expressing Tregs were rare, unexpectedly, the majority of Il10-expressing Tregs co-expressed Gzmb and displayed Th1-skewing. Single-cell profiling revealed that CD43 + CCR5 + Tregs represented the main subset within the Il10/Gzmb-expressing cell population in the dLN. Moreover, CD43 + CCR5 + CXCR3 - Tregs expressed skin-tropic chemokine receptors, were preferentially retained in inflamed skin and downregulated the cutaneous immune response. The identification of a rare Treg subset co-expressing multiple immunosuppressive molecules and having tissue-remaining capacity offers a novel strategy for the control of skin inflammatory responses.

  19. Interleukin 10 (IL-10)-mediated Immunosuppression

    PubMed Central

    Mittal, Sharad K.; Cho, Kyung-Jin; Ishido, Satoshi; Roche, Paul A.

    2015-01-01

    Efficient immune responses require regulated antigen presentation to CD4 T cells. IL-10 inhibits the ability of dendritic cells (DCs) and macrophages to stimulate antigen-specific CD4 T cells; however, the mechanisms by which IL-10 suppresses antigen presentation remain poorly understood. We now report that IL-10 stimulates expression of the E3 ubiquitin ligase March-I in activated macrophages, thereby down-regulating MHC-II, CD86, and antigen presentation to CD4 T cells. By contrast, IL-10 does not stimulate March-I expression in DCs, does not suppress MHC-II or CD86 expression on either resting or activated DCs, and does not affect antigen presentation by activated DCs. IL-10 does, however, inhibit the process of DC activation itself, thereby reducing the efficiency of antigen presentation in a March-I-independent manner. Thus, IL-10 suppression of antigen presenting cell function in macrophages is March-I-dependent, whereas in DCs, suppression is March- I-independent. PMID:26408197

  20. Maladie de Kaposi à localisation broncho-pulmonaire révélant une infection VIH

    PubMed Central

    Sebbar, Amal; Zaghba, Nahid; Benjelloun, Hanane; Bakhatar, Abdelaziz; Yassine, Najiba

    2015-01-01

    La maladie de Kaposi (MK) associée au VIH, forme dite épidémique, a été décrite la 1ère fois en 1981 par Hymmes. C'est l'affection maligne la plus fréquente au cours du SIDA. La MK est à l'origine de 10% des atteintes pleuropulmonaires au cours de l'infection par le VIH et 40% des pneumopathies en cas de MK cutanéomuqueuse. Les localisations pulmonaires occupent la deuxième place des atteintes viscérales après la forme digestive. Le diagnostic repose sur des arguments épidémiologiques, cliniques, radiologiques, biologiques, endoscopiques et histologiques. Nous rapportons un cas de MK broncho-pulmonaire compliquant une infection VIH chez un patient présentant une maladie de Kaposi cutanée de découverte fortuite au cours de l'atteinte pulmonaire. Le diagnostic a été retenu après avoir éliminé les maladies opportunistes à tropisme pulmonaire. Le Kaposi pulmonaire constitue l'atteinte la plus grave de la MK-sida et la survie après le diagnostic est courte malgré les thérapeutiques agressives. PMID:26958142

  1. Parasite-Antigen Driven Expansion of IL-5− and IL-5+ Th2 Human Subpopulations in Lymphatic Filariasis and Their Differential Dependence on IL-10 and TGFβ

    PubMed Central

    Anuradha, Rajamanickam; George, Parakkal Jovvian; Hanna, Luke E.; Chandrasekaran, Vedachalam; Kumaran, P. Paul; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Background Two different Th2 subsets have been defined recently on the basis of IL-5 expression – an IL-5+Th2 subset and an IL-5−Th2 subset in the setting of allergy. However, the role of these newly described CD4+ T cells subpopulations has not been explored in other contexts. Methods To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5+IL-4+IL-13+ CD4+ T cells and IL-5−IL-4 IL-13+ CD4+ T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP). Results INF individuals exhibited a significant increase in the spontaneously expressed and antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5+Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4+IL-5−Th2 subpopulation and the levels of parasite antigen – specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets. Conclusions Our findings suggest that both IL-5+ and IL-5−Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes. PMID:24498448

  2. IL-23 Receptor (IL-23R) Gene Protects Against Pediatric Crohn’s Disease

    PubMed Central

    Dubinsky, Marla C.; Wang, Dai; Picornell, Yoana; Wrobel, Iwona; Katzir, Lirona; Quiros, Antonio; Dutridge, Debra; Wahbeh, Ghassan; Silber, Gary; Bahar, Ron; Mengesha, Emebet; Targan, Stephan R.; Taylor, Kent D.; Rotter, Jerome I.

    2007-01-01

    Background The IL-23 receptor (IL-23R) has been found to be associated with small bowel Crohn’s disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL-23R is associated with IBD in children. The aim was to examine the association of IL-23R with susceptibility to IBD in pediatric patients. Methods DNA was collected from 609 subjects (151 CD and 52 ulcerative colitis [UC] trios). Trios were genotyped for the R381Q SNP of the IL-23R gene and SNP8, SNP12, SNP13, of the CARD15 gene using Taqman. The transmission disequilibrium test (TDT) was used for association to disease using GENEHUNTER 2.0. Results The rare allele of R381Q SNP was present in 2.7% of CD and 2.9% UC probands. The CARD15 frequency was 31.5% (CD) and 18% (UC). The IL-23R allele was negatively associated with inflammatory bowel disease (IBD): the R381Q SNP was undertransmitted in children with IBD (8 transmitted [T] versus 27 untransmitted [UT]; P = 0.001). This association was significant for all CD patients (6 T versus 19 UT; P = 0.009), especially for non-Jewish CD patients (2 T versus 17 UT; P = 0.0006). TDT showed a borderline association for UC (2 T versus 8 UT; P = 0.06). As expected, CARD15 was associated with CD in children by the TDT (58 T versus 22 UT P = 0.00006), but not with UC. Conclusions The protective IL-23R R381Q variant was particularly associated with CD in non-Jewish children. Thus, the initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD. PMID:17309073

  3. Aménorrhée chimio induite chez une population marocaine: à propos d'une cohorte retrospective

    PubMed Central

    Brahmi, Sami Aziz; Ziani, Fatima Zahra; Youssef, Seddik; Afqir, Said

    2016-01-01

    Introduction Le cancer du sein est un des cancers les plus fréquents chez la femme en pré ménopause et son traitement peut compromettre la fertilité. En effet, la chimiothérapie utilisée dans le cancer du sein peut conduire à une aménorrhée transitoire ou permanente chez les femmes non ménopausées. Méthodes Nous avons mené une étude rétrospective au service d'oncologie médicale du CHU Mohammed VI d'Oujda sur une période de 3 ans allant de janvier 2009 à décembre 2011 incluant les patientes jeunes ayant un cancer du sein localisé, pour étudier l'incidence de l'aménorrhée chimio-induite (ACI), ainsi que les facteurs prédictifs intervenant dans sa survenue. Résultats Dans notre série 74% de nos patientes ont présenté une ACI et 33.6% de nos patientes ont présenté une aménorrhée chimio-induite définitive. Plusieurs facteurs ont été étudiés à la recherche d’élément prédictifs de la survenue de l'aménorrhée. Concernant le facteur âge, l'analyse a montré que les femmes avec un âge supérieur à 40 ans étaient plus susceptibles de présenter une aménorrhée que celles avec un âge inférieur à 40 avec un pourcentage de 95,7% versus 56,1% avec une différence significative (p = 0.003). Conclusion L'incidence dans notre étude de l'ACI semble comparable à celle retrouvé dans la littérature, l’âge dans notre étude est le facteur prédictif le plus prédominant dans sa survenue. PMID:27642399

  4. Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.

    PubMed

    Shum, Thomas; Omer, Bilal; Tashiro, Haruko; Kruse, Robert L; Wagner, Dimitrios L; Parikh, Kathan; Yi, Zhongzhen; Sauer, Tim; Liu, Daofeng; Parihar, Robin; Castillo, Paul; Liu, Hao; Brenner, Malcolm K; Metelitsa, Leonid S; Gottschalk, Stephen; Rooney, Cliona M

    2017-11-01

    Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer. Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238-47. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1201 . ©2017 American Association for Cancer Research.

  5. The role of accessory cells in polyclonal T cell activation. I. Both induction of interleukin 2 production and of interleukin 2 responsiveness by concanavalin A are accessory cell dependent.

    PubMed

    Hünig, T; Loos, M; Schimpl, A

    1983-01-01

    Recent studies from other laboratories have shown that concanavalin A (Con A) acts at two separate steps in polyclonal T cell activation: interleukin 2 (IL2) production, and induction of responsiveness to IL2. Using a combination of techniques for the depletion of accessory cells from lymph node T cells, we have investigated which of these steps, if not both, is responsible for the known requirement for accessory cells in the Con A response. It was found that with increasing T cell purification, first the ability is lost to produce sufficient levels of endogenous IL2, whereas induction of IL2 responsiveness can still take place. Further removal of accessory cells however yields a population of resting T cells that cannot be induced by Con A to become IL2-reactive. It was concluded that both IL2 production and induction of reactivity to IL2 are accessory cell-dependent events.

  6. Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behçet's disease.

    PubMed

    Xavier, Joana M; Shahram, Farhad; Davatchi, Fereydoun; Rosa, Alexandra; Crespo, Jorge; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Jesus, Gorete; Barcelos, Filipe; Patto, José Vaz; Shafiee, Niloofar Mojarad; Ghaderibarim, Fahmida; Oliveira, Sofia A

    2012-08-01

    Independent replication of the findings from genome-wide association studies (GWAS) remains the gold standard for results validation. Our aim was to test the association of Behçet's disease (BD) with the interleukin-10 gene (IL10) and the IL-23 receptor-IL-12 receptor β2 (IL23R-IL12RB2) locus, each of which has been previously identified as a risk factor for BD in 2 different GWAS. Six haplotype-tagging single-nucleotide polymorphisms (SNPs) in IL10 and 42 in IL23R-IL12RB2 were genotyped in 973 Iranian patients with BD and 637 non-BD controls. Population stratification was assessed using a panel of 86 ancestry-informative markers. Subtle evidence of population stratification was found in our data set. In IL10, rs1518111 was nominally associated with BD before and after adjustment for population stratification (odds ratio [OR] for T allele 1.20, 95% confidence interval [95% CI] 1.02-1.40, unadjusted P [P(unadj) ] = 2.53 × 10(-2) ; adjusted P [P(adj) ] = 1.43 × 10(-2) ), and rs1554286 demonstrated a trend toward association (P(unadj) = 6.14 × 10(-2) ; P(adj) = 3.21 × 10(-2) ). Six SNPs in IL23R-IL12RB2 were found to be associated with BD after Bonferroni correction for multiple testing, the most significant of which were rs17375018 (OR for G allele 1.51, 95% CI 1.27-1.78, P(unadj) = 1.93 × 10(-6) ), rs7517847 (OR for T allele 1.48, 95% CI 1.26-1.74, P(unadj) = 1.23 × 10(-6) ), and rs924080 (OR for T allele 1.29, 95% CI 1.20-1.39, P = 1.78 × 10(-5) ). SNPs rs10489629, rs1343151, and rs1495965 were also significantly associated with BD in all tests performed. Results of meta-analyses of our data combined with data from other populations further confirmed the role of rs1518111, rs17375018, rs7517847, and rs924080 in the risk of BD, but no epistatic interactions between IL10 and IL23R-IL12RB2 were detected. Results of imputation analysis highlighted the importance of IL23R regulatory regions in the susceptibility to BD. These findings independently confirm

  7. Suppression of IL-7-dependent Effector T-cell Expansion by Multipotent Adult Progenitor Cells and PGE2

    PubMed Central

    Reading, James L; Vaes, Bart; Hull, Caroline; Sabbah, Shereen; Hayday, Thomas; Wang, Nancy S; DiPiero, Anthony; Lehman, Nicholas A; Taggart, Jen M; Carty, Fiona; English, Karen; Pinxteren, Jef; Deans, Robert; Ting, Anthony E; Tree, Timothy I M

    2015-01-01

    T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients. PMID:26216515

  8. IL-1RN and IL-1β Polymorphism and ARV-Associated Hepatotoxicity

    PubMed Central

    Samani, Dharmesh; Nema, Vijay; Gangakhedkar, R. R.

    2018-01-01

    The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1β production. Hence, we examined the association of IL-1 RN and IL-1β polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1β (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1β-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1β-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1β-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1β-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1β-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1β-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

  9. Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease.

    PubMed

    Cătană, Cristina-Sorina; Berindan Neagoe, Ioana; Cozma, Vasile; Magdaş, Cristian; Tăbăran, Flaviu; Dumitraşcu, Dan Lucian

    2015-05-21

    Inflammatory bowel diseases (IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis. These idiopathic diseases have environmental, genetic, immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type (Th) 1 and Th2 immune responses, other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin, microRNAs, and serum proinflammatory cytokines. An efficient strategy for IBD therapy is represented by the combination of IL-17A and IL-17F in acute IL-17A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17F knockout, DSS-induced colitis have been observed. Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused review in order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation.

  10. Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease

    PubMed Central

    Cătană, Cristina-Sorina; Berindan Neagoe, Ioana; Cozma, Vasile; Magdaş, Cristian; Tăbăran, Flaviu; Dumitraşcu, Dan Lucian

    2015-01-01

    Inflammatory bowel diseases (IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis. These idiopathic diseases have environmental, genetic, immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type (Th) 1 and Th2 immune responses, other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin, microRNAs, and serum proinflammatory cytokines. An efficient strategy for IBD therapy is represented by the combination of IL-17A and IL-17F in acute IL-17A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17F knockout, DSS-induced colitis have been observed. Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused review in order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation. PMID:26019446

  11. IL-4 production by group 2 innate lymphoid cells promotes food allergy by blocking regulatory T-cell function.

    PubMed

    Noval Rivas, Magali; Burton, Oliver T; Oettgen, Hans C; Chatila, Talal

    2016-09-01

    Food allergy is a major health issue, but its pathogenesis remains obscure. Group 2 innate lymphoid cells (ILC2s) promote allergic inflammation. However their role in food allergy is largely unknown. We sought to investigate the role of ILC2s in food allergy. Food allergy-prone mice with a gain-of-function mutation in the IL-4 receptor α chain (Il4raF709) were orally sensitized with food allergens, and the ILC2 compartment was analyzed. The requirement for ILC2s in food allergy was investigated by using Il4raF709, IL-33 receptor-deficient (Il1rl1(-/-)), IL-13-deficient (Il13(-/-)), and IL-4-deficient (Il4(-/-)) mice and by adoptive transfer of in vitro-expanded ILC2s. Direct effects of ILC2s on regulatory T (Treg) cells and mast cells were analyzed in coculture experiments. Treg cell control of ILC2s was assessed in vitro and in vivo. Il4raF709 mice with food allergy exhibit increased numbers of ILC2s. IL-4 secretion by ILC2s contributes to the allergic response by reducing allergen-specific Treg cell and activating mast cell counts. IL-33 receptor deficiency in Il4raF709 Il1rl1(-/-) mice protects against allergen sensitization and anaphylaxis while reducing ILC2 induction. Adoptive transfer of wild-type and Il13(-/-) but not Il4(-/-) ILC2s restored sensitization in Il4raF709 Il1rl1(-/-) mice. Treg cells suppress ILC2s in vitro and in vivo. IL-4 production by IL-33-stimulated ILC2s blocks the generation of allergen-specific Treg cells and favors food allergy. Strategies to block ILC2 activation or the IL-33/IL-33 receptor pathway can lead to innovative therapies in the treatment of food allergy. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  12. Myélome multiple survenant au cours d'une Fièvre Méditerranéenne Familiale

    PubMed Central

    Salem, Bouomrani; Afef, Farah; Nadia, Bouassida; Nabil, Ayadi; Zouhir, Bahloul; Maher, Béji

    2013-01-01

    L'objectif de ce travail est de rapporter une observation particulière de myélome multiple survenant au cours d'une maladie périodique. Il s'agit d'un patient tunisien de 53 ans suivi depuis le jeune âge pour maladie périodique dont le diagnostic était confirmé par l’étude génétique montrant l'homozygotie pour la mutation M694V du gène MEFV, fut admis pour exploration d'une douleur avec tuméfaction fessière droite récente. Les explorations biologiques et radiologiques ont permis de retenir le diagnostic d'un myélome multiple de type IgA à chaînes légères kappa stade III B, associé à une volumineuse localisation plasmocytaire très agressive de l'aile iliaque droite envahissant les structures musculaires avoisinantes. Notre observation, qui à notre connaissance est la deuxième signalant une telle association, se distingue par sa survenue brutale, sa progression rapide et le caractère très agressif de l'hémopathie. PMID:24255729

  13. Strikingly higher interleukin (IL)-1alpha, IL-1beta and soluble interleukin-1 receptor antagonist (sIL-1RA) but similar IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and interferon IFN-gamma urine levels in healthy females compared to healthy males: protection against urinary tract injury?

    PubMed

    Sadeghi, M; Daniel, V; Naujokat, C; Weimer, R; Opelz, G

    2005-11-01

    The aim of this prospective study was to examine gender-related differences of cytokines in the plasma and urine of healthy individuals that might provide a clue concerning the lower rate of chronic renal diseases in females. Soluble interleukin-1 receptor antagonist (sIL-1RA), interleukin (IL)-1alpha, IL-1beta, IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta(2) and interferon (IFN)-gamma were determined using standard enzyme-linked immunosorbent assay (ELISA). Cytokine levels were determined in simultaneously obtained plasma and urine samples of 18 male and 28 female healthy members of our laboratory staff. Urine cytokine levels were studied three times at 1-month intervals. All individuals had a negative urine nitrite test and showed no symptoms of urinary tract infection (UTI). Plasma levels of all studied cytokines were similar in males and females (P = n.s.). However, females had significantly higher urine IL-1alpha (P < 0.0001; P < 0.0001; P < 0.0001) and sIL-1RA (P = 0.0001; P = 0.0003; P = 0.0002) than males at three and higher IL-1beta at one of the three investigations (P = 0.098; P = 0.003; P = 0.073). Urine levels of the other cytokines were similar in males and females. Higher urine levels of IL-1alpha, IL-1beta and sIL-1RA in females may result from stimulation of cells in the urinary tract. Increased sIL-1RA might block T lymphocyte activation. The elevated cytokines may play a role in the protection of the female urinary tract from certain renal diseases, such as pyelonephritis and other inflammatory and sclerotic kidney diseases.

  14. The secreted form of the p40 subunit of interleukin (IL)-12 inhibits IL-23 functions and abrogates IL-23-mediated antitumour effects

    PubMed Central

    Shimozato, Osamu; Ugai, Shin-ichi; Chiyo, Masako; Takenobu, Hisanori; Nagakawa, Hiroyasu; Wada, Akihiko; Kawamura, Kiyoko; Yamamoto, Hiroshi; Tagawa, Masatoshi

    2006-01-01

    Interleukin (IL)-23 is a heterodimeric cytokine consisting of a novel p19 molecule and the p40 subunit of IL-12. Since secreted p40 can act as an antagonist for IL-12, we investigated whether p40 also inhibited IL-23-mediated immunological functions. p40 did not induce interferon (IFN)-γ or IL-17 production from splenocytes but impaired IL-23-induced cytokine production by competitive binding to the IL-23 receptors. Furthermore, a mixed population of murine colon carcinoma Colon 26 cells transduced with the p40 gene and those transduced with the IL-23 gene developed tumours in syngenic mice, whereas the IL-23-expressing Colon 26 cells were completely rejected. p40 also suppressed IFN-γ production of antigen-stimulated splenocytes and IL-23-mediated cytotoxic T-lymphocyte activities in the mice that rejected Colon 26 cells expressing IL-23. p40 can thereby antagonize IL-23 and is a possible therapeutic agent for suppression of IL-23 functions. PMID:16423037

  15. Association of Neuropeptide Y (NPY), Interleukin-1B (IL1B) Genetic Variants and Correlation of IL1B Transcript Levels with Vitiligo Susceptibility

    PubMed Central

    Laddha, Naresh C.; Dwivedi, Mitesh; Mansuri, Mohmmad Shoab; Singh, Mala; Patel, Hetanshi H.; Agarwal, Nishtha; Shah, Anish M.; Begum, Rasheedunnisa

    2014-01-01

    Background Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels. Objectives Aim of the present study was to explore NPY promoter −399T/C (rs16147) and exon2 +1128T/C (rs16139) polymorphisms as well as IL1B promoter −511C/T (rs16944) polymorphism and to correlate IL1B transcript levels with vitiligo. Methods PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B −511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR. Results Genotype and allele frequencies for NPY −399T/C, +1128T/C and IL1B −511C/T SNPs differed significantly (p<0.0001, p<0.0001; p = 0.0161, p = 0.0035 and p<0.0001, p<0.0001) between patients and controls. ‘TC’ haplotype containing minor alleles of NPY polymorphisms was significantly higher in patients and increased the risk of vitiligo by 2.3 fold (p<0.0001). Transcript levels of IL1B were significantly higher, in patients compared to controls (p = 0.0029), in patients with active than stable vitiligo (p = 0.015), also in female patients than male patients (p = 0.026). Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes. Conclusion Our results suggest that NPY −399T/C, +1128T/C and IL1B −511C/T polymorphisms are associated with vitiligo and IL1B −511C/T SNP influences its transcript levels leading to increased risk for vitiligo in

  16. Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory Phenotype

    PubMed Central

    Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D.; Lombardi, Giovanna; Nestle, Frank O.

    2012-01-01

    The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; “Hu-PBMC mice”) are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγnull), notably the NOD-scid IL-2Rγnull (NSG) and BALB/c-Rag2 null IL-2Rγnull (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45+ compartment and higher engraftment levels of CD3+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (TEM) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting TEM-cell driven GvHD. PMID:22937164

  17. An Assessment of Response, Direction and Place Learning by Rats in a Water T-Maze

    ERIC Educational Resources Information Center

    Whyte, Jacqueline T.; Martin, Gerard M.; Skinner, Darlene M.

    2009-01-01

    Behavioral data suggest that distinguishable orientations may be necessary for place learning even when distal cues define different start points in the room and a unique goal location. We examined whether changes in orientation are also important in place learning and navigation in a water T-maze. In Experiment 1, rats were trained to locate a…

  18. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP.

    PubMed

    Fabbi, Marina; Carbotti, Grazia; Ferrini, Silvano

    2015-04-01

    IL-18 is a proinflammatory and immune regulatory cytokine, member of the IL-1 family. IL-18 was initially identified as an IFN-γ-inducing factor in T and NK cells, involved in Th1 responses. IL-18 is produced as an inactive precursor (pro-IL-18) that is enzymatically processed into a mature form by Casp1. Different cells, such as macrophages, DCs, microglial cells, synovial fibroblasts, and epithelial cells, express pro-IL-18, and the production of bioactive IL-18 is mainly regulated at the processing level. PAMP or DAMP molecules activate inflammasomes, which trigger Casp1 activation and IL-18 conversion. The natural inhibitor IL-18BP , whose production is enhanced by IFN-γ and IL-27, further regulates IL-18 activity in the extracellular environment. Inflammasomes and IL-18 represent double-edged swords in cancer, as their activation may promote tumor development and progression or oppositely, enhance anti-tumor immunity and limit tumor growth. IL-18 has shown anti-tumor activity in different preclinical models of cancer immunotherapy through the activation of NK and/or T cell responses and has been tested in clinical studies in cancer patients. However, the dual role of IL-18 in different experimental tumor models and human cancers raises critical issues on its therapeutic use in cancer. This review will summarize the biology of the IL-18/IL-18R/IL-18BP system and will address the role of IL-18 and its inhibitor, IL-18BP, in cancer biology and immunotherapy. © Society for Leukocyte Biology.

  19. CD4+ Primary T Cells Expressing HCV-Core Protein Upregulate Foxp3 and IL-10, Suppressing CD4 and CD8 T Cells

    PubMed Central

    Aguado, Enrique; Garcia-Cozar, Francisco

    2014-01-01

    Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127lowPD-1highTIM-3high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein. PMID:24465502

  20. Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility

    PubMed Central

    Diaz-Gallo, Lina-Marcela; Simeon, Carmen P; Broen, Jasper C; Ortego-Centeno, Norberto; Beretta, Lorenzo; Vonk, Madelon C; Carreira, Patricia E; Vargas, Sofia; Román-Ivorra, José Andrés; González-Gay, Miguel A; Tolosa, Carlos; López-Longo, Francisco Javier; Espinosa, Gerard; Vicente, Esther F; Hesselstrand, Roger; Riemekasten, Gabriela; Witte, Torsten; Distler, Jörg H W; Voskuyl, Alexandre E; Schuerwegh, Annemie J; Shiels, Paul G; Nordin, Annika; Padyukov, Leonid; Hoffmann-Vold, Anna-Maria; Scorza, Raffaella; Lunardi, Claudio; Airo, Paolo; van Laar, Jacob M; Hunzelmann, Nicolas; Gathof, Birgit S; Kreuter, Alexander; Herrick, Ariane; Worthington, Jane; Denton, Christopher P; Zhou, Xiaodong; Arnett, Frank C; Fonseca, Carmen; Koeleman, Bobby PC; Assasi, Shervin; Radstake, Timothy R D J; Mayes, Maureen D; Martín, Javier

    2013-01-01

    Objective The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). Patients and methods The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. Results We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). Conclusions These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases. PMID:23172754

  1. Les traumatismes de l’étage antérieur de la base du crane: à propos d'une série de 136 cas

    PubMed Central

    Bouchaouch, Abdelali; Hassani, Fahd Derkaoui; Abboud, Hilal; Mukengeshay, Jeff Ntalaja; El Fatemi, Nizare; Gana, Rachid; El Maaqili, Moulay Rchid; El Abbadi, Najia; Bellakhdar, Fouad

    2015-01-01

    Les traumatismes de l’étage antérieur de la base du crâne représentent 15 à 20% des traumatismes crâniens en général. Ils menacent les structures neuro-encéphaliques sus jacentes et sont très souvent responsables de brèches ostéo-méningées exposant au risque infectieux. Notre travail a concerné 136 dossiers exploitables de traumatisme de l’étage antérieur de la base du crâne colligés sur une période de 10 ans entre janvier 2003 et décembre 2012. Le diagnostic a été suspecté devant les signes cliniques évocateurs (ecchymose péri-orbitaire, rhinorrhée…) et a été confirmé dans la plupart des cas par la TDM. Le traitement idéal est la fermeture chirurgicale de la brèche en association aux moyens médicaux (vaccination, anti-épileptiques, mesures de réanimation…) Le moment idéal de la réparation est au-delà de la 72ème heure après la diminution de l'oedème cérébral en cas d'absence d'une lésion intracrânienne nécessitant une intervention en urgence. Notre équipe ne pratiquant pas la voie endoscopique, l'abord frontal est souvent indiqué. Le pronostic dépend des lésions cérébrales associées et surtout de la présence d'une brèche dont le diagnostic et la réparation doivent être les plus rapides et les plus précis possibles. Ainsi toute rhinorrhée post-traumatique nécessite une exploration systématique, le timing idéal: c'est la disparition de l'oedème cérébral pour faciliter l'exploration, ceci est en général possible à partir de la 72ème heure sauf dans les cas associés à une autre lésion intra crânienne nécessitant une exploration en urgence. PMID:26327992

  2. The experimental violation of Bell's inequality [as predicted by quantum mechanics]: A contribution to the study of its meaning

    NASA Astrophysics Data System (ADS)

    Hespel, Bertrand

    Au vu des expériences déjà réalisées, il est permis de penser que la violation de l'inégalité de Bell conformément aux prédictions de la mécanique quantique sera bientôt un fait établi. D'après les lectures qui en ont été le plus souvent données, en raison de la non- localité qu'il met en évidence et de l'incompatibilité qu'il y aurait entre cette propriété et celle de localité postulée par la relativité, ce fait annihilerait inéluctablement l'espoir qui animait le fondateur de la physique moderne et bon nombre de ses successeurs: à moins d'accepter d'abandonner l'exigence d'exactitude, nous devrions définitivement nous résoudre à admettre que nous ne pourrons jamais fournir du monde qu'une image incomplète. L'histoire de la philosophie suggère une toute autre interprétation. Lorsqu'on reconstitue les tentatives oubliées menées par Spinoza, Malebranche et Leibniz, pour bâtir, comme Newton, à la suite de Descartes, un Monde tout à la fois exact et complet, ce fait apparaît plutôt comme la preuve empirique que le monde est tout à la fois local et inséparable-phénoménalement local mais fondamentalement inséparable-et qu'une image adéquate ne pourra donc en être donnée qu'à la condition de reconnaître qu'il ne se réduit pas au contenu de l'espace-temps, c'est-à-dire que ce monde qui est l'objet de la physique n'est pas le tout du monde et qu'il convient de prolonger cette science, désormais quantique et relativiste, par une méta-physique.

  3. Proinflammatory responses and higher IL-10 production by T cells correlate with protection against malaria during pregnancy and delivery outcomes.

    PubMed

    Requena, Pilar; Barrios, Diana; Robinson, Leanne J; Samol, Paula; Umbers, Alexandra J; Wangnapi, Regina; Ome-Kaius, Maria; Rosanas-Urgell, Anna; Mayor, Alfredo; López, Marta; de Lazzari, Elisa; Arévalo-Herrera, Myriam; Fernández-Becerra, Carmen; del Portillo, Hernando; Chitnis, Chetan E; Siba, Peter M; Rogerson, Stephen; Mueller, Ivo; Bardají, Azucena; Menéndez, Clara; Dobaño, Carlota

    2015-04-01

    Pregnancy triggers immunological changes aimed to tolerate the fetus. However, it has not been properly addressed whether similar changes occur in tropical areas with high infection pressure and whether these changes render women more susceptible to infectious diseases. We compared the frequencies of T cell subsets, including regulatory T cells, in pregnant and nonpregnant women from Papua New Guinea, a high malaria transmission area, and from Spain, a malaria-free country. We also assessed the relationship among these cellular subsets, malaria infection, and delivery outcomes. CD4(+)FOXP3(+)CD127(low) T cells (Tregs) were decreased in pregnant women in both countries but were not associated with malaria infection or poor delivery outcomes. An expansion of IFN-γ-producing cells and intracytoplasmic IFN-γ levels was found in pregnant compared with nonpregnant women only in Papua New Guinea. Increased CD4(+)IL-10(+)IFN-γ(+) frequencies and Treg-IFN-γ production were found in women with current Plasmodium falciparum infection. Higher CD4(+)IL-10(-)IFN-γ(+) T cells frequencies and production of proinflammatory cytokines (including TNF and IL-2) at recruitment (first antenatal visit) had a protective association with birth weight and future (delivery) P. falciparum infection, respectively. Higher intracellular IL-10 levels in T cells had a protective association with future P. falciparum infection and hemoglobin levels at delivery. The protective associations were found also with nonmalaria-specific T cell responses. Treg frequencies positively correlated with plasma eotaxin concentrations, but this subset did not express eotaxin receptor CCR3. Thus, an activated immune system during pregnancy might contribute to protection against malaria during pregnancy and poor delivery outcomes. Copyright © 2015 by The American Association of Immunologists, Inc.

  4. A distinct dendritic cell population arises in the thymus of IL-13Rα1-sufficient but not IL-13Rα1-deficient mice.

    PubMed

    Barik, Subhasis; Miller, Mindy; Cattin-Roy, Alexis; Ukah, Tobechukwu; Zaghouani, Habib

    2018-06-18

    IL-13 receptor alpha 1 (IL-13Rα1) associates with IL-4Rα to form a functional IL-4Rα/IL-13Rα1 heteroreceptor (HR) through which both IL-4 and IL-13 signal. Recently, HR expression was associated with the development of M2 type macrophages which function as antigen presenting cells (APCs). Herein, we show that a subset of thymic resident dendritic cells (DCs) expressing high CD11b (CD11b hi ) and intermediate CD11c (CD11c int ) arise in HR-sufficient but not HR-deficient mice. These DCs, which originate from the bone marrow are able to take up Ag from the peritoneum, traffic through the spleen and the lymph nodes and carry it to the thymus. In addition, since the DCs are able to present Ag to T cells, express high levels of the costimulatory molecule CD24, and comprise a CD8α + subset, it is likely that the cells contribute to T cell development and perhaps negative selection of self-reactive lymphocytes. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Chan, Liana C.; Chaili, Siyang; Filler, Scott G.; Barr, Kevin; Wang, Huiyuan; Kupferwasser, Deborah; Edwards, John E.; Xiong, Yan Q.; Ibrahim, Ashraf S.; Miller, Lloyd S.; Schmidt, Clint S.; Hennessey, John P.

    2015-01-01

    Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI) in humans. Moreover, the high frequency of recurring SSSI due to S. aureus, particularly methicillin-resistant S. aureus (MRSA) strains, suggests that infection induces suboptimal anamnestic defenses. The present study addresses the hypothesis that interleukin-17A (IL-17A) and IL-22 play distinct roles in immunity to cutaneous and invasive MRSA infection in a mouse model of SSSI. Mice were treated with specific neutralizing antibodies against IL-17A and/or IL-22 and infected with MRSA, after which the severity of infection and host immune response were determined. Neutralization of either IL-17A or IL-22 reduced T cell and neutrophil infiltration and host defense peptide elaboration in lesions. These events corresponded with increased abscess severity, MRSA viability, and CFU density in skin. Interestingly, combined inhibition of IL-17A and IL-22 did not worsen abscesses but did increase gamma interferon (IFN-γ) expression at these sites. The inhibition of IL-22 led to a reduction in IL-17A expression, but not vice versa. These results suggest that the expression of IL-17A is at least partially dependent on IL-22 in this model. Inhibition of IL-17A but not IL-22 led to hematogenous dissemination to kidneys, which correlated with decreased T cell infiltration in renal tissue. Collectively, these findings indicate that IL-17A and IL-22 have complementary but nonredundant roles in host defense against cutaneous versus hematogenous infection. These insights may support targeted immune enhancement or other novel approaches to address the challenge of MRSA infection. PMID:26351278

  6. Développement d’un programme multidisciplinaire de diagnostic de l’adrénoleucodystrophie liée à l’X au Maroc: résultats de la mise en œuvre du programme de diagnostic clinique et biologique

    PubMed Central

    Benjelloun, Fatima-Zohra Madani; Chabraoui, Layachi; Kriouile, Yamna

    2017-01-01

    Introduction L'adrénoleucodystrophie liée à l'X (X-ALD) est une maladie neurodégénérative sévère, due à des mutations du gène ABCD1. Elle se manifeste par une atteinte du système nerveux central et périphérique, une insuffisance surrénalienne et une atteinte des testicules chez le garçon. Son diagnostic repose sur le dosage des Acides Gras à Très Longue Chaine. Le diagnostic précoce est d'une grande importance puisque il définit l'accessibilité aux traitements selon le stage de la maladie. Méthodes Nous avons mis en place un programme de diagnostic de l'X-ALD au Maroc au niveau de l'Hôpital d'enfants et du Laboratoire centrale des maladies héréditaires et du métabolisme de Rabat. Le programme s'articule sur trois axes à savoir : le recrutement des patients, le diagnostic et la sensibilisation. Le diagnostic s'effectue selon trois protocoles : un protocole pour les cas symptomatiques, un deuxième pour les cas asymptomatiques et un troisième pour les femmes hétérozygotes. Résultats Durant trois ans après la mise en place de notre programme de diagnostic de l'Adrénoleucodystrophie liée à l'X, nous avons diagnostiqué la maladie chez sept familles, avec neuf garçons et trois femmes hétérozygotes. Tous les enfants diagnostiqués présentaient la forme cérébrale démyélinisante. Toutes les femmes hétérozygotes étaient asymptomatiques. Une prise en charge thérapeutique a été mise place selon la symptomatologie de chaque cas. Conclusion l'X-ALD est une maladie rare. Notre programme de diagnostique a permis de diagnostiquer un nombre important de cas, ce qui montre son importance. Les compagnes de sensibilisation auprès des professionnels permettront de mieux comprendre la maladie et mieux la diagnostiquer et ainsi donner accès à un nombre plus élevé de patients. PMID:29599883

  7. IL-23 (Interleukin-23)-Producing Conventional Dendritic Cells Control the Detrimental IL-17 (Interleukin-17) Response in Stroke.

    PubMed

    Gelderblom, Mathias; Gallizioli, Mattia; Ludewig, Peter; Thom, Vivien; Arunachalam, Priyadharshini; Rissiek, Björn; Bernreuther, Christian; Glatzel, Markus; Korn, Thomas; Arumugam, Thiruma Valavan; Sedlacik, Jan; Gerloff, Christian; Tolosa, Eva; Planas, Anna M; Magnus, Tim

    2018-01-01

    Inflammatory mechanisms can exacerbate ischemic tissue damage and worsen clinical outcome in patients with stroke. Both αβ and γδ T cells are established mediators of tissue damage in stroke, and the role of dendritic cells (DCs) in inducing the early events of T cell activation and differentiation in stroke is not well understood. In a murine model of experimental stroke, we defined the immune phenotype of infiltrating DC subsets based on flow cytometry of surface markers, the expression of ontogenetic markers, and cytokine levels. We used conditional DC depletion, bone marrow chimeric mice, and IL-23 (interleukin-23) receptor-deficient mice to further explore the functional role of DCs. We show that the ischemic brain was rapidly infiltrated by IRF4 + /CD172a + conventional type 2 DCs and that conventional type 2 DCs were the most abundant subset in comparison with all other DC subsets. Twenty-four hours after ischemia onset, conventional type 2 DCs became the major source of IL-23, promoting neutrophil infiltration by induction of IL-17 (interleukin-17) in γδ T cells. Functionally, the depletion of CD11c + cells or the genetic disruption of the IL-23 signaling abrogated both IL-17 production in γδ T cells and neutrophil infiltration. Interruption of the IL-23/IL-17 cascade decreased infarct size and improved neurological outcome after stroke. Our results suggest a central role for interferon regulatory factor 4-positive IL-23-producing conventional DCs in the IL-17-dependent secondary tissue damage in stroke. © 2017 American Heart Association, Inc.

  8. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

    PubMed Central

    Vicente, Carmen; Schwab, Claire; Broux, Michaël; Geerdens, Ellen; Degryse, Sandrine; Demeyer, Sofie; Lahortiga, Idoya; Elliott, Alannah; Chilton, Lucy; La Starza, Roberta; Mecucci, Cristina; Vandenberghe, Peter; Goulden, Nicholas; Vora, Ajay; Moorman, Anthony V.; Soulier, Jean; Harrison, Christine J.; Clappier, Emmanuelle; Cools, Jan

    2015-01-01

    T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia. PMID:26206799

  9. IL-22 promotes Fas expression in oligodendrocytes and inhibits FOXP3 expression in T cells by activating the NF-κB pathway in multiple sclerosis.

    PubMed

    Zhen, Jin; Yuan, Jun; Fu, Yongwang; Zhu, Runxiu; Wang, Meiling; Chang, Hong; Zhao, Yan; Wang, Dong; Lu, Zuneng

    2017-02-01

    Multiple sclerosis (MS) is characterized by an increase in interleukin-22 and Fas, and a decrease in FOXP3, among other factors. In this study, we examined patients with MS and healthy control subjects and used the experimental autoimmune encephalomyelitis (EAE) animal model to identify the effects of IL-22 on oligodendrocytes and T cells in MS development. In MS, the expression of Fas in oligodendrocytes and IL-22 in CD4 + CCR4 + CCR6 + CCR10 + T cells was enhanced. Ikaros and FOXP3 were both decreased in T cells. Depending on exogenous IL-22, Fas increased the phosphorylation of mitogen- and stress-activated protein kinase 1 and activated the nuclear factor-κB pathway in oligodendrocytes, leading to an increase in Fas and oligodendrocyte apoptosis. IL-22 decreased FOXP3 expression by activating NF-κB, and it further inhibited PTEN and Ikaros expression. Tregs reversed the functions of IL-22. Taken together, these findings help to elucidate the mechanisms of IL-22 in MS development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. During acute experimental infection with the reticulotropic Trypanosoma cruzi strain Tulahuen IL-22 is induced IL-23-dependently but is dispensable for protection.

    PubMed

    Erdmann, Hanna; Behrends, Jochen; Hölscher, Christoph

    2016-09-21

    Protective immunity against Trypanosoma cruzi, the causative agent of Chagas disease, depends on the activation of macrophages by IFN-γ and IL-17A. In contrast, IL-10 prevents immunopathology. IL-22 belongs to the IL-10 cytokine family and has pleiotropic effects during host defense and immunopathology, however its role in protection and pathology during T. cruzi infection has not been analyzed yet. Therefore, we examined the role of IL-22 in experimental Chagas disease using the reticulotropic Tulahuen strain of T. cruzi. During infection, IL-22 is secreted by CD4-positive cells in an IL-23-dependent fashion. Infected IL-22(-/-) mice exhibited an increased production of IFN-γ and TNF and displayed enhanced numbers of activated IFN-γ-producing T cells in their spleens. Additionally, the production of IL-10 was increased in IL-22(-/-) mice upon infection. Macrophage activation and by association the parasitemia was not affected in the absence of IL-22. Apart from a transient increase in the body weight loss, infected IL-22(-/-) mice did not show any signs for an altered immunopathology during the first fourteen days of infection. Taken together, although IL-22 is expressed, it seems to play a minor role in protection and pathology during the acute systemic infection with the reticulotropic Tulahuen strain of T. cruzi.

  11. Elaboration d'un plan de transition et de mise en oeuvre pour ameliorer la gestion de l'obsolescence dans une entreprise du secteur aeronautique =

    NASA Astrophysics Data System (ADS)

    Conrad, Heloise

    L'evolution technologique des composants electroniques entraine des problemes de gestion de l'obsolescence dans le secteur aeronautique. Les systemes aeronautiques ont en effet des durees de vie nettement superieures aux composants qu'ils contiennent. Cette difference de duree de vie et les normes strictes propres a l'aeronautique obligent les constructeurs a mettre en place une gestion efficace de l'obsolescence pour eviter les couts supplementaires de maintenance et de retards. De plus, a cause des faibles volumes de production qu'ils representent, les constructeurs aeronautiques n'ont que peu de controle sur leur chaine d'approvisionnement. La litterature offre beaucoup d'etudes sur l'obsolescence, appliquees a l'aeronautique. Les auteurs recommandent de mettre en place des processus de gestion et de prevision de l'obsolescence, et de construire des relations de collaboration avec leurs fournisseurs, qui ont plus de visibilite sur la chaine d'approvisionnement. Cette recherche presente d'abord l'elaboration d'une liste de criteres de bonne gestion de l'obsolescence, ainsi que la creation d'une methode de generation de plan de transition et de mise en oeuvre de l'amelioration de la gestion et de la prevision de l'obsolescence pour un cas concret. La methode est creee pour un manufacturier aeronautique ne possedant pas de systemes de gestion proactive ou de prevision de l'obsolescence. La creation de la methode s'est faite en suivant la methodologie de la science de la conception, en impliquant les employes concernes par la gestion de l'obsolescence. La methode comporte douze (12) etapes, amenant au developpement du plan de transition et de mise en oeuvre. Pour applique la methode, divers entretiens individuels et de groupe ont ete realises. Ces entretiens ont aussi permis de lister les criteres de gestion et de prevision efficaces de l'obsolescence. Cette liste a ete comparee avec les criteres issus de la litterature. En respect des besoins enonces par les

  12. Stimulation of hair follicle stem cell proliferation through an IL-1 dependent activation of γδT-cells

    PubMed Central

    Dutta, Abhik; Pincha, Neha; Rana, Isha; Ghosh, Subhasri; Witherden, Deborah; Kandyba, Eve; MacLeod, Amanda; Kobielak, Krzysztof; Havran, Wendy L

    2017-01-01

    The cutaneous wound-healing program is a product of a complex interplay among diverse cell types within the skin. One fundamental process that is mediated by these reciprocal interactions is the mobilization of local stem cell pools to promote tissue regeneration and repair. Using the ablation of epidermal caspase-8 as a model of wound healing in Mus musculus, we analyzed the signaling components responsible for epithelial stem cell proliferation. We found that IL-1α and IL-7 secreted from keratinocytes work in tandem to expand the activated population of resident epidermal γδT-cells. A downstream effect of activated γδT-cells is the preferential proliferation of hair follicle stem cells. By contrast, IL-1α-dependent stimulation of dermal fibroblasts optimally stimulates epidermal stem cell proliferation. These findings provide new mechanistic insights into the regulation and function of epidermal cell–immune cell interactions and into how components that are classically associated with inflammation can differentially influence distinct stem cell niches within a tissue. PMID:29199946

  13. [Changes of CD(4)(+) Foxp3+ regulatory T cells and CD(4)(+)IL-17+T cells in acrolein exposure rats].

    PubMed

    Wei, Ming; Tu, Ling; Liang, Yinghong; Li, Jia; Gong, Yanjie; Zhang, Yihua; Yang, Lu

    2015-09-01

    To evaluate the changes of CD(4)(+) IL-17+T (Th17) and CD(4)(+)Foxp3+regulatory T (Treg) cells in peripheral blood and bronchoalveolar lavage fluid (BALF) , and therefore to explore the role of Th17 and Treg in acrolein exposure airway inflammation in rats. Forty male Wistar rats were randomly divided into 4 groups: a 2 wk acrolein exposure group, a 4 wk acrolein exposure group, a 2 wk control group and a 4 wk control group (n=10 each). Cells in BALF were collected and analyzed by absolute and differential cell counts.IL-17 and IL-6 levels in serum and BALF were tested by enzyme linked immunosorbent assay (ELISA). The proportion of CD(4)(+)IL-17+T and CD(4)(+) Foxp3+Treg in peripheral blood and BALF were determined by flow cytometry.The mRNA expressions of IL-17 and Foxp3 were measured by real-time PCR. Comparisons of the data between different groups were performed using one-way ANOVA, and SNK and Games-Howell test were used for comparison between 2 groups. Levels of IL-17 were remarkable increased in the 2 wk acrolein exposure group and the 4 wk acrolein exposure group in serum [(52.64 ± 1.89) ng/L, (76.73 ± 5.57) ng/L], and BALF [(79.07 ± 5.67) ng/L, (96.61 ± 6.44) ng/L] compared with the 2 wk control group [(40.05 ± 3.12) ng/L, (56.75 ± 4.37) ng/L] and the 4 wk control group [(38.75 ± 3.23) ng/L, (53.27 ± 4.48) ng/L], all P<0.01. IL-6 was increased in the 2 wk and the 4 wk acrolein exposure group [ (33.28 ± 2.27) ng/L, (46.24 ± 3.16) ng/L] compared with the 2 wk and the 4 wk control group [ (16.37 ± 1.49) ng/L, (17.02 ± 1.43) ng/L] in BALF.Ratio of Th17 was higher in the 2 wk and the 4 wk acrolein exposure groups in peripheral blood (1.82 ± 0.18) %, (3.75 ± 0.48) % and BALF [(7.23 ± 0.27) %, (8.12 ± 0.38) %] compared with the 2 wk [(0.96 ± 0.07) %, (5.64 ± 0.63) %] and the 4 wk control group [(1.01 ± 0.08) %, (5.86 ± 0.57) %]. Ratio of Treg in BALF was higher in the acrolein exposure groups [ (8.83 ± 0.52) %, (12.05 ± 0.74) %] compared

  14. Differential effects of Denileukin Diftitox IL-2 immunotoxin on NK and regulatory T cells in non-human primates

    PubMed Central

    Yamada, Yohei; Aoyama, Akihiro; Tocco, Georges; Boskovic, Svjetlan; Nadazdin, Ognjenka; Alessandrini, Alessandro; Madsen, Joren C.; Cosimi, A. Benedict; Benichou, Gilles; Kawai, Tatsuo

    2012-01-01

    Denileukin Diftitox (DD), a fusion protein comprised of IL-2 and diphtheria toxin was initially expected to enhance anti-tumor immunity by selectively eliminating regulatory T cells (Tregs) displaying the high affinity IL-2R (α-β-γ trimers). While DD has been shown to deplete some Tregs in primates, its effects on NK cells (CD16+CD8+NKG2A+CD3−), which constitutively express the intermediate affinity IL-2R (β-γ dimers) and play a critical role in anti-tumor immunity, are still unknown. To address this question, cynomolgus monkeys were injected intravenously with two different doses of DD (8 or 18 μg/Kg). This treatment resulted in a rapid but short-term reduction in detectable peripheral blood resting Tregs (R-Tregs: CD4+CD45RA+Foxp3+) and a transient increase in the number of activated Tregs (A-Tregs: CD4+CD45RA−Foxp3high) followed by their partial depletion (50–60%). On the other hand, all NK cells were deleted immediately and durably after DD administration. This difference was not due to a higher binding or internalization of DD by NK cells as compared to Tregs. Co-administration of DD with IL-15, which binds to IL-2Rβ-γ, abrogated DD-induced NK cell deletion in vitro and in vivo while it did not affect Tregs elimination. Taken together, these results show that DD exerts a potent cytotoxic effect on NK cells, a phenomenon which might impair its anti-tumoral properties. However, co-administration of IL-15 with DD could alleviate this problem by selectively protecting potentially oncolytic NK cells while allowing the depletion of immunosuppressive regulatory T cells in cancer patients. PMID:22586034

  15. Facteurs associés à la tuberculose chez l'enfant au Centre Hospitalier Universitaire Mère-Enfant de Tsaralalàna, Antananarivo: une étude cas-témoins

    PubMed Central

    Randriatsarafara, Fidiniaina Mamy; Vololonarivelo, Barbara Elyan Edwige; Rabemananjara, Nambinina Nirina Gaby; Randrianasolo, Jean Baptiste Olivier; Rakotomanga, Jean de Dieu Marie; Randrianarimanana, Vahiniarison Dieudonné

    2014-01-01

    Introduction A Madagascar, la tuberculose reste un problème de santé publique majeur, l'incidence s’élevant à 16% depuis 2009. Le présent travail a pour objet d'identifier les facteurs de risque de tuberculose chez l'enfant. Méthodes Nous avons mené une étude rétrospective de type cas-témoins sur les facteurs de risque de la tuberculose chez les enfants de 0 à 15 ans au Centre Hospitalier Universitaire Mère-Enfant de Tsaralalàna, de Janvier 2009 à Décembre 2011. Les enfants diagnostiqués de tuberculose dont le diagnostic a été retenu par des éléments de certitude ou par le score pédiatrique de la tuberculose représentent les cas. Les enfants hospitalisés durant la même période, non tuberculeux et de même âge, sont classés témoins. L'Odds Ratio quantifie les associations. Résultats Au total, 91 cas et 173 témoins ont été inclus. Parmi les cas, 73,62% présentent une malnutrition. De fortes associations sont démontrées avec: la malnutrition sévère (OR=6 (IC95% 2,43-15,61 (p<10-5))); le contage tuberculeux (OR=4,71 (IC95% 1,76-12,7 (p=0,003))); la non vaccination par le BCG (OR=4,21 (IC95% 1,99-8,99 (p < 2.10-5))); le niveau intellectuel maternel bas (OR=4,17 (IC95% 0,67-28,14 (p=0,06))); la taille de la fratrie à partir de 5 (OR=4,5). Des associations faibles sont retrouvées pour les autres facteurs étudiés. Les cas présentent une létalité de 18,7% contre 6,3% chez les témoins (p<10-5); 64,7 % des décès sont dus aux formes méningées. Conclusion La tuberculose reste un fléau chez les enfants, avec une lourde responsabilité de la pauvreté rassemblant presque tous les facteurs sus-cités. PMID:25838852

  16. Etude de la flore bactérienne contaminant les téléphones mobiles avant et après la désinfection: comparaison entre les professionnels soignants de l'hôpital militaire d'instruction Mohammed V de Rabat et les témoins

    PubMed Central

    Uwingabiye, Jean; Moustanfii, Wafaa; Chadli, Meryem; Sekhsokh, Yassine

    2015-01-01

    Introduction L'objectif de notre travail était évaluer la contamination microbienne des téléphones mobiles utilisés par les personnels soignants des différents services de l'hôpital militaire d'instructions Mohammed V de Rabat et la comparer à celui d'une population témoin et aussi démontrer l'efficacité des solutions hydroalcoolique dans la désinfection de ces téléphones mobiles. Méthodes Il s'agit d'une étude descriptive transversale réalisée sur une période de 9 mois entre septembre 2010 et juin 2011, dans le service de bactériologie de l'hôpital militaire d'Instruction Mohammed V. Résultats L’étude bactériologique a été faite sur 240 téléphones mobiles dont 50% provenaient de personnels de sante. Le taux de contamination bactérienne de tous les téléphones mobiles était de 100%. Les cultures des bactéries isolées au niveau des téléphones mobiles du personnel médical étaient plus polymorphes que celles de la population témoin (p=0,028). Parmi 437 bactéries isolées: 223(51%) provenaient de téléphones de personnels de santé et 214(49%) de téléphones de la population témoin avec une différence qui n’était pas statistiquement significative(p>0,05) sauf pour les isolats de Staphylocoque à coagulase négative et Staphylococcus aureus. Les bactéries isolées étaient représentées par: Staphylocoque à coagulase (57,7%), Staphylococcus aureus (18,1%), Corynebacterium sp (18,8%), Bacillus sp (2,3%) et autres (2,2%). La différence entre la prévalence des bactéries isolées selon les services et les fonctions des personnels de santé n’était pas statistiquement significative (p>0,05). La désinfection des téléphones portables par la solution hydroalcoolique a réduit à 99,5% le nombre des colonies. Conclusion Ce travail montre que les téléphones portables pourraient jouer un rôle dans la transmission des infections nosocomiales et communautaires. Dans le cadre de prévention de ces risques, il faut

  17. Distribution of polymorphisms IL4-590 C/T and IL4 RP2 in the human populations of Madeira, Azores, Portugal, Cape Verde and Guinea-Bissau.

    PubMed

    Berenguer, Anabela G; Câmara, Rita A; Brehm, António D; Oliveira, Susana; Fernandes, Ana T

    2012-01-01

    The IL4 gene is located on chromosome 5q23.3-31.2. Polymorphisms within this cytokine gene, like the derivative allele T of IL4-590, have been reported as being associated to elevated IgE serum levels and asthma. In the present work, the allelic and genotypic frequency of the IL4-590 and IL4 RP2 polymorphisms was carried out in 599 individuals from Madeira, Azores, Portugal mainland, Cape Verde and Guinea-Bissau and in a sample of 101 asthmatics from Madeira population. In all populations the polymorphisms were in LD and presented a significant dissimilar allelic and genotypic distribution (p<0.05) except between mainland Portugal and Madeira when compared to Azores. Significant differences regarding both loci were found between Madeira population and the group of asthmatics. Genotype 183183TT frequency is higher for African populations while 253253CC prevails in Caucasian populations. The existence of a Hardy-Weinberg Disequilibrium in Guinea-Bissau population not observed in neutral markers leads to the hypothesis of natural selection occurring in these loci probably associated to a rapid population growth an hypothesis strengthened by neutral STRs D5S818 and CSF1PO gene diversity.

  18. Methodologie de modelisation aerostructurelle d'une aile utilisant un logiciel de calcul aerodynamique et un logiciel de calcul par elements finis =

    NASA Astrophysics Data System (ADS)

    Communier, David

    Lors de l'etude structurelle d'une aile d'avion, il est difficile de modeliser fidelement les forces aerodynamiques subies par l'aile de l'avion. Pour faciliter l'analyse, on repartit la portance maximale theorique de l'aile sur son longeron principal ou sur ses nervures. La repartition utilisee implique que l'aile entiere sera plus resistante que necessaire et donc que la structure ne sera pas totalement optimisee. Pour pallier ce probleme, il faudrait s'assurer d'appliquer une repartition aerodynamique de la portance sur la surface complete de l'aile. On serait donc en mesure d'obtenir une repartition des charges sur l'aile beaucoup plus fiable. Pour le realiser, nous aurons besoin de coupler les resultats d'un logiciel calculant les charges aerodynamiques de l'aile avec les resultats d'un logiciel permettant sa conception et son analyse structurelle. Dans ce projet, le logiciel utilise pour calculer les coefficients de pression sur l'aile est XFLR5 et le logiciel permettant la conception et l'analyse structurelle sera CATIA V5. Le logiciel XFLR5 permet une analyse rapide d'une aile en se basant sur l'analyse de ses profils. Ce logiciel calcule les performances des profils de la meme maniere que XFOIL et permet de choisir parmi trois methodes de calcul pour obtenir les performances de l'aile : Lifting Line Theory (LLT), Vortex Lattice Method (VLM) et 3D Panels. Dans notre methodologie, nous utilisons la methode de calcul 3D Panels dont la validite a ete testee en soufflerie pour confirmer les calculs sur XFLR5. En ce qui concerne la conception et l'analyse par des elements finis de la structure, le logiciel CATIA V5 est couramment utilise dans le domaine aerospatial. CATIA V5 permet une automatisation des etapes de conception de l'aile. Ainsi, dans ce memoire, nous allons decrire la methodologie permettant l'etude aerostructurelle d'une aile d'avion.

  19. Enrichment of Inflammatory IL-17 and TNF-α Secreting CD4+ T Cells within Colorectal Tumors despite the Presence of Elevated CD39+ T Regulatory Cells and Increased Expression of the Immune Checkpoint Molecule, PD-1

    PubMed Central

    Dunne, Margaret R.; Ryan, Ciara; Nolan, Bláthnaid; Tosetto, Miriam; Geraghty, Robert; Winter, Des C.; O’Connell, P. Ronan; Hyland, John M.; Doherty, Glen A.; Sheahan, Kieran; Ryan, Elizabeth J.; Fletcher, Jean M.

    2016-01-01

    T cell infiltration into colorectal tumors has been shown to correlate with improved patient outcomes. However, more detailed information on the makeup and relationships between the infiltrating T cell subsets is lacking. We therefore correlated the extent of immune infiltration into colorectal tumors with the frequencies of various T cell subsets. We prospectively recruited 22 patients at the time of surgical resection for colorectal cancer. The Klintrup–Mäkinen (KM) score was used to estimate the extent of immune infiltration into colorectal tumors. The frequencies of CD4 and CD8 T cells that produced cytokines or expressed the inhibitory molecule programed cell death 1 (PD-1) were determined by flow cytometry in colorectal tumor and matched uninvolved colonic tissue. In addition, the frequency of CD4 regulatory T cell (Treg) subsets was determined. An increased frequency of CD4 T cells producing IL-17 (Th17 cells) was observed in colorectal tumor tissue compared with adjacent uninvolved tissue. These Th17 cells mostly coproduced TNF-α, but not IFN-γ. IL-17 expression correlated positively with TNF-α and IL-10. Increased expression of the immune checkpoint molecule PD-1 was found in colorectal tumors compared with adjacent uninvolved tissue. There was a negative correlation between expression of PD-1 and IFN-γ, but not IL-17, for both CD4+ and CD8+ T cells. CD4+CD25+CD127lo and CD4+CD25+CD127loFoxP3+CD39+ Treg cells were enriched in colorectal tumors. A positive correlation between KM score and percentage CD4+CD25+CD127lo Treg cells was observed in tumors, suggesting that increased immune infiltration is associated with an increased proportion of Treg cells. In addition, there was a negative correlation between the frequency of CD4+CD25+CD127lo Treg cells and the expression of IFN-γ and IL-2, but not IL-17, in tumors. Taken together, these data suggest that both PD-1 expressing T cells and Treg cells within the tumor may have a suppressive effect on T

  20. Leptin enhances the secretion of interleukin (IL)-18, but not IL-1β, from human monocytes via activation of caspase-1.

    PubMed

    Jitprasertwong, Paiboon; Jaedicke, Katrin M; Nile, Christopher J; Preshaw, Philip M; Taylor, John J

    2014-02-01

    Circulating levels of leptin are elevated in type-2 diabetes mellitus (T2DM) and leptin plays a role in immune responses. Elevated circulating IL-18 levels are associated with clinical complications of T2DM. IL-18 regulates cytokine secretion and the function of a number of immune cells including T-cells, neutrophils and macrophages and as such has a key role in immunity and inflammation. Pro-inflammatory monocytes exhibiting elevated cytokine secretion are closely associated with inflammation in T2DM, however, little is known about the role of leptin in modifying monocyte IL-18 secretion. We therefore aimed to investigate the effect of leptin on IL-18 secretion by monocytes. We report herein that leptin increases IL-18 secretion in THP-1 and primary human monocytes but has no effect on IL-18mRNA. Leptin and LPS signalling in monocytes occurs by overlapping but distinct pathways. Thus, in contrast to a strong stimulation by LPS, leptin has no effect on IL-1βmRNA levels or IL-1β secretion. In addition, LPS stimulates the secretion of IL-6 but leptin did not whereas both treatments up regulate IL-8 secretion from the same cells. Although leptin (and LPS) has a synergistic effect with exogenous ATP on IL-18 secretion in both THP-1 and primary monocytes, experiments involving ATP assays and pharmacological inhibition of ATP signalling failed to provide any evidence that endogenous ATP secreted by leptin-stimulated monocytes was responsible for enhancement of monocyte IL-18 secretion by leptin. Analysis of the action of caspase-1 revealed that leptin up regulates caspase-1 activity and the effect of leptin on IL-18 release is prevented by caspase-1 inhibitor (Ac-YVAD-cmk). These data suggest that leptin activates IL-18 processing rather than IL-18 transcription. In conclusion, leptin enhances IL-18 secretion via modulation of the caspase-1 inflammasome function and acts synergistically with ATP in this regard. This process may contribute to aberrant immune responses

  1. Dermal γδ T Cells Do Not Freely Re-Circulate Out of Skin and Produce IL-17 to Promote Neutrophil Infiltration during Primary Contact Hypersensitivity

    PubMed Central

    Jiang, Xiaodong; Park, Chang Ook; Geddes Sweeney, Jenna; Yoo, Min Jae; Gaide, Olivier; Kupper, Thomas Seth

    2017-01-01

    The role of mouse dermal γδ T cells in inflammatory skin disorders and host defense has been studied extensively. It is known that dendritic epidermal T cells (DETC) have a monomorphic γδ T cell receptor (TCR) and reside in murine epidermis from birth. We asked if dermal γδ cells freely re-circulated out of skin, or behaved more like dermal resident memory T cells (TRM) in mice. We found that, unlike epidermal γδ T cells (DETC), dermal γδ cells are not homogeneous with regard to TCR, express the tissue resident T cell markers CD69 and CD103, bear skin homing receptors, and produce IL-17 and IL-22. We created GFP+: GFP− parabiotic mice and found that dermal γδ T cells re-circulate very slowly—more rapidly than authentic αβ TCR TRM, but more slowly than the recently described dermal αβ TCR T migratory memory cells (TMM). Mice lacking the TCR δ gene (δ-/-) had a significant reduction of 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). We created mice deficient in dermal γδ T cells but not DETC, and these mice also showed a markedly reduced CHS response after DNFB challenge. The infiltration of effector T cells during CHS was not reduced in dermal γδ T cell-deficient mice; however, infiltration of Gr-1+CD11b+ neutrophils, as well as ear swelling, was reduced significantly. We next depleted Gr-1+ neutrophils in vivo, and demonstrated that neutrophils are required for ear swelling, the accepted metric for a CHS response. Depletion of IL-17-producing dermal Vγ4+ cells and neutralization of IL-17 in vivo, respectively, also led to a significantly reduced CHS response and diminished neutrophil infiltration. Our findings here suggest that dermal γδ T cells have an intermediate phenotype of T cell residence, and play an important role in primary CHS through producing IL-17 to promote neutrophil infiltration. PMID:28081153

  2. A Th2-like cytokine response is involved in bullous pemphigoid. the role of IL-4 and IL-5 in the pathogenesis of the disease.

    PubMed

    Feliciani, C; Toto, P; Mohammad Pour, S; Coscione, G; Amerio, P; Amerio, P

    1999-01-01

    Bullous Pemphigoid is an autoimmune bullous disorder characterized by production of IgG against an hemidesmosomal antigen (230 kDa, 180 kDa) responsible for blistering of the skin. In the past several mediators have been implicated in the pathogenesis of the disease such as proteases and collagenases secreted by local inflammatory cells. In order to investigate the role of cytokines in BP, the cytokine pattern was evaluated by an immunohistochemical analysis and by reverse transcriptase polymerase chain reaction procedure in 13 BP patients. Cytokines examined were interleukin (IL)-2, IL-4, IL-5, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. The T cell inflammatory infiltrate was also characterized by monoclonal antibodies showing CD3+, CD4+ T cells with a perivascular and scattered distribution in lesional skin. IL-4 and IL-5 were detected in a similar distribution to the inflammatory infiltrate. IL-4 and IL-5 mRNA levels were also revealed by RT-PCR. Proinflammatory cytokines such as TNF-alpha, IL-6 and Th1-like cytokines (IL-2 and INF-gamma) were not detected neither as proteins nor as mRNA. Since IL-4 and IL-5 are important in eosinophil chemoattraction, maturation and functional activity, the presence of IL-4 and IL-5 in BP suggest that these cytokines could be important in the pathogenesis of the disease.

  3. Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals.

    PubMed

    Tao, Le; Qiu, Jianxin; Jiang, Ming; Song, Wenbin; Yeh, Shuyuan; Yu, Hong; Zang, Lijuan; Xia, Shujie; Chang, Chawnshang

    2016-08-01

    The tumor microenvironment impacts tumor progression and individual cells, including CD4(+) T cells, which have been detected in bladder cancer tissues. The detailed mechanism of how these T cells were recruited to the bladder cancer tumor and their impact on bladder cancer progression, however, remains unclear. Using a human clinical bladder cancer sample survey and in vitro coculture system, we found that bladder cancer has a greater capacity to recruit T cells than surrounding normal bladder tissues. The consequences of higher levels of recruited T cells in bladder cancer included increased bladder cancer metastasis. Mechanism dissection revealed that infiltrating T cells might function through secreting the cytokine IL1, which increases the recruitment of T cells to bladder cancer and enhances the bladder cancer androgen receptor (AR) signaling that results in increased bladder cancer cell invasion via upregulation of hypoxia-inducible factor-1α (HIF1α)/VEGFa expression. Interruption of the IL1→AR→HIF1α→VEGFa signals with inhibitors of HIF1α or VEGFa partially reversed the enhanced bladder cancer cell invasion. Finally, in vivo mouse models of xenografted bladder cancer T24 cells with CD4(+) T cells confirmed in vitro coculture studies and concluded that infiltrating CD4(+) T cells can promote bladder cancer metastasis via modulation of the IL1→AR→HIF1α→VEGFa signaling. Future clinical trials using small molecules to target this newly identified signaling pathway may facilitate the development of new therapeutic approaches to better suppress bladder cancer metastasis. Mol Cancer Ther; 15(8); 1943-51. ©2016 AACR. ©2016 American Association for Cancer Research.

  4. Measurement of Compression Factor and Error Sensitivity Factor of Five Selected Two-Dimensional Facsimile Coding Techniques

    DTIC Science & Technology

    1979-09-01

    et do $a mise en oeuvre done tie r~glon-pilote. La g~n~ralisation ultdrieure do lapplication realis~t dane cette region-pilote depend des reaultats...informiation*, une v~sritable " Banque tie donn(’es", ropartle stir des nioyens detraitoment nationaux et roglonaux, et qui devra rester alinientoe, mime A jour...tiouveaux 4 inettre en place pour aborder la roalisation du aysttme informatif. L’obligation tie fait e appel il des ordinateut’s tie troisi~me gcon

  5. In vivo Expansion of Naïve CD4+CD25high FOXP3+ Regulatory T Cells in Patients with Colorectal Carcinoma after IL-2 Administration

    PubMed Central

    Beyer, Marc; Schumak, Beatrix; Weihrauch, Martin R.; Andres, Bettina; Giese, Thomas; Endl, Elmar; Knolle, Percy A.; Classen, Sabine; Limmer, Andreas; Schultze, Joachim L.

    2012-01-01

    Regulatory T cells (Treg cells) are increased in context of malignancies and their expansion can be correlated with higher disease burden and decreased survival. Initially, interleukin 2 (IL-2) has been used as T-cell growth factor in clinical vaccination trials. In murine models, however, a role of IL-2 in development, differentiation, homeostasis, and function of Treg cells was established. In IL-2 treated cancer patients a further Treg-cell expansion was described, yet, the mechanism of expansion is still elusive. Here we report that functional Treg cells of a naïve phenotype - as determined by CCR7 and CD45RA expression - are significantly expanded in colorectal cancer patients. Treatment of 15 UICC stage IV colorectal cancer patients with IL-2 in a phase I/II peptide vaccination trial further enlarges the already increased naïve Treg-cell pool. Higher frequencies of T-cell receptor excision circles in naïve Treg cells indicate IL-2 dependent thymic generation of naïve Treg cells as a mechanism leading to increased frequencies of Treg cells post IL-2 treatment in cancer patients. This finding could be confirmed in naïve murine Treg cells after IL-2 administration. These results point to a more complex regulation of Treg cells in context of IL-2 administration. Future strategies therefore might aim at combining IL-2 therapy with novel strategies to circumvent expansion and differentiation of naïve Treg cells. PMID:22276195

  6. Maturation of monocyte derived dendritic cells with OK432 boosts IL-12p70 secretion and conveys strong T-cell responses

    PubMed Central

    2011-01-01

    Background Design of tumour specific immunotherapies using the patients' own dendritic cells (DC) is a fast advancing scientific field. The functional qualities of the DC generated in vitro are critical, and today's gold standard for maturation is a cytokine cocktail consisting of IL-1β, IL-6, TNF-α and PGE2 generating cells lacking IL-12p70 production. OK432 is an immunotherapeutic agent derived from killed Streptococcus pyogenes that has been used clinically to treat malignant and benign neoplasms for decades. Methods In this study, we analysed the effects of OK432 on DC maturation, DC migration, cytokine and chemokine secretion as well as T-cell stimulatory capacity, and compared it to the cytokine cocktail alone and combinations of OK432 with the cytokine cocktail. Results OK432 induced a marked up-regulation of CD40 on the cell surface as well as a strong inflammatory response from the DC with significantly more secretion of 19 different cytokines and chemokines compared to the cytokine cocktail. Interestingly, secretion of IL-15 and IL-12p70 was detected at high concentrations after maturation of DC with OK432. However, the OK432 treated DC did not migrate as well as DC treated with cytokine cocktail in a transwell migration assay. During allogeneic T-cell stimulation OK432 treated DC induced proliferation of over 50 percent of CD4 and 30 percent of CD8 T-cells for more than two cell divisions, whereas cytokine cocktail treated DC induced proliferation of 12 and 11 percent of CD4 and CD8 T-cells, respectively. Conclusions The clinically approved compound OK432 has interesting properties that warrants its use in DC immunotherapy and should be considered as a potential immunomodulating agent in cancer immunotherapy. PMID:21208424

  7. IFN-gamma Impairs Release of IL-8 by IL-1beta-stimulated A549 Lung Carcinoma Cells

    PubMed Central

    Boost, Kim A; Sadik, Christian D; Bachmann, Malte; Zwissler, Bernhard; Pfeilschifter, Josef; Mühl, Heiko

    2008-01-01

    Background Production of interferon (IFN)-γ is key to efficient anti-tumor immunity. The present study was set out to investigate effects of IFNγ on the release of the potent pro-angiogenic mediator IL-8 by human A549 lung carcinoma cells. Methods A549 cells were cultured and stimulated with interleukin (IL)-1β alone or in combination with IFNγ. IL-8 production by these cells was analyzed with enzyme linked immuno sorbent assay (ELISA). mRNA-expression was analyzed by real-time PCR and RNase protection assay (RPA), respectively. Expression of inhibitor-κ Bα, cellular IL-8, and cyclooxygenase-2 was analyzed by Western blot analysis. Results Here we demonstrate that IFNγ efficiently reduced IL-8 secretion under the influence of IL-1β. Surprisingly, real-time PCR analysis and RPA revealed that the inhibitory effect of IFNγ on IL-8 was not associated with significant changes in mRNA levels. These observations concurred with lack of a modulatory activity of IFNγ on IL-1β-induced NF-κB activation as assessed by cellular IκB levels. Moreover, analysis of intracellular IL-8 suggests that IFNγ modulated IL-8 secretion by action on the posttranslational level. In contrast to IL-8, IL-1β-induced cyclooxygenase-2 expression and release of IL-6 were not affected by IFNγ indicating that modulation of IL-1β action by this cytokine displays specificity. Conclusion Data presented herein agree with an angiostatic role of IFNγ as seen in rodent models of solid tumors and suggest that increasing T helper type 1 (Th1)-like functions in lung cancer patients e.g. by local delivery of IFNγ may mediate therapeutic benefit via mechanisms that potentially include modulation of pro-angiogenic IL-8. PMID:18801189

  8. Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15.

    PubMed

    Litjens, Nicolle H R; Boer, Karin; Zuijderwijk, Joke M; Klepper, Mariska; Peeters, Annemiek M A; Prens, Errol P; Verschoor, Wenda; Kraaijeveld, Rens; Ozgur, Zeliha; van den Hout-van Vroonhoven, Mirjam C; van IJcken, Wilfred F J; Baan, Carla C; Betjes, Michiel G H

    2015-06-01

    Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4(+)CD25(bright)CD127(-) T cells) was alloantigen-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR- and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-γ, and TNF-α, but few IL-17-producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function. Copyright © 2015 by The American Association of Immunologists, Inc.

  9. High Incidence of Malaria Along the Sino-Burmese Border Is Associated With Polymorphisms of CR1, IL-1A, IL-4R, IL-4, NOS, and TNF, But Not With G6PD Deficiency.

    PubMed

    Ren, Na; Kuang, Ying-Min; Tang, Qiong-Lin; Cheng, Long; Zhang, Chun-Hua; Yang, Zao-Qing; He, Yong-Shu; Zhu, Yue-Chun

    2015-10-01

    Malaria is highly endemic in Yunnan Province, China, with the incidence of malaria being highest along the Sino-Burmese border. The aim of our study was to determine whether genetic polymorphisms are associated with the prevalence of malaria among Chinese residents of the Sino-Burmese border region. Fourteen otherwise healthy people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, 50 malaria patients, and 67 healthy control subjects were included in our cross-sectional study. We analyzed the frequency of the G3093T and T520C single-nucleotide polymorphisms (SNPs) of CR1. Logistic regression was used to calculate the prevalence odds ratio (POR) and 95% confidence interval (CI) of malaria for the T520C SNP of CR1 and SNPs of G6PD, IL-4, IL-4R, IL-1A, NOS, CD40LG, TNF, and LUC7L. The frequency of the 3093T/3093T genotype of CR1 in the malaria group (0.16) was significantly higher than that in the control group (0.045, P < 0.05), and significantly lower than that in the G6PD deficiency group (0.43, P < 0.01). The frequency of the 520T/520T genotype of CR1 was significantly higher in the malaria patients (0.78) than that in the control group (0.67, P < 0.05) and G6PD-deficiency group (0.36, P < 0.05). The T allele of the T520C variant of CR1 was significantly associated with the prevalence of malaria (POR: 1.460; 95% CI: 0.703-3.034). Polymorphisms of G6PD did not significantly influence the prevalence malaria (P > 0.05). A GTGTGTC haplotype consisting of IL-1A (rs17561), IL-4 (rs2243250), TNF (rs1800750), IL-4R (rs1805015), NOS (rs8078340), CD40LG (rs1126535), and LUC7L (rs1211375) was significantly associated with the prevalence of malaria (POR: 1.822, 95% CI: 0.998-3.324). The 3093G/3093G and 520T/520T genotypes are the predominant genetic variants of CR1 among Chinese residents near the Sino-Burmese border, and the T allele of T520C is associated with the prevalence of malaria in this region. Although G6PD deficiency does not protect against malaria, it may

  10. Diagnostic tardif d'une hyperoxalurie primitive au stade d'insuffisance rénale chronique terminale avec hypoparathyroïdie sévère

    PubMed Central

    El Ghali, Zineb; Lahcen, Zineb Ait; Fadili, Wafaa; Kaitouni, Abderrahim Idrissi; Hakkou, Mohamed; Hamdaoui, Abderrachid; Laouad, Inass

    2014-01-01

    L'hyperoxalurie primitive est une anomalie métabolique congénitale rare caractérisée par un excès de production avec accumulation d'oxalate secondaire à un déficit enzymatique hépatique. Nous rapportons le cas d'un patient de 18 ans qui avait comme antécédent des lithiases rénales récidivantes depuis l'enfance évoluant vers l'insuffisance rénale chronique terminale, mis en hémodialyse périodique depuis 4 ans avec apparition d'une anémie résistante à l’érythropoïétine pour laquelle il a été multitransfusé et qui était admis pour prise en charge de douleurs osseuses invalidantes d'aggravation progressive associées à un syndrome tumoral fait d'adénopathies périphériques et de splénomégalie avec dyspnée et altération de l’état général. Le bilan réalisé avait objectivé de multiples images lytiques lacunaires et condensantes au niveau des poignets et des mains avec des petits reins calcifiés, une pleurésie avec péricardite de grande abondance drainée, une ascite de moyenne abondance avec splénomégalie homogène, une anémie normochrome normocytaire à 7.2 g/dl avec hyperferritinémie à 1129 μg/l et un syndrome inflammatoire biologique. La calcémie était spontanément normale à 97 mg/l avec hyperphosphorémie à 83 mg/l et hypoparathyroïdie à 74,85 pg/ml. Les PAL étaient à 136 UI/l, l'aluminium sérique à 13μg/l et la Vitamine D native à 20,87ng/ml. Le diagnostic d'hyperoxalurie a été retenu sur les données de la biopsie ostéomédullaire objectivant des dépôts de cristaux d'oxalate de calcium avec fibrose médullaire et réaction macrophagique à corps étranger. L’évolution a été marquée par la survenue de fractures spontanées récidivantes au niveau de l’épaule et des 2 hanches. PMID:25328593

  11. Microsomal Prostaglandin E Synthase-1 Facilitates an Intercellular Interaction between CD4⁺ T Cells through IL-1β Autocrine Function in Experimental Autoimmune Encephalomyelitis.

    PubMed

    Takemiya, Takako; Takeuchi, Chisen; Kawakami, Marumi

    2017-12-19

    Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme that produces prostaglandin E₂ (PGE₂). In our previous study, we investigated the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, using mPGES - 1 -deficient ( mPGES-1 -/- ) and wild-type (wt) mice. We found that mPGES-1 facilitated inflammation, demyelination, and paralysis and was induced in vascular endothelial cells and macrophages and microglia around inflammatory foci. Here, we investigated the role of interleukin-1β (IL-1β) in the intercellular mechanism stimulated by mPGES-1 in EAE spinal cords in the presence of inflammation. We found that the area invaded by CD4-positive (CD4⁺) T cells was extensive, and that PGE₂ receptors EP1-4 were more induced in activated CD4⁺ T cells of wt mice than in those of mPGES - 1 -/- mice. Moreover, IL-1β and IL-1 receptor 1 (IL-1r1) were produced by 65% and 48% of CD4⁺ T cells in wt mice and by 44% and 27% of CD4⁺ T cells in mPGES-1 -/- mice. Furthermore, interleukin-17 (IL-17) was released from the activated CD4⁺ T cells. Therefore, mPGES-1 stimulates an intercellular interaction between CD4⁺ T cells by upregulating the autocrine function of IL-1β in activated CD4⁺ T cells, which release IL-17 to facilitate axonal and myelin damage in EAE mice.

  12. IL-2 immunotherapy in chronically SIV-infected Rhesus Macaques

    PubMed Central

    2012-01-01

    Background Despite inducing a sustained increase in CD4+ T cell counts, intermittent recombinant IL-2 (rIL-2) therapy did not confer a better clinical outcome in HIV-infected patients enrolled in large phase III clinical trials ESPRIT and SILCAAT. Several hypotheses were evoked to explain these discrepancies. Here, we investigated the impact of low and high doses of IL-2 in Rhesus macaques of Chinese origin infected with SIVmac251 in the absence of antiretroviral therapy (ART). Results We demonstrated that rIL-2 induced a dose dependent expansion of CD4+ and CD8+ T cells without affecting viral load. rIL-2 increased CD4 and CD8 Treg cells as defined by the expression of CD25highFoxP3+CD127low. We also showed that rIL-2 modulated spontaneous and Fas-mediated CD4+ and CD8+ T cell apoptosis. The higher dose exhibited a dramatic pro-apoptotic effect on both CD4+ and CD8+ T cell populations. Finally, all the animals treated with rIL-2 developed a wasting syndrome in the month following treatment simultaneously to a dramatic decrease of circulating effector T cells. Conclusion These data contribute to the understanding of the homeostatic and dosage effects of IL-2 in the context of SIV/HIV infection. PMID:23021024

  13. Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy

    PubMed Central

    Shi, Lewis Zhichang; Fu, Tihui; Guan, Baoxiang; Chen, Jianfeng; Blando, Jorge M.; Allison, James P.; Xiong, Liangwen; Subudhi, Sumit K.; Gao, Jianjun; Sharma, Padmanee

    2016-01-01

    Combination therapy with α-CTLA-4 and α-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-γ signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Rα expression on tumour-infiltrating T cells in an IFN-γ/IFN-γR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN-γ/IFN-γR and IL-7/IL-7R pathways. PMID:27498556

  14. Etude microdosimetrique de l'influence des materiaux sur l'efficacite biologique d'une source d'iode-125

    NASA Astrophysics Data System (ADS)

    Taschereau, Richard

    Cette these concerne les implants permanents pour la prostate. Les isotopes employes, le 103Pd et l'125I, semblent produire les memes resultats cliniques: le premier a cause d'une radiation plus efficace et le second a cause de sa demi-vie plus longue. La recherche utilise le cadre theorique de la microdosimetrie et des simulations Monte Carlo. Elle propose d'employer le spectre d'ejection dans le calcul de l'efficacite; ce changement fait passer l'efficacite relative du 103Pd de 10% a 5%. Elle montre ensuite qu'il est possible d'ameliorer l'efficacite de la radiation de 125I par l'exploitation des rayons X caracteristiques de la capsule. Une source amelioree faite de molybdene et d'yttrium est donnee en exemple. Elle procure une radiation de 5--7% plus efficace, ce qui surclasse les deux sources existantes. Les applications ne se limitent pas au traitement de la prostate; le traitement du melanome oculaire et la curietherapie endovasculaire pourraient en beneficier.

  15. Humanized Mouse Model of Skin Inflammation Is Characterized by Disturbed Keratinocyte Differentiation and Influx of IL-17A Producing T Cells

    PubMed Central

    de Oliveira, Vivian L.; Keijsers, Romy R. M. C.; van de Kerkhof, Peter C. M.; Seyger, Marieke M. B.; Fasse, Esther; Svensson, Lars; Latta, Markus; Norsgaard, Hanne; Labuda, Tord; Hupkens, Pieter; van Erp, Piet E. J.; Joosten, Irma; Koenen, Hans J. P. M.

    2012-01-01

    Humanized mouse models offer a challenging possibility to study human cell function in vivo. In the huPBL-SCID-huSkin allograft model human skin is transplanted onto immunodeficient mice and allowed to heal. Thereafter allogeneic human peripheral blood mononuclear cells are infused intra peritoneally to induce T cell mediated inflammation and microvessel destruction of the human skin. This model has great potential for in vivo study of human immune cells in (skin) inflammatory processes and for preclinical screening of systemically administered immunomodulating agents. Here we studied the inflammatory skin response of human keratinocytes and human T cells and the concomitant systemic human T cell response. As new findings in the inflamed human skin of the huPBL-SCID-huSkin model we here identified: 1. Parameters of dermal pathology that enable precise quantification of the local skin inflammatory response exemplified by acanthosis, increased expression of human β-defensin-2, Elafin, K16, Ki67 and reduced expression of K10 by microscopy and immunohistochemistry. 2. Induction of human cytokines and chemokines using quantitative real-time PCR. 3. Influx of inflammation associated IL-17A-producing human CD4+ and CD8+ T cells as well as immunoregulatory CD4+Foxp3+ cells using immunohistochemistry and -fluorescence, suggesting that active immune regulation is taking place locally in the inflamed skin. 4. Systemic responses that revealed activated and proliferating human CD4+ and CD8+ T cells that acquired homing marker expression of CD62L and CLA. Finally, we demonstrated the value of the newly identified parameters by showing significant changes upon systemic treatment with the T cell inhibitory agents cyclosporine-A and rapamycin. In summary, here we equipped the huPBL-SCID-huSkin humanized mouse model with relevant tools not only to quantify the inflammatory dermal response, but also to monitor the peripheral immune status. This combined approach will gain our

  16. Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.

    PubMed

    Bloch, Yehudi; Bouchareychas, Laura; Merceron, Romain; Składanowska, Katarzyna; Van den Bossche, Lien; Detry, Sammy; Govindarajan, Srinath; Elewaut, Dirk; Haerynck, Filomeen; Dullaers, Melissa; Adamopoulos, Iannis E; Savvides, Savvas N

    2018-01-16

    Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Antitumor effect of interleukin (IL)-12 in the absence of endogenous IFN-gamma: a role for intrinsic tumor immunogenicity and IL-15.

    PubMed

    Gri, Giorgia; Chiodoni, Claudia; Gallo, Elena; Stoppacciaro, Antonella; Liew, Foo Y; Colombo, Mario P

    2002-08-01

    IFN-gamma knockout mice (GKO) rejected C26 colon carcinoma cells transduced to secrete interleukin(IL)-12 but do not reject similarly transduced TSA mammary adenocarcinoma (C26/12 and TSA/12 cells, respectively). To determine whether such difference could be because of a different tumor response to IFN-gamma, we injected BALB/c mice with TSA, C26, and their IL-12-transduced counterparts rendered unresponsive to IFN-gamma by stable transduction of a dominant negative (DN), truncated IFN-gamma receptor alpha chain. TSA/DN and C26/DN showed the same in vivo growth kinetics as parental cells, whereas coexpression of IL-12 induced rejection independent of tumor-cell responsiveness to IFN-gamma. This suggests that the role of IFN-gamma is primarily in activating the host immune response, which appears to depend on the intrinsic immunogenicity of the target tumor. C26 and TSA share a common tumor-associated antigen, yet C26 cells are more immunogenic than TSA. C26/12 expressed 10-fold higher levels of class I MHC molecules and induced higher CTL activity compared with TSA/12 cells in GKO mice. Moreover, whereas in GKO mice the TSA/12 tumor was associated with a greater number of infiltrating T cells, only those infiltrating C26/12 tumor expressed the activation marker OX40. The search for cytokine(s) that might contribute in determining the different T-cell response to these IL-12-transduced tumors in GKO mice revealed a role of IL-15. In situ hybridization showed IL-15 expression in C26/12 but not in TSA/12 tumors. In addition, injection of GKO mice with soluble IL-15 receptor-alpha to block IL-15 expression prevented rejection of C26/12 cells. Together, the results suggest that in the absence of IFN-gamma, IL-12 can exert antitumor activity through alternative mechanisms, depending on the tumor cell type and the availability of cytokines that can replace IFN-gamma in sustaining T-cell functions.

  18. IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection.

    PubMed

    Booty, Matthew G; Barreira-Silva, Palmira; Carpenter, Stephen M; Nunes-Alves, Cláudio; Jacques, Miye K; Stowell, Britni L; Jayaraman, Pushpa; Beamer, Gillian; Behar, Samuel M

    2016-11-07

    IL-21 is produced predominantly by activated CD4 + T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (γ c ) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8 + T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4 + and CD8 + T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility of IL-21R -/- mice, which have increased lung bacterial burden and earlier mortality compared to WT mice. Finally, to causally link the immune defects with host susceptibility, we use an adoptive transfer model to show that IL-21R -/- T cells transfer less protection than WT T cells. These results prove that IL-21 signaling has an intrinsic role in promoting the protective capacity of T cells. Thus, the net effect of IL-21 signaling is to enhance host resistance to M. tuberculosis. These data position IL-21 as a candidate biomarker of resistance to tuberculosis.

  19. IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection

    PubMed Central

    Booty, Matthew G.; Barreira-Silva, Palmira; Carpenter, Stephen M.; Nunes-Alves, Cláudio; Jacques, Miye K.; Stowell, Britni L.; Jayaraman, Pushpa; Beamer, Gillian; Behar, Samuel M.

    2016-01-01

    IL-21 is produced predominantly by activated CD4+ T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (γc) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8+ T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4+ and CD8+ T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility of IL-21R−/− mice, which have increased lung bacterial burden and earlier mortality compared to WT mice. Finally, to causally link the immune defects with host susceptibility, we use an adoptive transfer model to show that IL-21R−/− T cells transfer less protection than WT T cells. These results prove that IL-21 signaling has an intrinsic role in promoting the protective capacity of T cells. Thus, the net effect of IL-21 signaling is to enhance host resistance to M. tuberculosis. These data position IL-21 as a candidate biomarker of resistance to tuberculosis. PMID:27819295

  20. Effects of flurbiprofen axetil on postoperative serum IL-2 and IL-6 levels in patients with colorectal cancer.

    PubMed

    Jiang, W W; Wang, Q H; Peng, P; Liao, Y J; Duan, H X; Xu, M; Li, Y; Zhang, P B

    2015-12-09

    We explored the effects of flurbiprofen axetil on interleukin (IL)-2 and IL-6 levels in postoperative patients with colorectal cancer. A total of 120 patients (American Society of Anesthesiologists I and II) scheduled to undergo colorectal cancer surgery were randomly divided into 3 groups (N = 40 in each group): flurbiprofen axetil group (group F), morphine group (group M), and tramadol group (group T). Group M received 0.1 mg/kg morphine, group T received 1.5 mg/kg tramadol, and group F received 1.5 mg/kg flurbiprofen axetil. Patients in the 3 groups were administered treatments through intravenous injection 10 min before surgery. Serum IL-2 and IL-6 levels were detected. Postoperative adverse reactions were recorded, such as nausea, vomiting, and pruritus. The serum IL-6 level of the 3 groups increased 3 h after surgery. Compared with group M, IL-6 level was higher in group T and group F at 1 day after the surgery, and the differences between group M and the other groups were significant (P < 0.05). Moreover, the incidence of adverse reactions was significantly different among 3 groups (P < 0.05). Flurbiprofen axetil promoted the secretion of IL-2 and inhibited IL-6; additionally, flurbiprofen axetil may have a lower incidence of adverse reactions compared to other treatments.

  1. [The study on the changes of serum IL- 6, TNF-α and peripheral blood T lymphocyte subsets in the pregnant women during perinatal period].

    PubMed

    Li, Juan

    2011-03-01

    To study the change law of serum IL-6, TNF-α and peripheral blood T lymphocyte subsets in the pregnant women during perinatal period. 100 pregnant women in our hospital from November 2009 to October 2010 were selected as research object, and the serum IL-6, TNF-α and peripheral blood T lymphocyte subsets be-fore and at labor onset occurring, after delivery at the first and third day were analyzed and compared. According the study, the serum IL-6 and TNF-aat labor onset occurring were higher than those before labor onset and af-ter delivery at the first and third day , the CD3(+), CD4 (+), CD8(+) and CD4/CD8 decreased first and then increased, all P < 0. 05, there were significant differences. The changes of serum IL-6, TNF-α and peripheral blood T lymphocyte subsets in the pregnant women during perinatal period has a regular pattern, and it is worthy of.

  2. La Station Laser ultra mobile: de l'Obtention d'une Exactitude centimétrique des Mesures à des Applications en Océanographie et Géodésie Spatiales

    NASA Astrophysics Data System (ADS)

    Nicolas, Joëlle

    2000-12-01

    La Station Laser Ultra Mobile est la plus petite station de télémétrie laser au monde, ne pesant que 300 kg, dédiée à la poursuite de satellites équipés de rétroréflecteurs laser. Elle utilise un petit télescope de 13 cm de diamètre placé sur une monture issue d'un théodolite de précision et motorisé, un laser très compact et une photodiode à avalanche permettant la détection au niveau du simple photo-électron. Les premières expériences (Corse, fin 1996) ont révélé de nombreuses instabilités dans la qualité des mesures. Ce travail concerne l'étude et la mise en place de nombreuses modifications techniques afin d'atteindre une exactitude centimétrique des mesures et de pouvoir participer à la campagne de validation des orbites et d'étalonnage de l'altimètre du satellite océanographique JASON-1 (2001). La précision instrumentale souhaitée a été vérifiée avec succès en laboratoire. Outre cet aspect instrumental et métrologique, une analyse a été développée afin de pouvoir estimer l'exactitude et la stabilité des observations de la station mobile après intégration des modifications. A partir d'une expérience de co-localisation entre les deux stations laser fixe du plateau de Calern, l'analyse est basée sur l'ajustement, par station, de coordonnées et d'un biais instrumental moyen à partir d'une orbite de référence des satellites LAGEOS. Des variations saisonnières ont été mises en évidence dans les séries temporelles des différentes composantes. La comparaison locale des déformations de la croûte terrestre se traduisant par des variations d'altitude issues des données laser a montré une cohérence remarquable avec les mesures du gravimètre absolu transportable FG5. Des signaux de même amplitude ont aussi été observés par GPS. Ces variations sont également mises en évidence à l'échelle mondiale et leur interprétation géophysique est faite (combinaison des effets de marées terrestres et polaire

  3. Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells

    PubMed Central

    Saito, Masako; Nagasawa, Masayuki; Takada, Hidetoshi; Hara, Toshiro; Tsuchiya, Shigeru; Agematsu, Kazunaga; Yamada, Masafumi; Kawamura, Nobuaki; Ariga, Tadashi; Tsuge, Ikuya; Nonoyama, Shigeaki; Karasuyama, Hajime

    2011-01-01

    Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17–producing CD4+ T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (Treg cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of Treg cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10–treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4+ T cells to FOXP3+ induced Treg cells (iTreg cells). These results suggest that the defective generation of IL-10–induced tolerogenic DCs and iTreg cells may contribute to inflammatory changes in HIES. PMID:21300911

  4. Distribution of polymorphisms IL4-590 C/T and IL4 RP2 in the human populations of Madeira, Azores, Portugal, Cape Verde and Guinea-Bissau

    PubMed Central

    Berenguer, Anabela G; Câmara, Rita A; Brehm, António D; Oliveira, Susana; Fernandes, Ana T

    2012-01-01

    The IL4 gene is located on chromosome 5q23.3-31.2. Polymorphisms within this cytokine gene, like the derivative allele T of IL4-590, have been reported as being associated to elevated IgE serum levels and asthma. In the present work, the allelic and genotypic frequency of the IL4-590 and IL4 RP2 polymorphisms was carried out in 599 individuals from Madeira, Azores, Portugal mainland, Cape Verde and Guinea-Bissau and in a sample of 101 asthmatics from Madeira population. In all populations the polymorphisms were in LD and presented a significant dissimilar allelic and genotypic distribution (p<0.05) except between mainland Portugal and Madeira when compared to Azores. Significant differences regarding both loci were found between Madeira population and the group of asthmatics. Genotype 183183TT frequency is higher for African populations while 253253CC prevails in Caucasian populations. The existence of a Hardy-Weinberg Disequilibrium in Guinea-Bissau population not observed in neutral markers leads to the hypothesis of natural selection occurring in these loci probably associated to a rapid population growth an hypothesis strengthened by neutral STRs D5S818 and CSF1PO gene diversity. PMID:22724055

  5. Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation.

    PubMed

    Ahn, H J; Tomura, M; Yu, W G; Iwasaki, M; Park, W R; Hamaoka, T; Fujiwara, H

    1998-12-01

    While IL-12 is known to activate JAK2 and TYK2 and induce the phosphorylation of STAT4 and STAT3, little is known regarding how the activation of these signaling molecules is related to the biologic effects of IL-12. Using an IL-12-responsive T cell clone (2D6), we investigated their requirements for proliferation and IFN-gamma production of 2D6 cells. 2D6 cells could be maintained with either IL-12 or IL-2. 2D6 lines maintained with IL-12 (2D6(IL-12)) or IL-2 (2D6(IL-2)) exhibited comparable levels of proliferation, but produced large or only small amounts of IFN-gamma, respectively, when restimulated with IL-12 after starvation of either cytokine. 2D6(IL-12) induced TYK2 and STAT4 phosphorylation. In contrast, their phosphorylation was marginally induced in 2D6(IL-2). The reduced STAT4 phosphorylation was due to a progressive decrease in the amount of STAT4 protein along with the passages in IL-2-containing medium. 2D6(IL-12) and 2D6(IL-2) similarly proliferating in response to IL-12 induced comparable levels of JAK2 activation and STAT5 phosphorylation. JAK2 was associated with STAT5, and IL-12-induced STAT5 phosphorylation was elicited in the absence of JAK3 activation. These results indicate that IL-12 has the capacity to induce/maintain STAT4 and STAT5 proteins, and that TYK2 and JAK2 activation correlate with STAT4 phosphorylation/IFN-gamma induction and STAT5 phosphorylation/cellular proliferation, respectively.

  6. Endogenous IL-1 in Cognitive Function and Anxiety: A Study in IL-1RI−/− Mice

    PubMed Central

    Murray, Carol L.; Obiang, Pauline; Bannerman, David; Cunningham, Colm

    2013-01-01

    Interleukin-1 (IL-1) is a key pro-inflammatory cytokine, produced predominantly by peripheral immune cells but also by glia and some neuronal populations within the brain. Its signalling is mediated via the binding of IL-1α or IL-1β to the interleukin-1 type one receptor (IL-1RI). IL-1 plays a key role in inflammation-induced sickness behaviour, resulting in depressed locomotor activity, decreased exploration, reduced food and water intake and acute cognitive deficits. Conversely, IL-1 has also been suggested to facilitate hippocampal-dependent learning and memory: IL-1RI−/− mice have been reported to show deficits on tasks of visuospatial learning and memory. We sought to investigate whether there is a generalised hippocampal deficit in IL-1RI−/− animals. Therefore, in the current study we compared wildtype (WT) mice to IL-1RI−/− mice using a variety of hippocampal-dependent learning and memory tasks, as well as tests of anxiety and locomotor activity. We found no difference in performance of the IL-1RI−/− mice compared to WT mice in a T-maze working memory task. In addition, the IL-1RI−/− mice showed normal learning in various spatial reference memory tasks including the Y-maze and Morris mater maze, although there was a subtle deficit in choice behaviour in a spatial discrimination, beacon watermaze task. IL-1RI−/− mice also showed normal memory for visuospatial context in the contextual fear conditioning paradigm. In the open field, IL-1RI−/− mice showed a significant increase in distance travelled and rearing behaviour compared to the WT mice and in the elevated plus-maze spent more time in the open arms than did the WT animals. The data suggest that, contrary to prior studies, IL-1RI−/− mice are not robustly impaired on hippocampal-dependent memory and learning but do display open field hyperactivity and decreased anxiety compared to WT mice. The results argue for a careful evaluation of the roles of endogenous IL-1 in

  7. MTOR ACTIVATION TRIGGERS IL-4 PRODUCTION AND NECROTIC DEATH OF DOUBLE-NEGATIVE T CELLS IN PATIENTS WITH SYSTEMIC LUPUS ERYHTHEMATOSUS

    PubMed Central

    Lai, Zhi-Wei; Borsuk, Rebecca; Shadakshari, Ashwini; Yu, Jianghong; Dawood, Maha; Garcia, Ricardo; Francis, Lisa; Tily, Hajra; Bartos, Adam; Faraone, Stephen V.; Phillips, Paul; Perl, Andras

    2013-01-01

    The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T-cell lineage development, however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. Here, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBL relative to SLE disease activity index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p<0.0005); increased mitochondrial mass of CD3+/CD4−/CD8− double-negative (DN) T cells (p=1.1×10−22) and FoxP3 depletion in CD4+/CD25+ T cells were top contributors (p=6.7×10−7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥4) relative to 61 visits of remission (SLEDAI decrease ≥4). mTOR activation in DN T cells was also noted at pre-flare visits of SLE patients relative to those of stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FoxP3 in CD25+/CD4+T cells, and expanded CD25+/CD19+ B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE. PMID:23913957

  8. CD8α+ DC trans-presentation of IL-15 to naïve CD8+ T cells produces antigen inexperienced T cells in the periphery with memory phenotype and function

    PubMed Central

    Sosinowski, Tomasz; White, Jason T.; Cross, Eric; Haluszczak, Catherine; Marrack, Philippa; Gapin, Laurent; Kedl, Ross M.

    2013-01-01

    Various populations of memory phenotype CD8+ T cells have been described over the last 15–20 years, all of which possess elevated effector functions relative to naïve phenotype cells. Using a technique for isolating antigen specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal antigen, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation (HP). We show here that these “Virtual Memory” cells are independent of previously identified “innate memory” cells, arising as a result of their response to IL-15 trans-presentation by lymphoid tissue-resident CD8α+ DCs in the periphery. The absence of IL-15, CD8+ T cell expression of either CD122 or Eomes, or of CD8a+ DCs all lead to the loss of Virtual Memory cells in the host. Our results show that CD8+ T cell homeostatic expansion is an active process within the non-lymphopenic environment, is mediated by IL-15, and produces antigen inexperienced memory cells which retain the capacity to respond to nominal antigen with memory-like function. Preferential engagement of these “Virtual Memory” T cells into a vaccine response could dramatically enhance the rate by which immune protection develops. PMID:23355737

  9. La miliaire hépatique: une présentation échographique rare de la tuberculose hépatique découverte chez un adolescent immuno-compétent

    PubMed Central

    N'goran, Kouamé; Akaffou, Evelyne; Konan, Anhum Nicaise; N'goan-Domoua, Anne-Marie

    2011-01-01

    Ce cas clinique rapporte un cas de tuberculose hépatique de présentation échographique exceptionnelle. Nous avons réalisé l’échographie abdominale d'un adolescent de 12 ans, immuno-compétent, sans notion de contage tuberculeux, se plaignant de douleur abdominale chronique évoluant depuis 8 mois associée à des signes frustres d‘imprégnation tuberculeuse. L'examen échographique a été réalisé à l'aide d'un appareil écho-doppler de marque Logic 400 de la firme General Electric. L’échographie abdominale a mis en évidence, une hépatomégalie comportant de multiples micro-abcès hypoéchogènes homogènes, mesurant entre 3 et 4 mm de diamètre et disséminés dans tout le parenchyme hépatique donnant l'aspect de miliaire. Une ascite de moyenne abondance localisée dans le pelvis a été objectivée. Il n'y avait pas d'adénopathies profondes ni de nodules péritonéaux. La ponction biopsie hépatique sous guidage échographique a permis de faire le diagnostic de tuberculose hépatique à l'histologie et à la bactériologie. Le patient a été mis sous traitement spécifique avec une surveillance échographique mensuelle. La disparition des micro-abcès et le tarissement de l'ascite ont été obtenus au bout du 4ème mois du traitement. Celle de l'hépatomégalie est survenue un mois plus tard. L’échographie joue un rôle très important dans la détection précoce de la tuberculose hépatique, son diagnostic précis et la surveillance du traitement. Lors de sa réalisation dans un contexte de douleur abdominale chronique chez l'enfant, l’échographiste devrait évoquer le diagnostic de tuberculose hépatique devant une hépatomégalie multi-micro-abcédée, même chez l'enfant immuno-compétent. PMID:22355417

  10. Simulation d'ecoulements internes compressibles laminaires et turbulents par une methode d'elements finis

    NASA Astrophysics Data System (ADS)

    Rebaine, Ali

    1997-08-01

    Ce travail consiste en la simulation numerique des ecoulements internes compressibles bidimensionnels laminaires et turbulents. On s'interesse, particulierement, aux ecoulements dans les ejecteurs supersoniques. Les equations de Navier-Stokes sont formulees sous forme conservative et utilisent, comme variables independantes, les variables dites enthalpiques a savoir: la pression statique, la quantite de mouvement et l'enthalpie totale specifique. Une formulation variationnelle stable des equations de Navier-Stokes est utilisee. Elle est base sur la methode SUPG (Streamline Upwinding Petrov Galerkin) et utilise un operateur de capture des forts gradients. Un modele de turbulence, pour la simulation des ecoulements dans les ejecteurs, est mis au point. Il consiste a separer deux regions distinctes: une region proche de la paroi solide, ou le modele de Baldwin et Lomax est utilise et l'autre, loin de la paroi, ou une formulation nouvelle, basee sur le modele de Schlichting pour les jets, est proposee. Une technique de calcul de la viscosite turbulente, sur un maillage non structure, est implementee. La discretisation dans l'espace de la forme variationnelle est faite a l'aide de la methode des elements finis en utilisant une approximation mixte: quadratique pour les composantes de la quantite de mouvement et de la vitesse et lineaire pour le reste des variables. La discretisation temporelle est effectuee par une methode de differences finies en utilisant le schema d'Euler implicite. Le systeme matriciel, resultant de la discretisation spatio-temporelle, est resolu a l'aide de l'algorithme GMRES en utilisant un preconditionneur diagonal. Les validations numeriques ont ete menees sur plusieurs types de tuyeres et ejecteurs. La principale validation consiste en la simulation de l'ecoulement dans l'ejecteur teste au centre de recherche NASA Lewis. Les resultats obtenus sont tres comparables avec ceux des travaux anterieurs et sont nettement superieurs concernant les

  11. Autocrine IL-6 mediates pituitary tumor senescence

    PubMed Central

    Fuertes, Mariana; Ajler, Pablo; Carrizo, Guillermo; Cervio, Andrés; Sevlever, Gustavo; Stalla, Günter K.; Arzt, Eduardo

    2017-01-01

    Cellular senescence is a stable proliferative arrest state. Pituitary adenomas are frequent and mostly benign, but the mechanism for this remains unknown. IL-6 is involved in pituitary tumor progression and is produced by the tumoral cells. In a cell autonomous fashion, IL-6 participates in oncogene-induced senescence in transduced human melanocytes. Here we prove that autocrine IL-6 participates in pituitary tumor senescence. Endogenous IL-6 inhibition in somatotroph MtT/S shRNA stable clones results in decreased SA-β-gal activity and p16INK4a but increased pRb, proliferation and invasion. Nude mice injected with IL-6 silenced clones develop tumors contrary to MtT/S wild type that do not, demonstrating that clones that escape senescence are capable of becoming tumorigenic. When endogenous IL-6 is silenced, cell cultures derived from positive SA-β-gal human tumor samples decrease the expression of the senescence marker. Our results establish that IL-6 contributes to maintain senescence by its autocrine action, providing a natural model of IL-6 mediated benign adenoma senescence. PMID:27902467

  12. IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

    PubMed Central

    Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Furuya, Takefumi; Kobashigawa, Tsuyoshi; Kamatani, Naoyuki; Kotake, Shigeru

    2007-01-01

    This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis. PMID:17888176

  13. IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats.

    PubMed

    Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Furuya, Takefumi; Kobashigawa, Tsuyoshi; Kamatani, Naoyuki; Kotake, Shigeru

    2007-01-01

    This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.

  14. IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

    PubMed

    Betts, Brian C; Pidala, Joseph; Kim, Jongphil; Mishra, Asmita; Nishihori, Taiga; Perez, Lia; Ochoa-Bayona, Jose Leonel; Khimani, Farhad; Walton, Kelly; Bookout, Ryan; Nieder, Michael; Khaira, Divis K; Davila, Marco; Alsina, Melissa; Field, Teresa; Ayala, Ernesto; Locke, Frederick L; Riches, Marcie; Kharfan-Dabaja, Mohamed; Fernandez, Hugo; Anasetti, Claudio

    2017-05-01

    Graft- versus -host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16 th April 2014 and 19 th December 2015, 20 patients received IL-2 (200,000 IU/m 2 thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P =0.0016; 0.052 k/uL vs. 0.037 k/uL, P =0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P =0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3 + CD4 + T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. ( clinicaltrials.gov identifier: 01927120 ). Copyright© Ferrata Storti Foundation.

  15. The role of IL-23 and the IL-23/TH 17 immune axis in the pathogenesis and treatment of psoriasis.

    PubMed

    Girolomoni, G; Strohal, R; Puig, L; Bachelez, H; Barker, J; Boehncke, W H; Prinz, J C

    2017-10-01

    Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the UK population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (IL-23)/T-helper 17 (T H 17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine IL-23, a heterodimer composed of a p40 subunit also found in IL-12 and a p19 subunit exclusive to IL-23. IL-23 is important for maintaining T H 17 responses, and levels of IL-23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit IL-23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the IL-23/T H 17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways. © 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

  16. La problématique du coût des nouvelles thérapeutiques en oncologie: qu'en-est-il du Maroc?

    PubMed Central

    Brahmi, Sami Aziz; Zahra, Ziani Fatima; Seddik, Youssef; Afqir, Said

    2016-01-01

    Le cancer est un problème majeur de santé public en Afrique. Les progrès réalisé dans le traitement des cancers ces dix dernières années est indéniable. L’émergence des thérapies ciblés en oncologie a permit de modifier l'histoire naturelle de certains cancers réputés de mauvais pronostic. En dépit de leurs efficacité, ces thérapeutiques pose un problème majeur de coût qui les rend inaccessible à la majorité des patients dans les pays en voie développement. Au Maroc, le cancer est reconnu comme a une affection de longue durée et les patients bénéficient de ce fait d'une couverture médicale totale. L'implication de la société civile a permis aussi d'améliorer la prise en charge ainsi qu'un accès plus élargi aux médicaments innovants pour les patients les plus démunis. PMID:27642392

  17. Plasmodium berghei ANKA infection increases Foxp3, IL-10 and IL-2 in CXCL-10 deficient C57BL/6 mice

    PubMed Central

    2011-01-01

    Background Cerebral malaria (CM) is a major cause of malaria mortality. Sequestration of infected red blood cells and leukocytes in brain vessels coupled with the production of pro-inflammatory factors contribute to CM. CXCL-10 a chemokine that is chemotactic to T cells has been linked to fatal CM. Mice deficient for CXCL-10 gene are resistant to murine CM, while antibody ablation of CXCL-10 enhanced the production of regulatory T cells (CD4+Cd25+Foxp3+) and IL-10 which regulate the immune system. Interleukin-2 (IL-2), a pro-inflammatory cytokine implicated in malaria pathogenesis has also been shown to be a key regulator of Foxp3. However the role of Foxp3 in resistant murine CM is not well understood. Methods The hypothesis that resistance of CXCL-10-/- mice to murine CM may be due to enhanced expression of Foxp3 in concert with IL-10 and IL-2 was tested. CXCL-10-/- and WT C57BL/6 mice were infected with Plasmodium berghei ANKA and evaluated for CM symptoms. Brain, peripheral blood mononuclear cells (PBMCs) and plasma were harvested from infected and uninfected mice at days 2, 4 and 8. Regulatory T cells (CD4+CD25+) and non-T regs (CD4+CD25-) were isolated from PBMCs and cultured with P. berghei antigens in vitro with dendritic cells as antigen presenting cells. Regulatory T cell transcription and specific factor Foxp3, was evaluated in mouse brain and PBMCs by realtime-PCR and Western blots while IL-10, and IL-2 were evaluated in plasma and cultured supernatants by ELISA. Results Wild type mice exhibited severe murine CM symptoms compared with CXCL-10-/- mice. Foxp3 mRNA and protein in brain and PBMC's of CXCL-10-/- mice was significantly up-regulated (p < 0.05) by day 4 post-infection (p.i) compared with WT. Plasma levels of IL-10 and IL-2 in infected CXCL-10-/- were higher than in WT mice (p < 0.05) at days 2 and 4 p.i. Ex-vivo CD4+CD25+ T cells from CXCL-10-/- re-stimulated with P. berghei antigens produced more IL-10 than WT CD4+CD25+ T cells. Conclusion The

  18. Requirement for Pathogenic IL-23 Signaling Is Restricted to Initiation of Autoimmune Myocarditis

    PubMed Central

    Wu, Lei; Diny, Nicola L.; Ong, SuFey; Barin, Jobert G.; Hou, Xuezhou; Rose, Noel R.; Talor, Monica V.; Čiháková, Daniela

    2016-01-01

    Using a mouse model of experimental autoimmune myocarditis (EAM), we showed for the first time that IL-23 stimulation of CD4+ T cells is required only briefly at the initiation of GM-CFS-dependent cardiac autoimmunity. IL-23 signal, acting as a switch, turns on pathogenicity of CD4+ T cells, and becomes dispensable once autoreactivity is established. Il23a−/− mice failed to mount an efficient Th17 response to immunization, and were protected from myocarditis. However, remarkably, transient IL-23 stimulation ex vivo fully restored pathogenicity in otherwise nonpathogenic CD4+ T cells raised from Il23a−/− donors. Thus, IL-23 may no longer be necessary to uphold inflammation in established autoimmune diseases. In addition, we demonstrated that IL-23 induced GM-CSF mediates the pathogenicity of CD4+ T cells in EAM. The neutralization of GM-CSF abrogated cardiac inflammation. However, sustained IL-23 signaling is required to maintain IL-17A production in CD4+ T cells. Despite inducing inflammation in Il23a−/− recipients comparable to WT, autoreactive CD4+ T cells downregulated IL-17A production without persistent IL-23 signaling. This divergence on the controls of GM-CSF-dependent pathogenicity on one side and IL-17A production on the other side may contribute to the discrepant efficacies of anti-IL-23 therapy in different autoimmune diseases. PMID:26660726

  19. IL-6 Receptor Isoforms and Ovarian Cancer Progression

    DTIC Science & Technology

    2010-10-01

    carcinoma cell ines, respectively, were obtained from merican Type Culture Collection (Man- ssas, VA). Cells were maintained in Dul- ecco’s Modified...tien IL6R hist stra (ind trans 010L6R. Cross -reactivity between human rican Journal of Obstetrics & Gynecology 1.e3 a o T 5 g m S D w t R T l a 1 c ( m...allele of IL-6ra (Il6rafl/+) were first crossed with FLPe+/+ mice (38) to delete the FRT-flanked Neo cassette in the targeting vector. Progeny with

  20. Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

    PubMed Central

    Hasegawa, Hideaki; Mizoguchi, Izuru; Chiba, Yukino; Ohashi, Mio; Xu, Mingli; Yoshimoto, Takayuki

    2016-01-01

    The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus

  1. Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases.

    PubMed

    Fragoulis, George E; Siebert, Stefan; McInnes, Iain B

    2016-01-01

    The discovery of the biological functions of the interleukin-23/-17 axis led to the identification of IL-23 and IL-17 as important participants in the pathogenesis of several immune-mediated diseases. Therapeutic agents targeting these cytokines and/or their receptors have now been developed as potential treatment strategies for common immune-mediated diseases. Anti-IL-17 and anti-IL-12/-23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging. Overall, these agents appear well tolerated, with adverse-event rates that are commensurate with those in other biologic treatment programs. The strategic utility of these new agents, however, remains uncertain, and further studies will be required to determine their place in the context of existing conventional and biologic immune-modifying agents.

  2. Antitumor effects of a tumor cell vaccine expressing a membrane-bound form of the IL-12 p35 subunit.

    PubMed

    Lim, Ho Yong; Ju, Hee Young; Chung, Hee-Yong; Kim, Young Sang

    2010-08-15

    We investigated whether expression of the IL-12 p35 subunit in membrane-bound form in tumor cells enhanced their immunogenicity. Since p35 is only secreted when associated with the IL-12 p40 subunit, we generated tumor cells expressing membrane-bound forms of p35 and p40 as chimeras with the transmembrane/cytoplasmic region of TNFα (mbIL-12p35 and mbIL-12p40). The relevant vectors were transfected into MethA fibrosarcoma cells, and mbIL-12p35 or mbIL-12p40-expressing tumor clones were isolated and their ability to induce antitumor immunity studied. Cells of the mbIL-12p35 tumor clone induced CD69 expression and IFNγ production in purified CD8(+) T cells in vitro, and their in vivo tumorigenicity was reduced. Cells of the mbIL-12p40 tumor clone failed to show either of these activities. Mice that had rejected cells of the mbIL-12p35 tumor clone possessed systemic antitumor immunity to wild type tumor cells. The growth rate of mbIL-12p35 tumor cells was greater in CD8(+) T cell-depleted mice than in CD4(+) T-cell- and NK cell-depleted mice or normal mice, suggesting that CD8(+) T cells were mainly responsible for the antitumor immunity. These results indicate that expression of mbIL-12p35 on tumor cells enhances their immunogenicity by increasing their ability to activate CD8(+) T cells, possibly by direct priming.

  3. The IL-1B Genetic Polymorphism Is Associated with Aspirin-Induced Peptic Ulcers in a Korean Ethnic Group

    PubMed Central

    Cho, Jae Hee; Choi, Ja Sung; Chun, Song Wook; Lee, Sangheun; Han, Ki Jun; Kim, Hee Man

    2016-01-01

    Background/Aims Single nucleotide polymorphisms (SNPs) are associated with aspirin-induced peptic ulcers. However, SNPs of specific genes vary among races, and data regarding SNPs in the Korean population are scarce. In this study, we aimed to investigate the relationships between SNPs of the COX-1, IL-1β, IL-1RN, and TNF genes and aspirin-induced peptic ulcers, as pilot research in a Korean population. Methods Patients who had been taking low-dose aspirin (100 mg) for at least 4 weeks were prospectively enrolled. DNA was extracted from whole blood, and DNA sequencing was subsequently performed. Results A total of 48 patients were enrolled (23 peptic ulcer patients vs 25 nonulcer controls). Three exon SNPs (IL-1β -581C/T [rs1143627], IL-1β -1061C/T [rs16944], and IL-1RN -1129 [rs4251961]) and one intron SNP (IL-1β IVS2+242C/T) were significantly different between the two groups. On the multivariate analysis after adjustments for age and sex, the CC/CT genotypes of IL-1β -581C/T, and the CT/TT genotypes of IL-1β -1061C/T were positively associated with aspirin-induced peptic ulcers (odds ratio [OR], 4.6, 95% confidence interval [CI], 1.054 to 20.303, p=0.04; OR, 4.6, 95% CI, 1.054 to 20.303, p=0.04). Conclusions The IL-1β -581C/T and IL-1β -1061C/T genotypes may be associated with low-dose aspirin-induced peptic ulcers in a Korean ethnic group. PMID:26601827

  4. The IL-1B Genetic Polymorphism Is Associated with Aspirin-Induced PepticUlcers in a Korean Ethnic Group.

    PubMed

    Cho, Jae Hee; Choi, Ja Sung; Chun, Song Wook; Lee, Sangheun; Han, Ki Jun; Kim, Hee Man

    2016-05-23

    Single nucleotide polymorphisms (SNPs) are associated with aspirin-induced peptic ulcers. However, SNPs of specific genes vary among races, and data regarding SNPs in the Korean population are scarce. In this study, we aimed to investigate the relationships between SNPs of the COX-1, IL-1β, IL-1RN, and TNF genes and aspirin-induced peptic ulcers, as pilot research in a Korean population. Patients who had been taking low-dose aspirin (100 mg) for at least 4 weeks were prospectively enrolled. DNA was extracted from whole blood, and DNA sequencing was subsequently performed. A total of 48 patients were enrolled (23 peptic ulcer patients vs 25 nonulcer controls). Three exon SNPs (IL-1β -581C/T [rs1143627], IL-1β -1061C/ T [rs16944], and IL-1RN -1129 [rs4251961]) and one intron SNP (IL-1β IVS2+242C/T) were significantly different between the two groups. On the multivariate analysis after adjustments for age and sex, the CC/CT genotypes of IL-1β -581C/ T, and the CT/TT genotypes of IL-1β -1061C/T were positively associated with aspirin-induced peptic ulcers (odds ratio [OR], 4.6, 95% confidence interval [CI], 1.054 to 20.303, p=0.04; OR, 4.6, 95% CI, 1.054 to 20.303, p=0.04). The IL-1β -581C/T and IL-1β -1061C/T genotypes may be associated with low-dose aspirin-induced peptic ulcers in a Korean ethnic group.

  5. CXCR3 expression defines a novel subset of innate CD8+ T cells that enhance immunity against bacterial infection and cancer upon stimulation with IL-15

    PubMed Central

    Oghumu, Steve; Terrazas, Cesar A.; Varikuti, Sanjay; Kimble, Jennifer; Vadia, Stephen; Yu, Lianbo; Seveau, Stephanie; Satoskar, Abhay R.

    2015-01-01

    Innate CD8+ T cells are a heterogeneous population with developmental pathways distinct from conventional CD8+ T cells. However, their biology, classification, and functions remain incompletely understood. We recently demonstrated the existence of a novel population of chemokine (C-X-C motif) receptor 3 (CXCR3)-positive innate CD8+ T cells. Here, we investigated the functional properties of this subset and identified effector molecules and pathways which mediate their function. Adoptive transfer of IL-15 activated CXCR3+ innate CD8+ T cells conferred increased protection against Listeria monocytogenes infection in susceptible IFN-γ−/− mice compared with similarly activated CXCR3− subset. This was associated with enhanced proliferation and IFN-γ production in CXCR3+ cells. Further, CXCR3+ innate cells showed enhanced cytotoxicity against a tumor cell line in vitro. In depth analysis of the CXCR3+ subset showed increased gene expression of Ccl5, Klrc1, CtsW, GP49a, IL-2Rβ, Atp5e, and Ly6c but reduced IFN-γR2 and Art2b. Ingenuity pathway analysis revealed an up-regulation of genes associated with T-cell activation, proliferation, cytotoxicity, and translational initiation in CXCR3+ populations. Our results demonstrate that CXCR3 expression in innate CD8+ T cells defines a subset with enhanced cytotoxic potential and protective antibacterial immune functions. Immunotherapeutic approaches against infectious disease and cancer could utilize CXCR3+ innate CD8+ T-cell populations as novel clinical intervention strategies.—Oghumu, S., Terrazas, C. A., Varikuti, S., Kimble, J., Vadia, S., Yu, L., Seveau, S., Satoskar, A. R. CXCR3 expression defines a novel subset of innate CD8+ T cells that enhance immunity against bacterial infection and cancer upon stimulation with IL-15. PMID:25466888

  6. Fréquence, implication clinique et valeur pronostique de la lymphopénie au cours du lupus érythémateux systémique: étude cas témoin

    PubMed Central

    Ha-ou-nou, Fatima Zahra; Essaadouni, Lamiaa

    2015-01-01

    Le lupus érythémateux systémique (LES) est une maladie auto-immune dotée d'un grand polymorphisme clinique et caractérisée par la production d'une grande variété d'autoanticorps. Sa définition repose sur les critères de l'ACR dont fait partie la lymphopénie. Afin de déterminer s'il existe une corrélation entre la présence de la lymphopénie d'une part et les manifestations cliniques, immunologiques et l'activité du lupus érythémateux systémique d'autre part, nous avons réalisé une étude rétrospective, comparative portant sur 148 cas de LES colligés dans un service de médecine interne entre 2006 et 2012. Ces patients ont été subdivisés en 2 groupes: Groupe 1 avec lymphopénie (taux de lymphocytes < 1500/mm3) et groupe 2 sans lymphopénie (taux de lymphocytes ≥ 1500/mm3). Les 2 groupes ont été comparés en fonction de la présentation clinique et immunologique et l'activité de la maladie mesurée par le SLEDAI (Systemic Lupus Erythematosus Disease Activity Index). L’âge moyen des patients (134 femmes et 14 hommes) était de 35,64 ans. L'atteinte hématologique était présente dans 81,1% des cas avec une lymphopénie dans 69,2% des cas. Une association statistiquement significative était notée entre la lymphopénie et l'atteinte rénale (p = 0,025), l'atteinte cardiaque (p = 0,004), l'anémie hémolytique (p = 0,020), la présence d'anticorps anti DNA (p = 0,046), le traitement par cyclophosphamide (p = 0.035) et l'activité de la maladie (p < 0,01). En revanche il n'y avait pas de corrélation entre la présence de lymphopénie et les atteintes cutanées, articulaires et neuropsychiatriques. La lymphopénie est une manifestation fréquente du lupus systémique. Notre étude a démontré que sa présence est associée à plusieurs manifestations cliniques graves dont les atteintes cardiaque et rénale. Ceci pourrait faire d'elle un outil utile dans l’évaluation du pronostic de la maladie. PMID:26401197

  7. γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

    PubMed

    Kohlgruber, Ayano C; Gal-Oz, Shani T; LaMarche, Nelson M; Shimazaki, Moto; Duquette, Danielle; Nguyen, Hung N; Mina, Amir I; Paras, Tyler; Tavakkoli, Ali; von Andrian, Ulrich; Banks, Alexander S; Shay, Tal; Brenner, Michael B; Lynch, Lydia

    2018-05-01

    γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (T reg ) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF + γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα + and Pdpn + stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2 + T reg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.

  8. IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice.

    PubMed

    Takahara, Masahiro; Nemoto, Yasuhiro; Oshima, Shigeru; Matsuzawa, Yu; Kanai, Takanori; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Yamamoto, Kazuhide; Watanabe, Mamoru

    2013-01-01

    Colitogenic memory CD4(+) T cells are important in the pathogenesis of inflammatory bowel disease (IBD). Although memory stem cells with high survival and self-renewal capacity were recently identified in both mice and humans, it is unclear whether a similar subset is present in chronic colitis mice. We sought to identify and purify a long-lived subset of colitogenic memory CD4(+) T cells, which may be targets for treatment of IBD. A long-lived subset of colitogenic memory CD4(+) T cells was purified using a long-term culture system. The characteristics of these cells were assessed. Interleukin (IL)-7 promoted the in vitro survival for >8 weeks of lamina propria (LP) CD4(+) T cells from colitic SCID mice previously injected with CD4(+)CD45RB(high) T cells. These cells were in a quiescent state and divided a maximum of 5 times in 4 weeks. LP CD4(+) T cells expressed higher levels of Bcl-2, integrin-α4β7, CXCR3 and CD25 after than before culture, as well as secreting high concentrations of IL-2 and low concentrations of IFN-γ and IL-17 in response to intestinal bacterial antigens. LP CD4(+) T cells from colitic mice cultured with IL-7 for 8 weeks induced more severe colitis than LP CD4(+) T cells cultured for 4 weeks. We developed a novel culture system to purify a long-lived, highly pathogenic memory subset from activated LP CD4(+) T cells. IL-7 promoted long-term in vitro survival of this subset in a quiescent state. This subset will be a novel, effective target for the treatment of IBD. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Effects of exogenous IL-37 on the biological characteristics of human lung adenocarcinoma A549 cells and the chemotaxis of regulatory T cells.

    PubMed

    Chen, Yu-Hua; Zhou, Bi-Yun; Wu, Guo-Cai; Liao, De-Quan; Li, Jing; Liang, Si-Si; Wu, Xian-Jin; Xu, Jun-Fa; Chen, Yong-Hua; Di, Xiao-Qing; Lin, Qiong-Yan

    2018-02-14

    This study aims to investigate the effects of exogenous interleukin (IL)-37 on the biological characteristics of human lung adenocarcinoma A549 cells and the chemotaxis of regulatory T (Treg) cells. After isolating the CD4+ CD25+ Treg cells from the peripheral blood, flow cytometry was used to detect the purity of the Treg cells. A549 cells were divided into blank (no transfection), empty plasmid (transfection with pIRES2-EGFP empty plasmid) or IL-37 group (transfection with pIRES2-EGFP-IL-37 plasmid). RT-PCR was used to detect mRNA expression of IL-37 and ELISA to determine IL-37 and MMP-9 expressions. Western blotting was applied to detect the protein expressions of PCNA, Ki-67, Cyclin D1, CDK4, cleaved caspase-3 and cleaved caspase-9. MTT assay, flow cytometry, scratch test and transwell assay were performed to detect cell proliferation, cycle, apoptosis, migration and invasion. Effect of exogenous IL-37 on the chemotaxis of Treg cells was measured through transwell assay. Xenograft models in nude mice were eastablished to detect the impact of IL-37 on A549 cells. The IL-37 group had a higher IL-37 expression, cell apoptosis in the early stage and percentage of cells in the G0/G1 phase than the blank and empty plasmid groups. The IL-37 group had a lower MMP-9 expression, optical density (OD), percentage of cells in the S and G2/M phases, migration, invasion and chemotaxis of CD4+CD25+ Foxp3+ Treg cells. The xenograft volume and weight of nude mice in the IL-37 group were lower than those in the blank and empty plasmid groups. Compared with the blank and empty plasmid groups, the IL-37 group had significantly reduced expression of PCNA, Ki-67, Cyclin D1 and CDK4 but elevated expression of cleaved caspase-3 and cleaved caspase-9. Therefore, exogenous IL-37 inhibits the proliferation, migration and invasion of human lung adenocarcinoma A549 cells as well as the chemotaxis of Treg cells while promoting the apoptosis of A549 cells.

  10. Regulatory CD8+CD122+ T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells

    PubMed Central

    Lapato, Andrew; Vandenbark, Arthur A.; Murphy, Stephanie J.; Saugstad, Julie A.; Offner, Halina

    2014-01-01

    Clinical stroke induces inflammatory processes leading to cerebral and splenic injury and profound peripheral immunosuppression. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that transfer of IL-10+ B-cells reduced infarct volume in male C57BL/6J (wild-type, WT) recipient mice when given 24 h prior to or 4 h after middle cerebral artery occlusion (MCAO). The purpose of this study was to determine if passively transferred IL-10+ B-cells can exert therapeutic and immunoregulatory effects when injected 24 hours after MCAO induction in B-cell-sufficient male WT mice. The results demonstrated that IL-10+ B-cell treated mice had significantly reduced infarct volumes in the ipsilateral cortex and hemisphere and improved neurological deficits vs. Vehicle-treated control mice after 60 min occlusion and 96 h of reperfusion. The MCAO-protected B-cell recipient mice had less splenic atrophy and reduced numbers of activated, inflammatory T-cells, decreased infiltration of T-cells and a less inflammatory milieu in the ischemic hemispheres compared with Vehicle-treated control mice. These immunoregulatory changes occurred in concert with the predominant appearance of IL-10-secreting CD8+CD122+ Treg cells in both the spleen and the MCAO-affected brain hemisphere. This study for the first time demonstrates a major neuroprotective role for IL-10+ B-cells in treating MCAO in male WT mice at a time point well beyond the ~4 h tPA treatment window, leading to the generation of a dominant IL-10+CD8+CD122+ Treg population associated with spleen preservation and reduced CNS inflammation. PMID:25537181

  11. IL-7 treatment augments and prolongs sepsis-induced expansion of IL-10-producing B lymphocytes and myeloid-derived suppressor cells

    PubMed Central

    Win, Stephanie J.; Bauer, Michael

    2018-01-01

    Immunological dysregulation in sepsis is associated with often lethal secondary infections. Loss of effector cells and an expansion of immunoregulatory cell populations both contribute to sepsis-induced immunosuppression. The extent and duration of this immunosuppression are unknown. Interleukin 7 (IL-7) is important for the maintenance of lymphocytes and can accelerate the reconstitution of effector lymphocytes in sepsis. How IL-7 influences immunosuppressive cell populations is unknown. We have used the mouse model of peritoneal contamination and infection (PCI) to investigate the expansion of immunoregulatory cells as long-term sequelae of sepsis with or without IL-7 treatment. We analysed the frequencies and numbers of regulatory T cells (Tregs), double negative T cells, IL-10 producing B cells and myeloid-derived suppressor cells (MDSCs) for 3.5 months after sepsis induction. Sepsis induced an increase in IL-10+ B cells, which was enhanced and prolonged by IL-7 treatment. An increased frequency of MDSCs in the spleen was still detectable 3.5 months after sepsis induction and this was more pronounced in IL-7-treated mice. MDSCs from septic mice were more potent at suppressing T cell proliferation than MDSCs from control mice. Our data reveal that sepsis induces a long lasting increase in IL-10+ B cells and MDSCs. Late-onset IL-7 treatment augments this increase, which should be relevant for clinical interventions. PMID:29466409

  12. IL-7 treatment augments and prolongs sepsis-induced expansion of IL-10-producing B lymphocytes and myeloid-derived suppressor cells.

    PubMed

    Kulkarni, Upasana; Herrmenau, Christoph; Win, Stephanie J; Bauer, Michael; Kamradt, Thomas

    2018-01-01

    Immunological dysregulation in sepsis is associated with often lethal secondary infections. Loss of effector cells and an expansion of immunoregulatory cell populations both contribute to sepsis-induced immunosuppression. The extent and duration of this immunosuppression are unknown. Interleukin 7 (IL-7) is important for the maintenance of lymphocytes and can accelerate the reconstitution of effector lymphocytes in sepsis. How IL-7 influences immunosuppressive cell populations is unknown. We have used the mouse model of peritoneal contamination and infection (PCI) to investigate the expansion of immunoregulatory cells as long-term sequelae of sepsis with or without IL-7 treatment. We analysed the frequencies and numbers of regulatory T cells (Tregs), double negative T cells, IL-10 producing B cells and myeloid-derived suppressor cells (MDSCs) for 3.5 months after sepsis induction. Sepsis induced an increase in IL-10+ B cells, which was enhanced and prolonged by IL-7 treatment. An increased frequency of MDSCs in the spleen was still detectable 3.5 months after sepsis induction and this was more pronounced in IL-7-treated mice. MDSCs from septic mice were more potent at suppressing T cell proliferation than MDSCs from control mice. Our data reveal that sepsis induces a long lasting increase in IL-10+ B cells and MDSCs. Late-onset IL-7 treatment augments this increase, which should be relevant for clinical interventions.

  13. [Correlation of SNP of IL-2-330T/G Gene with Genetic Susceptibility and Efficacy of Immunosuppressive Therapy in Patients with Aplastic Anemia].

    PubMed

    Zeng, Qiang; Chang, Hong

    2016-10-01

    To investigate the correlation of single nucleotide polymorphism (SNP) of Interleukin-2(IL-2)-330T/G with genetic susceptibility and the efficacy of immunosuppressive therapy in patients with aplastic anemia. The peripheral blood samples from 103 patients with aplastic anemia in our hospital were collected. Out of 103 patients 46 received immuosuppressive therapy and were observed for 4 months, and 100 healthy adults were selected as control. The electrophoresis and DNA sequence were performed. The polymerase chain reaction(PCR) was used to amplify the polymorphic gene segment of IL-2 -330T/G from 103 aplastic anemia patients and 100 healthy adults. The frequencis of IL-2-330 GG genotype and G allele were a little higher in patients with aplastic anemia than that in the healthy adults(12.6% vs 12.0%, P>0.05; 27.7% vs 33.5%, P>0.05), but not statistically significant(P>0.05); in the 103 patients with aplastic anemia, 46 received immunosuppressive therapy, whereas 29 patients showed response, no significant difference was found between the responders and non-responders in the IL-2-330 GG genotype and G allele (31.0% vs 48.3%, P>0.05; 64.8% vs 61.8%, P>0.05). IL-2 -330T/G gene polymorphism may not correlate with the susceptibility of aplastic anemia or the efficacy of immunosuppressive therapy.

  14. Cause rare d'une perforation de la cloison nasale

    PubMed Central

    Jahidi, Ali; Hemmaoui, Bouchaïb; Itoua, Wulfran Rosaire; Errami, Noureddine; Benariba, Fouad

    2014-01-01

    Les perforations de la cloison nasale constituent une pathologie fréquente en ORL. Leurs causes sont multiples et restent dominées par les traumatismes chirurgicaux. Les étiologies infectieuses et notamment la tuberculose sont rares. Nous présentons le cas d'une patiente ayant bénéficié d'une méatotomie bilatérale et chez laquelle une perforation de la cloison nasale a été découverte lors d'un examen systématique à un an de son intervention. D'abord considérée comme une complication de la chirurgie, la biopsie des berges de la perforation a permis de déterminer son origine tuberculeuse. La présentation clinique des perforations de la cloison nasale n'est pas spécifique. Elles sont souvent asymptomatiques et de découverte fortuite. Les traumatismes notamment chirurgicaux sont le plus siuvent en cause. L′orogine tuberculeuse resta très rare. Le diagnostic de certitude de tuberculose repose sur la biopsie des berges de cette perforation. Le but de ce travail est de mettre en avant l'intérêt de la biopsie dans le diagnostic de la tuberculose de la cloison nasale. Cette biopsie doit être systématique même en cas d'antécédents de chirurgie endonasale qui est le plus souvent en cause dans les perforations de la cloison nasale. PMID:24932334

  15. Histoire d’un itinéraire épidémiologique entre le Burkina Faso et la Côte d’Ivoire : le cas des foyers de maladie du sommeil de Koudougou

    PubMed Central

    Kiendrébéogo, D.; Kambiré, R.; Jamonneau, V.; Lingué, K.; Solano, P.; Courtin, F.

    2012-01-01

    Dans la première moitié du XXème siècle, alors que la Haute-Volta (actuel Burkina Faso) subissait une terrible épidémie de maladie du sommeil, l’administration coloniale française a orchestré des déplacements massifs de populations de la Haute-Volta vers la Côte d’Ivoire, pour exploiter le territoire. Cela a conduit à la mise en place de villages de colonisation Mossi en zone forestière ivoirienne, comme ceux de Koudougou, issus de l’une des régions les plus peuplées de Haute-Volta, mais aussi l’une des plus touchées par la maladie du sommeil. Depuis 2000, au Burkina Faso, c’est dans le district sanitaire de Koudougou que sont dépistés passivement le plus grand nombre de trypanosomés en provenance de Côte d’Ivoire. Qui sont-ils ? Où habitent-ils au Burkina Faso ? D’où viennent-ils de Côte d’Ivoire ? Après avoir retracé l’histoire épidémiologique des villages de Koudougou au Burkina Faso et en Côte d’Ivoire, nous avons recherché les trypanosomés dépistés passivement depuis 2000 dans le district sanitaire de Koudougou au Burkina Faso. Au total, dix trypanosomés ont été enquêtés. Le processus de propagation de la maladie du sommeil dans l’espace ivoiro-burkinabé a été mis en évidence et des zones à risque de la maladie identifiées dans ce même espace. PMID:23193525

  16. IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization

    PubMed Central

    Yoon, Juhan; Oyoshi, Michiko K.; Hoff, Sabine; Chervonsky, Alexander; Oppenheim, Joost J.; Rosenstiel, Philip

    2016-01-01

    Atopic dermatitis (AD) is a Th2-dominated inflammatory skin disease characterized by epidermal thickening. Serum levels of IL-22, a cytokine known to induce keratinocyte proliferation, are elevated in AD, and Th22 cells infiltrate AD skin lesions. We show that application of antigen to mouse skin subjected to tape stripping, a surrogate for scratching, induces an IL-22 response that drives epidermal hyperplasia and keratinocyte proliferation in a mouse model of skin inflammation that shares many features of AD. DC-derived IL-23 is known to act on CD4+ T cells to induce IL-22 production. However, the mechanisms that drive IL-23 production by skin DCs in response to cutaneous sensitization are not well understood. We demonstrate that IL-23 released by keratinocytes in response to endogenous TLR4 ligands causes skin DCs, which selectively express IL-23R, to up-regulate their endogenous IL-23 production and drive an IL-22 response in naive CD4+ T cells that mediates epidermal thickening. We also show that IL-23 is released in human skin after scratching and polarizes human skin DCs to drive an IL-22 response, supporting the utility of IL-23 and IL-22 blockade in AD. PMID:27551155

  17. Polymorphism in the IL-8 Gene Promoter and the Risk of Acne Vulgaris in a Pakistani Population.

    PubMed

    Hussain, Sabir; Iqbal, Tahir; Sadiq, Irfan; Feroz, Saima; Shafique Satti, Humayoon

    2015-08-01

    Interleukin-8 (IL-8) is a well-known inflammatory chemokine and suggested to be involved in the development of acne vulgaris. This study investigates IL-8 plasma levels in acne patients and healthy controls and the molecular basis for the regulation of the IL-8 gene in a Pakistani population. Patients with acne vulgaris (n = 264) and healthy individuals (n = 264) were enrolled in this investigation. Plasma IL-8 levels were determined by enzyme-linked immunosorbent assay (ELISA). The genotyping for IL-8 gene was performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Our data showed a statistically significant increase in IL-8 levels from acne patients compared with healthy subjects (154.2 ± 52.1 pg/mL in patients vs. 101.6 ± 33.5 pg/mL in controls, p<0.0001). The IL-8-251T>A (rs4073) polymorphism was significantly higher in patients with acne compared with the control group (p=0.013). There was a significant difference between the T and A alleles from acne cases and controls (odds ratio OR=1.6,95 % CI= 1.16-2.19, p=0.003). Logistic-regression analysis showed that the increased IL-8 levels, and the IL-8-251T>A polymorphism were significantly associated with acne. Our data suggest that the elevated IL-8 levels and the IL-8-251T>A polymorphism may be associated with acne vulgaris in the study population.

  18. Immunomodulatory effect of an isolated fraction from Tinospora crispa on intracellular expression of INF-γ, IL-6 and IL-8.

    PubMed

    Abood, Walaa Najm; Fahmi, Iman; Abdulla, Mahmood Ameen; Ismail, Salmah

    2014-06-27

    Immunomodulators are substances that modify immune system response to a threat. Immunomodulators modulate and potentiate the immune system, keeping it highly prepared for any threat. The immunomodulatory effect of the traditional medicine Tinospora crispa is investigated in this work. T. crispa ethanol extract was fractionated by using different solvents. The ethanol extract and effective isolated fraction were used to investigate the potential immunomodulatory effect of different T. crispa doses ranging from 25 μg/mL to 1000 μg/mL on RAW 246.7 cells by detecting intracellular INF-γ, IL-6, and IL-8 expressions. The antioxidant activity of T. crispa was evaluated through FRAP and DPPH. The total phenolic and total flavonoid contents were also quantified. Results show that T. crispa extract has higher antioxidant potential than ascorbic acid. The FRAP value of T. crispa extract is 11011.11 ± 1145.42 μmol Fe(+2)/g, and its DPPH inhibition percentage is 55.79 ± 7.9, with 22 μg/mL IC50. The results also reveal that the total phenolic content of T. crispa extract is 213.16- ± 1.31 mg GAE/g dry stem weight, and the total flavonoid content is 62.07- ± 39.76 mg QE/g dry stem weight. T. crispa crude extract and its isolated fraction significantly stimulate RAW264.7 cell viability (P ≤ 0.05) and intracellular INF-γ, IL-6, and IL-8 expressions. The results of LC-MS show that four of the active compounds detected in the T. crispa isolated fraction are cordioside, quercetin, eicosenoic acid (paullinic acid), and boldine. The results of this study obviously indicate that T. crispa has immunomodulatory effects through the stimulation of INF-γ, IL-6, and IL-8 expressions. LC-MS phytochemical analysis showed that the T. crispa fraction has cordioside, quercetin, eicosenoic acid (paullinic acid), and boldine, which may be responsible for the immunostimulator effect of T. crispa.

  19. Combined effect of aerobic interval training and selenium nanoparticles on expression of IL-15 and IL-10/TNF-α ratio in skeletal muscle of 4T1 breast cancer mice with cachexia.

    PubMed

    Molanouri Shamsi, M; Chekachak, S; Soudi, S; Quinn, L S; Ranjbar, K; Chenari, J; Yazdi, M H; Mahdavi, M

    2017-02-01

    Cancer cachexia is characterized by inflammation, loss of skeletal muscle and adipose tissue mass, and functional impairment. Oxidative stress and inflammation are believed to regulate pathways controlling skeletal muscle wasting. The aim of this study was to determine the effects of aerobic interval training and the purported antioxidant treatment, selenium nanoparticle supplementation, on expression of IL-15 and inflammatory cytokines in 4T1 breast cancer-bearing mice with cachexia. Selenium nanoparticle supplementation accelerated cachexia symptoms in tumor-bearing mice, while exercise training prevented muscle wasting in tumor-bearing mice. Also, aerobic interval training enhanced the anti-inflammatory indices IL-10/TNF-α ratio and IL-15 expression in skeletal muscle in tumor-bearing mice. However, combining exercise training and antioxidant supplementation prevented cachexia and muscle wasting and additionally decreased tumor volume in 4T1 breast cancer mice. These finding suggested that combining exercise training and antioxidant supplementation could be a strategy for managing tumor volume and preventing cachexia in breast cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Ketamine, as adjuvant analgesics for patients with refractory cancer pain, does affect IL-2/IFN-γ expression of T cells in vitro?: A prospective, randomized, double-blind study.

    PubMed

    Zhou, Naibao; Fu, Zhijian; Li, Hao; Wang, Kaiguo

    2017-04-01

    Ketamine has been used as an analgesic adjuvant with morphine in the treatment of refractory cancer pain recently. But both morphine and ketamine have been reported to produce a number of immunomodulatory effects. The current study was performed to assess whether the concentration of ketamine, as adjuvant analgesics for patient with refractory cancer pain, was related to its effect on T cells interleukin-2 (IL-2)/interferon-γ (IFN-γ) expression in vitro. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood of patients with refractory cancer pain over a Ficoll-Hypaque density gradient. T cells were isolated from by positive selection using anti-CD3 beads. T cells were then treated with vehicle (C group), morphine (200 ng/mL, M group), morphine (200 ng/mL), and different dose of ketamine (100, 200, 1000 ng/mL; MK1, MK5, MK10 group) for 24 hours before stimulation with anti-CD3 and anti-CD28. Then supernatant IL-2 and IFN-γ protein analysis, quantitative reverse transcription polymerase chain reaction (RT-PCR) for IL-2 and IFN-γ were done. There were no significant difference of supernatant IL-2 and IFN-γ among C group, M group, and MK1 group, but the mRNA of M group and MK1 group were decreased compared with C group (P < .05). Compared with C group, both of the supernatant protein and the mRNA of MK5 group and MK10 group were all significantly decreased (P < .01). Compared with M group, both of the supernatant protein and the mRNA of MK5 group and MK10 group were all decreased (P < .05), while supernatant IL-2 and the mRNA of MK10 group were significantly decreased (P < .01). In conclusion, we confirmed that just as morphine, ketamine dose-dependently suppressed IL-2 and IFN-γ of activated T lymphocyte of patients with refractory cancer pain in vitro, but the inhibitory action of low dose ketamine could be neglected.

  1. A New Biomarkers Feature Pattern Consisting of TNF-α, IL-10, and IL-8 for Blood Stasis Syndrome with Myocardial Ischemia

    PubMed Central

    Chen, Jianxin; Chuo, Wenjing; Liu, Lei; Lian, Hongjian; Zheng, Lei; Wang, Yong; Xie, Hua; Luo, Liangtao; Zheng, Chenglong; Fu, Bangze; Wang, Wei

    2013-01-01

    Objective. To explore new diagnostic patterns for syndromes to overcome the insufficiency of obtainable macrocharacteristics and specific biomarkers. Methods. Chinese miniswines were subjected to Ameroid constrictor, placed around the proximal left anterior descending branch. On the 4th week, macrocharacteristics, coronary angiography, echocardiography, and hemorheology indices were detected for diagnosis. IL-1, IL-6, IL-8, IL-10, TNF-α, and hsCRP in serum were detected, and Decision Tree was built. Results. According to current official-issued standard, model animals matched the diagnosis of blood stasis syndrome with myocardial ischemia based on findings, including >90% occlusion, attenuated left ventricular segmental motion, dark red or purple tongues, and higher blood viscosity. Significant decrease of IL-10 and increase of TNF-α were found in model animals. However, in the Decision Tree, besides IL-10 and TNF-α, IL-8 helped to increase the accuracy of classification to 86%. Conclusions. The Decision Tree building with TNF-α, IL-10, and IL-8 is helpful for the diagnosis of blood stasis syndrome in myocardial ischemia animals. What is more is that our data set up a new path to the differentiation of syndrome by feature patterns consisting of multiple biomarkers not only for animals but also for patients. We believe that it will contribute to the standardization and international application of syndromes. PMID:24371451

  2. Developpement d'une commande pour une hydrolienne de riviere et optimisation =

    NASA Astrophysics Data System (ADS)

    Tetrault, Philippe

    Suivant le developpement des energies renouvelables, la presente etude se veut une base theorique quant aux principes fondamentaux necessaires au bon fonctionnement et a l'implementation d'une hydrolienne de riviere. La problematique derriere ce nouveau type d'appareil est d'abord presentee. La machine electrique utilisee dans l'application, c'est-a-dire la machine synchrone a aimants permanents, est etudiee : ses equations dynamiques mecaniques et electriques sont developpees, introduisant en meme temps le concept de referentiel tournant. Le fonctionnement de l'onduleur utilise, soit un montage en pont complet a deux niveaux a semi-conducteurs, est explique et mit en equation pour permettre de comprendre les strategies de modulation disponibles. Un bref historique de ces strategies est fait avant de mettre l'emphase sur la modulation vectorielle qui sera celle utilisee pour l'application en cours. Les differents modules sont assembles dans une simulation Matlab pour confirmer leur bon fonctionnement et comparer les resultats de la simulation avec les calculs theoriques. Differents algorithmes permettant de traquer et maintenir un point de fonctionnement optimal sont presentes. Le comportement de la riviere est etudie afin d'evaluer l'ampleur des perturbations que le systeme devra gerer. Finalement, une nouvelle approche est presentee et comparee a une strategie plus conservatrice a l'aide d'un autre modele de simulation Matlab.

  3. Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells.

    PubMed

    Gautier, Violette; Cayrol, Corinne; Farache, Dorian; Roga, Stéphane; Monsarrat, Bernard; Burlet-Schiltz, Odile; Gonzalez de Peredo, Anne; Girard, Jean-Philippe

    2016-10-03

    IL-33 is a nuclear cytokine from the IL-1 family that plays important roles in health and disease. Extracellular IL-33 activates a growing number of target cells, including group 2 innate lymphoid cells, mast cells and regulatory T cells, but it remains unclear whether intracellular nuclear IL-33 has additional functions in the nucleus. Here, we used a global proteomic approach based on high-resolution mass spectrometry to compare the extracellular and intracellular roles of IL-33 in primary human endothelial cells, a major source of IL-33 protein in human tissues. We found that exogenous extracellular IL-33 cytokine induced expression of a distinct set of proteins associated with inflammatory responses in endothelial cells. In contrast, knockdown of endogenous nuclear IL-33 expression using two independent RNA silencing strategies had no reproducible effect on the endothelial cell proteome. These results suggest that IL-33 acts as a cytokine but not as a nuclear factor regulating gene expression in endothelial cells.

  4. IL-22 from T cells: better late than never.

    PubMed

    Honda, Kenya

    2012-12-14

    Interleukin-22 (IL-22) enhances mucosal barrier function and is important in antimicrobial host defense. In this issue of Immunity, Basu et al. (2012) reveal that Th22 cells are the critical adaptive source of IL-22 during late-phase infection by Citrobacter rodentium. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Une nouvelle voie pour la conception des implants intervertébraux

    NASA Astrophysics Data System (ADS)

    Gradel, T.; Tabourot, L.; Arrieux, R.; Balland, P.

    2002-12-01

    L'objectif de notre travail est la conception d'une nouvelle génération d'implants intersomatiques qui s'adapte parfaitement à la géométrie des plateaux vertébraux en se déformant. Pour cela, nous avons utilisé une nouvelle démarche qui consiste à simuler entièrement le procédé de fabrication en l'occurrence l'emboutissage, Cette simulation, en concervant l'historique des sollicitations exercées sur le matériau lors de sa mise en œuvre permet de valider très précisément sa résistance mécanique en fin de cycle. Au cours de cette étude, nous avons mené en parallèle deux analyses dites “ coopératives ” : l'une fondée sur un modèle phénoménologique de type HILL et l'autre sur un modèle multi-échelles prenant en compte des phénomènes plus physiques afin d'acquérir une bonne connaissance du comportement du matériau lors de la déformation. C'est pour sa bonne résistance, sa biocompatibilité et ses propriétés radiologiques que nous avons choisi le T40 (titane pur) comme matériau.

  6. Interleukin (IL)-18, cooperatively with IL-23, induces prominent inflammation and enhances psoriasis-like epidermal hyperplasia.

    PubMed

    Shimoura, Noriko; Nagai, Hiroshi; Fujiwara, Susumu; Jimbo, Haruki; Yoshimoto, Takayuki; Nishigori, Chikako

    2017-05-01

    The interleukin (IL)-23/IL-17 axis is strongly implicated in the pathogenesis of psoriasis. Previous studies showed that IL-18 was elevated in early active and progressive plaque-type psoriatic lesions and that serum or plasma levels of IL-18 correlated with the Psoriasis Area and Severity Index. However, the mechanism whereby IL-18 affects disease severity remains unknown. In this study, we investigated the effects of IL-18 on a psoriasis-like skin inflammation model induced by recombinant mouse IL-23. We found that IL-18, cooperatively with IL-23, induced prominent inflammation and enhanced psoriasis-like epidermal hyperplasia. In the skin of mice treated with IL-23 plus IL-18, the expression of interferon-γ was significantly upregulated and that of chemokine (C-X-C motif) ligand 9 (CXCL9) was synergistically increased. Histologically, strong positive signals of CXCL9 were observed around the infiltrating inflammatory cells. The current results suggest that IL-18 might synergize with IL-23 to induce a T helper 1 immune reaction, without inhibiting the IL-23/IL-17 axis, and thus may aggravate psoriatic inflammation.

  7. Une rare cause de sciatique non discale: une polyarthrite rhumatoïde

    PubMed Central

    Akasbi, Nessrine; Abourazzak, Fatima Ezzahra; Harzy, Taoufik

    2014-01-01

    La polyarthrite rhumatoïde est le rhumatisme inflammatoire chronique le plus fréquent. Ses complications neurologiques sont dominées par les neuropathies périphériques, cliniquement asymptomatiques, mais peuvent être détectées sur l’électromyogramme (EMG). Nous rapportons l'observation d'une patiente qui a présenté une neuropathie sensitivo-motrice aux deux membres inférieurs associée à une sciatique de topographie L5 d'origine rhumatoïde. PMID:25709734

  8. Serum IL-18 level, clinical symptoms and IL-18-607A/C polymorphism among chronic patients with schizophrenia in a Chinese Han population.

    PubMed

    Zhang, Xiang Yang; Tan, Yun-Long; Chen, Da-Chun; Tan, Shu-Ping; Malouta, Michelle Z; Bernard, Jared D; Combs, Jessica L; Bhatti, Sarai; Davis, Michael C; Kosten, Thomas R; Soares, Jair C

    2016-06-01

    Literature suggests that alterations in the inflammatory and immune systems are involved in the pathogenesis of schizophrenia. Specifically, patients diagnosed with schizophrenia exhibit increased IL-18, a pleiotropic proinflammatory cytokine in type 1 T-helper (Th1) responses. The functional 607A/C promoter polymorphism of the IL-18 gene is also associated with the psychopathology of this disorder. However, no current study has explored its role in the clinical symptoms of schizophrenia as mediated through IL-18 levels. We recruited 772 inpatients with schizophrenia and 775 healthy controls in a Han Chinese population and genotyped the IL-18-607A/C polymorphism. Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Serum IL-18 levels were measured in 80 patients and 93 healthy controls. Our results showed that there were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls. Both increased IL-18 serum level and the IL-18-607A/C polymorphism were positively associated with the PANSS general psychopathology subscore and the PANSS total score. Moreover, interaction of increased IL-18 serum level and the IL-18-607A/C polymorphism influenced the clinical psychopathological symptoms, indicating that association of IL-18 level with the PANSS general psychopathology subscale or the total scores was present only among patients carrying the C allele. We demonstrate an association between the IL-18-607A/C variant and clinical psychopathological symptoms in schizophrenia. Findings suggest that the association between higher IL-18 levels and clinical symptoms in schizophrenia is dependent on the IL-18-607A/C polymorphism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Co-administration of avian influenza virus H5 plasmid DNA with chicken IL-15 and IL-18 enhanced chickens immune responses.

    PubMed

    Lim, Kian-Lam; Jazayeri, Seyed Davoud; Yeap, Swee Keong; Alitheen, Noorjahan Banu Mohamed; Bejo, Mohd Hair; Ideris, Aini; Omar, Abdul Rahman

    2012-08-06

    DNA vaccines offer several advantages over conventional vaccines in the development of effective vaccines against avian influenza virus (AIV). However, one of the limitations of the DNA vaccine in poultry is that it induces poor immune responses. In this study, chicken interleukin (IL) -15 and IL-18 were used as genetic adjuvants to improve the immune responses induced from the H5 DNA vaccination in chickens. The immunogenicity of the recombinant plasmid DNA was analyzed based on the antibody production, T cell responses and cytokine production, following inoculation in 1-day-old (Trial 1) and 14-day-old (Trial 2) specific-pathogen-free chickens. Hence, the purpose of the present study was to explore the role of chicken IL-15 and IL-18 as adjuvants following the vaccination of chickens with the H5 DNA vaccine. The overall HI antibody titer in chickens immunized with pDis/H5 + pDis/IL-15 was higher compared to chickens immunized with pDis/H5 (p < 0.05). The findings revealed that the inoculation of the 14-day-old chickens exhibited a shorter time to achieve the highest HI titer in comparison to the inoculation of the 1-day-old chickens. The cellular immunity was assessed by the flow cytometry analysis to enumerate CD4+ and CD8 + T cells in the peripheral blood. The chickens inoculated with pDis/H5 + pDis/IL-15 demonstrated the highest increase in CD4+ T cells population relative to the control chickens. However, this study revealed that pDis/H5 + pDis/IL-15 was not significant (P > 0.05) in inducing CD8+ T cells. Meanwhile, with the exception of Trial 1, the flow cytometry results for Trial 2 demonstrated that the pDis/H5 + pDis/IL-18 inoculated group was able to trigger a higher increase in CD4+ T cells than the pDis/H5 group (P < 0.05). On the other hand, the pDis/H5 + pDis/IL-18 group was not significant (P > 0.05) in modulating CD8+ T cells population in both trials. The pDis/H5 + pDis/IL-15 inoculated group showed the highest IL-15 gene

  10. Glycyrrhizin restores the impaired IL-12 production in thermally injured mice.

    PubMed

    Utsunomiya, T; Kobayashi, M; Ito, M; Herndon, D N; Pollard, R B; Suzuki, F

    2001-04-07

    Mice 6 days after thermal injury (TI-mice) did not respond to lipopolysaccharide (LPS) stimulation for production of serum interleukin 12 (IL-12; 2 h after LPS stimulation, <20 pg/ml in TI-mice; 1091+/-162 pg/ml in normal mice). However, 2 h after LPS stimulation, 1456+/-118 pg/ml of IL-12 were demonstrated in sera of TI-mice previously treated with a 10 mg/kg i.p. dose of glycyrrhizin (GR). IL-12 was not induced by LPS in sera of normal mice inoculated with burn-associated type 2 T cells (IL-4/IL-10-producing CD8+CD11b+TCRgamma/delta+T cells isolated from spleens of TI-mice). However, IL-12 production was induced by LPS in sera of these mice previously treated with GR or a mixture of monoclonal antibodies (mAbs) for type 2 cytokines. Also, IL-12 production was induced by LPS in TI-mice inoculated with CD4+T cells from spleens of GR-treated normal mice (GR-CD4+T cells, 5x10(6)cells/mouse). Since GR-CD4+T cells have been shown to be antagonistic cells against production of type 2 cytokines by burn-associated type 2 T cells, these results indicate that IL-12 unresponsiveness shown in TI-mice is recovered by GR through the regulation of burn-associated type 2 T cell responses. Copyright 2001 Academic Press.

  11. ÉVALUER UNE INTERVENTION COMPLEXE: ENJEUX CONCEPTUELS, MÉTHODOLOGIQUES, ET OPÉRATIONNELS

    PubMed Central

    Contandriopoulos, André-Pierre; Rey, Lynda; Brousselle, Astrid; Champagne, François

    2016-01-01

    L’évaluation doit théoriquement aider les décideurs à relever les défis des systèmes de santé contemporains. Paradoxalement, malgré le développement rapide du domaine, l’utilisation des résultats des évaluations par ces décideurs reste faible. Le degré d’utilisation ne dépendrait-il pas de la capacité de l’évaluateur à rendre compte de la complexité des systèmes de santé? La nature complexe d’une intervention amène souvent les évaluateurs à adopter des approches non conventionnelles tenant compte du jeu des acteurs. L’évaluation d’une intervention complexe soulève des enjeux conceptuels, méthodologiques, et opérationnels que doit surmonter l’évaluateur pour accroître le degré d’utilisation des résultats par les décideurs. PMID:27293310

  12. Efficacy of anti-IL-23 monotherapy versus combination therapy with anti-IL-17 in estrogen deficiency induced bone loss conditions.

    PubMed

    Shukla, Priyanka; Mansoori, Mohd Nizam; Singh, Divya

    2018-05-01

    Recent studies have identified that Interleukin (IL)-23/IL-17 axis plays crucial role in pathogenesis of inflammation and bone destruction. IL-23 is thought to promote joint destruction in arthritis by stimulating Th17 cells. IL-23 directly mediates bone loss by inducing osteoclastogenesis and receptor activator of kappa B ligand (RANKL) expression in T cells. IL-23 also promotes tartrate-resistant acid phosphatase (TRAP) activity of osteoclast in osteoblast-osteoclast co-culture. The role of IL-23 has not been studied in estrogen deficiency induced bone loss. Here, we study the effect of IL-23 neutralization in ovariectomized (Ovx) estrogen deficient mice on various immune and skeletal parameters. We also determine whether the combination of anti-IL-23 and anti-IL17 has enhanced osteoprotective effects compared to monotherapies. Treatment of anti-IL-23 and its combination with anti-IL-17 suppressed Th17 cell differentiation and promoted development of T regulatory cells. Anti-IL-23 and its combination with anti-IL-17 prevented bone loss. However, the individual monotherapies of anti-IL-23 and anti-IL-17 were more effective than combination therapy. Treatment of IL-17 and IL-23 cytokines to bone marrow stromal cells led to increased differentiation towards osteoblast lineage. Double neutralization of IL-23 and IL-17 might be inhibiting this phenomenon thus producing less potent effects. Our studies thus support bone protective effects of anti-IL-23 and that the monotherapies of neutralizing antibodies against IL-17 and IL-23 may be a more accepted mode of treatment in management of post-menopausal bone loss rather than combination therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. IL-35-producing B cells in gastric cancer patients.

    PubMed

    Wang, Ke; Liu, Jianming; Li, Jiansheng

    2018-05-01

    A significant characteristic of advanced gastric cancer (GC) is immune suppression, which can promote the progression of GC. Interleukin 35 (IL-35) is an immune-suppressing cytokine, and it is generally recognized that this cytokine is secreted by regulatory T (Treg) cells. Recently, studies have found that IL-35 can also be produced by B cells in mice. However, scientific studies reporting that IL-35 is secreted by B cells in humans, specifically in cancer patients, are very rare.Blood samples were collected from 30 healthy controls (HCs) and 50 untreated GC patients, and IL-35-producing B cells in the peripheral blood were investigated. Moreover, Treg cells (CD4CD25CD127), myeloid-derived suppressor cells (MDSCs) (CD14HLA-DR) and other lymphocyte subsets (CD3, CD4, CD8 T cells, activated and memory CD4 T cells, activated CD8 T cells, CD14 monocytes, and IL-10-producing B cells) were also examined.IL-35-producing B cells were significantly upregulated in patients with advanced GC. Furthermore, the frequency of IL-35-producing B cells was positively correlated with the frequencies of Treg cells (CD4CD25CD127), MDSCs (CD14HLA-DR), IL-10-producing B cells, and CD14 monocytes in these GC patients.In summary, the frequency of IL-35-producing B cells is significantly elevated in advanced GC; this outcome implies that this group of B cells may participate in GC progression.

  14. Patients with cystic fibrosis have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes.

    PubMed

    Chan, Yvonne R; Chen, Kong; Duncan, Steven R; Lathrop, Kira L; Latoche, Joseph D; Logar, Alison J; Pociask, Derek A; Wahlberg, Brendon J; Ray, Prabir; Ray, Anuradha; Pilewski, Joseph M; Kolls, Jay K

    2013-04-01

    IL-17 is an important cytokine signature of the TH differentiation pathway TH17. This T-cell subset is crucial in mediating autoimmune disease or antimicrobial immunity in animal models, but its presence and role in human disease remain to be completely characterized. We set out to determine the frequency of TH17 cells in patients with cystic fibrosis (CF), a disease in which there is recurrent infection with known pathogens. Explanted lungs from patients undergoing transplantation or organ donors (CF samples=18; non-CF, nonbronchiectatic samples=10) were collected. Hilar nodes and parenchymal lung tissue were processed and examined for TH17 signature by using immunofluorescence and quantitative real-time PCR. T cells were isolated and stimulated with antigens from Pseudomonas aeruginosa and Aspergillus species. Cytokine profiles and staining with flow cytometry were used to assess the reactivity of these cells to antigen stimulation. We found a strong IL-17 phenotype in patients with CF compared with that seen in control subjects without CF. Within this tissue, we found pathogenic antigen-responsive CD4+IL-17+ cells. There were double-positive IL-17+IL-22+ cells [TH17(22)], and the IL-22+ population had a higher proportion of memory characteristics. Antigen-specific TH17 responses were stronger in the draining lymph nodes compared with those seen in matched parenchymal lungs. Inducible proliferation of TH17(22) with memory cell characteristics is seen in the lungs of patients with CF. The function of these individual subpopulations will require further study regarding their development. T cells are likely not the exclusive producers of IL-17 and IL-22, and this will require further characterization. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  15. [Changes of CD(4)(+)Foxp3(+) regulatory T cells and CD(4)(+)IL-17(+)T cells in cigarette smoke-exposed rats].

    PubMed

    Meng, Jing-jing; Zhong, Xiao-ning; Bai, Jing; He, Zhi-yi; Zhang, Jian-quan; Huang, Qiu-pin

    2012-01-01

    To evaluate the changes of CD(4)(+)IL-17(+) T (Th17) and CD(4)(+)Foxp3(+) regulatory T (Treg) cells in peripheral blood and bronchoalveolar lavage fluid (BALF), and therefore to explore the role of Th17 and Treg in cigarette smoke-induced airway inflammation/COPD in rats. Forty male Wistar rats were randomly divided into 4 groups: a 12 wk smoke-exposure group, a 24 wk smoke-exposure group, a 12 wk control group and a 24 wk control group (n = 10 each). Cells in BALF were collected and analyzed by absolute and differential cell counts. IL-17 and IL-6 levels in serum and BALF were tested by enzyme linked immunosorbent assay (ELISA). The proportion of CD(4)(+)IL-17(+) T and CD(4)(+)Foxp3(+) Treg in peripheral blood and BALF were determined by flow cytometry. The mRNA expressions of IL-17 and Foxp3 were measured by real-time PCR. Comparisons of the data between different groups were performed using one-way ANOVA, and SNK and Games-Howell test were used for comparison between 2 groups. Levels of IL-17 were remarkable increased in the 12 wk smoke-exposure group and the 24 wk smoke-exposure group in serum [(52.6 ± 1.8) ng/L, (75.4 ± 6.0) ng/L] and BALF [(78.1 ± 5.8) ng/L, (95.0 ± 6.8) ng/L] compared with the 12 wk control group [(40.0 ± 3.2)ng/L, (54.5 ± 4.6) ng/L] and the 24 wk control group [(36.7 ± 3.2) ng/L, (53.9 ± 3.7) ng/L], all P < 0.05. IL-6 in serum was significantly increased in the 24 wk smoke-exposure group [(31.4 ± 2.1) ng/L] compared with the 24 wk control group [(11.5 ± 0.5) ng/L], and it was increased in the 12 wk and the 24 wk smoke-exposure group [(33.3 ± 2.3) ng/L, (44.6 ± 3.0) ng/L] compared with the 12 wk and the 24 wk control group [(15.6 ± 1.8) ng/L, (18.0 ± 1.9) ng/L] in BALF. Ratio of Th17 was higher in the 12 wk and the 24 wk smoke-exposure groups in peripheral blood [(1.81 ± 0.19)%, (3.74 ± 0.55)%] and BALF [(7.84 ± 0.28)%, (8.01 ± 0.39)%] compared with the12 wk [(0.97 ± 0.08)%, (5.64 ± 0.54)%] and the 24 wk control group [(1

  16. CD3+ICOS+ T cells show differences in the synthesis of nitric oxide, IFN-γ, and IL-10 in patients with pulmonary tuberculosis or in healthy household contacts.

    PubMed

    Lara-Rodríguez, Carmen; Alvarado-Vásquez, Noé; Bernal, Demetrio; Gorocica, Patricia; Zenteno, Edgar; Lascuraín, Ricardo

    2016-11-01

    Evidence indicates that more than 90 % of infected individuals never develop active tuberculosis. This fact highlights the relevance of the immune response in tuberculosis control. The inducible co-stimulator (ICOS) is a regulator of the function, differentiation, proliferation, and activation of T cells. Moreover, T cells synthesise nitric oxide (NO), interferon gamma (IFN-γ), and interleukin (IL)-10, which help regulate the immune response to tuberculosis. Therefore, we assessed the synthesis of NO, IFN-γ, and IL-10 in CD3 + ICOS + T cells from healthy individuals, household contacts (HHC), and patients with active pulmonary tuberculosis (PTB), previously stimulated with the antigen H37Rv. Our results indicated a significant increase in both the percentage of ICOS + cells and CD3 + ICOS + T cells producing NO, IFN-γ, and IL-10 in cells obtained from patients with PTB (p < 0.01). In addition, a high mitochondrial membrane potential (ΔΨ m ) in CD3 + ICOS + T cells was observed in the cells from HHC and from PTB patients, and is associated with the activation of T cells. In conclusion, results show that the CD3 + ICOS + T cells obtained from PTB patients are the main producers of NO, IFN-γ, and IL-10. In addition, our results imply that NO is a modulator of ICOS expression of T cells from PTB patients.

  17. IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity.

    PubMed

    Silva, Susana L; Albuquerque, Adriana S; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T; Victorino, Rui M M; Sousa, Ana E

    2017-01-01

    Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31 - subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31 + naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6 , a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31 - naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31 + naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.

  18. Human amniotic epithelial cells inhibit CD4+ T cell activation in acute kidney injury patients by influencing the miR-101-c-Rel-IL-2 pathway.

    PubMed

    Liu, Junfeng; Hua, Rong; Gong, Zhangbin; Shang, Bin; Huang, Yongyi; Guo, Lihe; Liu, Te; Xue, Jun

    2017-01-01

    In the pathogenesis of acute kidney injury (AKI), the release of multiple interleukins can lead to increased kidney damage. Human amniotic epithelial cells (HuAECs) can inhibit immune cell activation in vivo and in vitro. We hypothesized that HuAECs could weaken patient-derived peripheral blood CD4+ T-cell activation and decreasing the ability of these cells to express and release IL-2. -Cell proliferation assay revealed that under the same culture conditions, activated AKI patient-derived CD4+ T cells had a significantly reduced proliferation rate when were co-cultured with HuAECs. And the level of IL-2 released was also significantly reduced. Western blot and qRT-PCR assays showed that the expression of c-Rel in the CD4+ T cells was also significantly reduced. However, the expression level of endogenous miR-101 in the CD4+ T cells co-cultured with HuAECs was significantly increased. Luciferase reporter assay results suggested that miR-101 could bind to a specific site in the c-Rel 3' UTR and induce the post-transcriptional silencing of c-Rel. Subsequently, we over-expressed miR-101 in AKI patient-derived CD4+ T cells. The qRT-PCR and western blot assay results revealed that the expression of endogenous c-Rel was significantly reduced, while the ELISA results indicated that the level of IL-2 released was also significantly decreased. Finally, ChIP-PCR assay results showed that the miR-101-overexpressing CD4+ T-cell group and the HuAEC co-culture CD4+ T-cell group exhibited significantly decreased binding capacities between the 'c-Rel-NFκB' complex and the IL-2 gene promoter, and the transcriptional activity of IL-2 was also significantly decreased. Therefore, we confirmed that HuAECs can stimulate miR-101 expression in AKI patient-derived peripheral blood CD4+ T cells, thus inhibiting the expression of the miR-101 target gene c-Rel and leading to a reduction in IL-2 expression and release. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Possibilité d'une nouvelle technologie de traitement des minerais de fer de l'Ouenza par radiométrie

    NASA Astrophysics Data System (ADS)

    Idres, A.; Bounouala, M.

    2005-05-01

    En l'absence d'une technologie fiable de traitement des haldes de minerais de fer, les caractéristiques minéralogiques et chimiques complexes et les effets néfastes des résidus miniers posent réellement un problème environnemental. A cet effet, une étude minéralogique et chimique du minerai de fer a été menée en utilisant des techniques multiples (microscopie optique, DRX, FX, MEB). En tenant compte de la nature des résidus, des échantillons représentatifs ont été testés par séparation radiométrique. Plusieurs paramètres ont été caractérisés tels que la vitesse de la bande transporteuse, le temps d'émission des rayons gamma et la granulométrie d'alimentation du procédé. Les résultats ainsi obtenus par cette méthode de séparation sont très significatifs en récupération et en teneur fer. Cependant, cette nouvelle technologie permet d'une part une meilleure valorisation des minerais de fer et d'autre part une réduction du tonnage stocké sur le carreau de la mine.

  20. Aspirin induces IL-4 production: augmented IL-4 production in aspirin-exacerbated respiratory disease

    PubMed Central

    Kong, Su-Kang; Soo Kim, Byung; Gi Uhm, Tae; Soo Chang, Hun; Sook Park, Jong; Woo Park, Sung; Park, Choon-Sik; Chung, Il Yup

    2016-01-01

    Aspirin hypersensitivity is a hallmark of aspirin-exacerbated respiratory disease (AERD), a clinical syndrome characterized by the severe inflammation of the respiratory tract after ingestion of cyclooxygenase-1 inhibitors. We investigated the capacity of aspirin to induce interleukin-4 (IL-4) production in inflammatory cells relevant to AERD pathogenesis and examined the associated biochemical and molecular pathways. We also compared IL-4 production in peripheral blood mononuclear cells (PBMCs) from patients with AERD vs aspirin-tolerant asthma (ATA) upon exposure to aspirin. Aspirin induced IL-4 expression and activated the IL-4 promoter in a report assay. The capacity of aspirin to induce IL-4 expression correlated with its activity to activate mitogen-activated protein kinases, to form DNA–protein complexes on P elements in the IL-4 promoter and to synthesize nuclear factor of activated T cells, critical transcription factors for IL-4 transcription. Of clinical importance, aspirin upregulated IL-4 production twice as much in PBMCs from patients with AERD compared with PBMCs from patients with ATA. Our results suggest that IL-4 is an inflammatory component mediating intolerance reactions to aspirin, and thus is crucial for AERD pathogenesis. PMID:27534531