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Sample records for localized th1 th2

  1. Differential effects of myelin basic protein-activated Th1 and Th2 cells on the local immune microenvironment of injured spinal cord.

    PubMed

    Hu, Jian-Guo; Shi, Ling-Ling; Chen, Yue-Juan; Xie, Xiu-Mei; Zhang, Nan; Zhu, An-You; Jiang, Zheng-Song; Feng, Yi-Fan; Zhang, Chen; Xi, Jin; Lü, He-Zuo

    2016-03-01

    Myelin basic protein (MBP) activated T cells (MBP-T) play an important role in the damage and repair process of the central nervous system (CNS). However, whether these cells play a beneficial or detrimental role is still a matter of debate. Although some studies showed that MBP-T cells are mainly helper T (Th) cells, their subtypes are still not very clear. One possible explanation for MBP-T immunization leading to conflicting results may be the different subtypes of T cells are responsible for distinct effects. In this study, the Th1 and Th2 type MBP-T cells (MBP-Th1 and -Th2) were polarized in vitro, and their effects on the local immune microenvironment and tissue repair of spinal cord injury (SCI) after adoptive immunization were investigated. In MBP-Th1 cell transferred rats, the high levels of pro-inflammatory cells (Th1 cells and M1 macrophages) and cytokines (IFN-γ, TNF-α, -β, IL-1β) were detected in the injured spinal cord; however, the anti-inflammatory cells (Th2 cells, regulatory T cells, and M2 macrophages) and cytokines (IL-4, -10, and -13) were found in MBP-Th2 cell transferred animals. MBP-Th2 cell transfer resulted in decreased lesion volume, increased myelination of axons, and preservation of neurons. This was accompanied by significant locomotor improvement. These results indicate that MBP-Th2 adoptive transfer has beneficial effects on the injured spinal cord, in which the increased number of Th2 cells may alter the local microenvironment from one primarily populated by Th1 and M1 cells to another dominated by Th2, Treg, and M2 cells and is conducive for SCI repair.

  2. TH1/TH2 cytokines in the central nervous system.

    PubMed

    Sredni-Kenigsbuch, Dvora

    2002-06-01

    For the past 20 years it has become increasingly evident that cytokines play an important role in both the normal development of the brain, acting as neurotrophic factors, and in brain injuries. Although cytokines and their receptors are synthesized and expressed in the brain (normally at low levels), increased cytokine production levels are now associated with various neurological disorders. T lymphocytes are the cells responsible for coordinating the immune response and a major source of cytokines. Different cytokines induce different subsets of T cells or have different effects on proliferation within a particular subset. Recent studies suggest that the immune response is in fact regulated by the balance between Th1 and Th2 cytokines. These two pathways are often mutually exclusive, the one resulting in protection and the other in progression of disease. Various studies describe the function and production of proinflammatory cytokines in the central nervous system (CNS) and their role in health and disease. Inflammation is upregulated following activation of Th1 cells, whereas Th2 cells may play a significant role in downregulating Th1 proinflammatory responses in those instances in which there is overproduction of Th2 cytokines. Although both Th1 and Th2 cytokines may influence CNS functioning, most studies have so far dealt with proinflammatory cytokines, probably because they directly affect CNS cells and are thought to be implicated in CNS pathology. It is of interest that endogenous glucocorticoids also control Th1-Th2 balance, favoring Th2 cell development. This review presents the evidence that cytokines have important functions in the CNS, both during development and as a part of brain pathology. In particular, the author highlighted recent work that supports a major role for the so-called inflammatory cytokines, Th1, and the anti-inflammatory Th2 cytokines.

  3. Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal human pregnancy and preeclampsia

    PubMed Central

    Saito, S; Sakai, M; Sasaki, Y; Tanebe, K; Tsuda, H; Michimata, T

    1999-01-01

    We calculated the percentage of Th1, Th2, Th0 cells and the Th1:Th2 cell ratio of peripheral blood from normal pregnant subjects and preeclampsia patients using flow cytometry which can analyse both the surface marker, CD4, and intracellular cytokines, interleukin (IL)-4 and interferon (IFN)-γ. In normal pregnancy, the percentage of Th1 cells was significantly lower in the third trimester, and the ratios of Th1:Th2 were significantly lower in the second and third trimester than in nonpregnant subjects. In contrast, the percentage of Th1 cells and the ratios of Th1:Th2 in preeclampsia were significantly higher than in normal third trimester pregnant subjects. The percentage of Th2 cells in preeclampsia was significantly lower than in third trimester of normal pregnancy. Additionally, peripheral blood mononuclear cells from these subjects and patients were cultured with phytohemagglutinin stimulation, and IL-4 and IFN-γ concentrations were determined in the supernatant by enzymed linked immunosorbent assays. The percentage of Th1 and Th2, and the ratios of Th1:Th2 were correlated with cytokine (IFN-γ and IL-4) secretion level. These results demonstrated that Th2 cells were predominant in the second and third trimesters of normal pregnancy, but Th1 cells predominated in preeclamptic patients. PMID:10469061

  4. Expression of Th1- Th2- and Th17-associated cytokines in laryngeal carcinoma

    PubMed Central

    Xu, Xiaoqun; Wang, Rui; Su, Qinghong; Huang, Haiyan; Zhou, Peng; Luan, Junwen; Liu, Jingsheng; Wang, Junfu; Chen, Xuemei

    2016-01-01

    T-helper (Th) 0 cell differentiation into Th1 or Th2 cells is dependent on a number of transcription factors that act at specific time points to regulate gene expression. Th17 cells, a subset of interleukin (IL)-17-producing T cells distinct from Th1 or Th2 cells, are considered to exhibit a critical function in inflammation and autoimmune diseases, as well as cancer development. In the present study, the expression of Th1-, Th2- and Th17-associated cytokines in laryngeal cancer and pericarcinoma tissues obtained from 57 laryngeal carcinoma patients was investigated. The association between Th1, Th2 and Th17 infiltration and tumor development was also evaluated. Reverse transcription-polymerase chain reaction and western blotting results revealed that the mRNA and protein expression of Th2 cytokines was lower, while the expression of Th1 and Th17 cytokines was higher in tumor tissues than in pericarcinoma tissues. Furthermore, the early stage cancer patients exhibited a higher level of interferon-γ, IL-2 and IL-17 mRNA expression than those at advanced stages. Cancer tissues exhibited higher Th17 cytokine expression than pericarcinoma tissues. By contrast, Th1 cytokine expression was increased in pericarcinoma tissues compared with cancer tissues. These results indicate that high expression of Th1- and Th17-associated cytokines in laryngeal carcinoma may contribute to suppression of cancer development and a relatively good prognosis. PMID:27588143

  5. Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance

    PubMed Central

    Martino, Matteo; Rocchi, Giulio; Escelsior, Andrea; Fornaro, Michele

    2012-01-01

    Neurotransmitters and hormones regulate major immune functions, including the selection of T helper (Th)1 or Th2 cytokine responses, related to cell-mediated and humoral immunity, respectively. A role of imbalance and dynamic switching of Th1/Th2 system has been proposed, with relative displacement of the immune reserve in relation to complex interaction between Th1/Th2 and neuro-hormonal balance fluctuations, in the pathogenesis of various chronic human diseases, probably also including psychiatric disorders. Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance. It could be therefore hypothesized that the antidepressant-related increase in NE tone enhances the Th2 response, while the decrease in NE tone or the increase in 5-HT tone enhances the Th1 response. However, the neurotransmitter and Th1/Th2 balance modulation could be relative, aiming to restore physiological levels a previous imbalance in receptor sensitivity and cytokine production. The considerations on neuro-immunomodulation could represent an additional aid in the study of pathophysiology of psychiatric disorders and in the choice of specific antidepressants in specific clusters of symptoms, especially in comorbidity with internal pathologies. Furthermore limited data, reviewed here, have shown the effectiveness of some antidepressants as pure immunomodulators. However, these considerations are tentative and require experimental confirmation or refutation by future studies. PMID:23204981

  6. Altered Th1/Th2 commitment contributes to lung senescence in CXCR3-deficient mice.

    PubMed

    Huang, Junmin; Li, Zongli; Yao, Xiujuan; Li, Yan; Reng, Xiaoxia; Li, Junfa; Wang, Wei; Gao, Jinming; Wang, Chen; Tankersley, Clarke G; Huang, Kewu

    2013-08-01

    Aging is an inevitable process associated with immune imbalance, which is characterized by a progressive functional decline in major organs, including lung. However, effects of altered Th1/Th2 commitment on lung senescence are largely unknown. To examine effects of altered Th1/Th2 balance on lung aging, we measured proportions of Th1 and Th2 cells and expression of cytokines, chemokines, collagen deposition and other relevant physiological and pathological parameters in 2- and 20-months-old (mo) CXCR3-deficient (CXCR3(-/-)) C57BL/6J mice compared with wild-type (WT) mice. There was a significant weight-loss observed in 20-mo CXCR3(-/-) mice compared with the same aged WT group. Although lung function and structure changed with age in both groups, central airway resistance (Rn), tissue elastance (H) and damping (G) were significantly lower in 20-mo CXCR3(-/-) mice than those of WT mice. In contrast, the whole lung volume (V(L)), the mean linear intercept length of alveolar (L(m)), and the total lung collagen content were significantly elevated in 20-mo CXCR3(-/-) mice. With aging, the lungs of WT mice had typical Th1-type status (increased population of Th1 cells and concentrations of cytokine IFN-γ and CXCR3 ligands) while CXCR3(-/-) mice showed Th2-type polarization (decreased proportion of Th1 cells and concentrations of CXCR3 ligands but increased level of IL-4). Our data suggest that Immunosenescence is associated with lung aging, and that altered Th1/Th2 imbalance favors Th2 predominance in CXCR3(-/-) mice, which contributes to the process of accelerated lung aging in this model.

  7. Diisononyl phthalate induces asthma via modulation of Th1/Th2 equilibrium.

    PubMed

    Hwang, Yun-Ho; Paik, Man-Jeong; Yee, Sung-Tae

    2017-03-12

    Diisononyl phthalate (DINP), a member of the phthalate family, is used to plasticize polyvinyl chloride (PVC). This chemical is known to enhance airway inflammation in the OVA-induced asthma model (adjuvant effects) and aggravate allergic dermatitis. Moreover, DINP enhances the production of interleukin-4 in activated CD4(+) T cells. However, the effect of DINP itself on the differentiation of naïve CD4(+) T cells into T helper cells (Th1/Th2) in vitro and allergic asthma in vivo has not yet been studied. In this study, DINP was shown to suppress the polarization of Th1 and enhance the polarization of Th2 from naïve CD4(+) T cells in vitro. Also, DINP induced allergic asthma via the production of IL-4, IL-5, IgE and IgG1 and the reduction of IFN-γ and IgG2a. Finally, we confirmed that exposure to DINP induces the infiltration of inflammatory cells and PAS positive cells and increases the expression of caspase-1 and caspase-3 in asthmatic mice. In conclusion, we suggest that DINP as an environmental pollutant or endocrine disruptor (ECD) induces asthma via the modulation of the Th1/Th2 equilibrium and production of Th2 mediated cytokines and immunoglobulin.

  8. Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

    PubMed Central

    Jones, Stephen W.; Roberts, Reid A.; Robbins, Gregory R.; Perry, Jillian L.; Kai, Marc P.; Chen, Kai; Bo, Tao; Napier, Mary E.; Ting, Jenny P.Y.; DeSimone, Joseph M.; Bear, James E.

    2013-01-01

    Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopy–based assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte–derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans. PMID:23778144

  9. Th1, Th2 and Treg/T17 cytokines in two types of proliferative glomerulonephritis

    PubMed Central

    Stangou, M.; Bantis, C.; Skoularopoulou, M.; Korelidou, L.; Kouloukouriotou, D.; Scina, M.; Labropoulou, I. T.; Kouri, N. M.; Papagianni, A.; Efstratiadis, G.

    2016-01-01

    IgA nephropathy (IgAN) and focal segmental necrotizing glomerulonephritis (FSNGN) are characterized by proliferation of native glomerular cells and infiltration by inflammatory cells. Several cytokines act as mediators of kidney damage in both diseases. The aim of the present study was to investigate the role of Th1, Th2 and Treg/T17 cytokines in these types of proliferative glomerulonephritis. Simultaneous measurement of Th1 interleukin (IL-2, IL-12, tumor necrosis factor-alpha [TNF-α], interferon-gamma [INF-γ]), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), Treg/T17 transforming growth factor-beta 1 (TGF-β1, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17) cytokines and C-C chemokines Monocyte chemoattractant protein-1 (MCP-1, macrophage inflammatory protein-1 [MIP-1] β) was performed in first-morning urine samples, at the day of renal biopsy, using a multiplex cytokine assay. Cytokine concentrations were correlated with histological findings and renal function outcome. Urinary excretion of Th1, Th2 and Treg/Th17 cytokines were significantly higher in FSNGN compared to IgAN patients. In IgAN patients (n = 50, M/F: 36/14, M age: 40.7 [17–67] years), Th1, Th2 and T17 cytokines correlated significantly with the presence of endocapillary proliferation, while in FSNGN patients (n = 40, M/F: 24/16, M age: 56.5 [25–80] years), MCP-1 and TGF-β1 had a positive correlation with severe extracapillary proliferation (P = 0.001 and P = 0.002, respectively). Urinary IL-17 was the only independent parameter associated with endocapillary proliferation in IgAN and with MCP-1 urinary excretion in FSNGN. Response to treatment was mainly predicted by IL-6 in IgAN, and by Th2 (IL-4, IL-6), Treg (GM-CSF) cytokines and MIP-1 β in FSNGN. Th1, Th2 and T17 cytokines were directly implicated in renal pathology in IgAN and possibly through MCP-1 production in FSNGN. IL-17 and IL-6 seem to have a central role in inflammation and progression of kidney injury. PMID:27194829

  10. The expanding universe of T-cell subsets: Th1, Th2 and more.

    PubMed

    Mosmann, T R; Sad, S

    1996-03-01

    Since their discovery nearly ten years ago, T helper 1 (Th1) and Th2 subsets have been implicated in the regulation of many immune responses. In this article, Tim Mosmann and Subash Sad discuss the increasing number of T-cell subsets defined by cytokine patterns; the differentiation pathways of CD4+ and CD8+ T cells; the contribution of other cell types to these patterns; and the cytokine interactions during infection and pregnancy.

  11. Th-1, Th-2 Cytokines Profile among Madurella mycetomatis Eumycetoma Patients

    PubMed Central

    Nasr, Amre; Abushouk, Amir; Hamza, Anhar; Siddig, Emmanuel; Fahal, Ahmed H.

    2016-01-01

    Eumycetoma is a progressive and destructive chronic granulomatous subcutaneous inflammatory disease caused by certain fungi, the most common being Madurella mycetomatis. The host defence mechanisms against fungi usually range from an early non-specific immune response to activation and induction of specific adaptive immune responses by the production of Th-1 and Th-2 cytokines. The aim of this study is to determine the levels of Th-1 and Th-2 cytokines in patients infected with Madurella mycetomatis, and the association between their levels and disease prognosis. This is a descriptive cross-sectional study conducted at the Mycetoma Research Centre, University of Khartoum, Sudan, where 70 patients with confirmed M. mycetomatis eumycetoma were enrolled; 35 with, and 35 without surgical excision. 70 healthy individuals from mycetoma endemic areas were selected as controls. The levels of serum cytokines were determined by cytometric bead array technique. Significantly higher levels of the Th-1 cytokines (IFN-γ, TNF-α, IL-1β and IL-2) were recorded in patients treated with surgical excision, compared to those treated without surgical excision. In contrast, the Th-2 cytokines (IL-4, IL-5, IL-6 and IL-10) were significantly lower in patients treated with surgical excision compared to those treated without surgical excision. In conclusion, the results of this study suggest that cell-mediated immunity can have a role to play in the pathogenesis of eumycetoma. PMID:27434108

  12. Distinct Th1- and Th2-Type prenatal cytokine responses to Plasmodium falciparum erythrocyte invasion ligands.

    PubMed

    Malhotra, Indu; Mungai, Peter; Muchiri, Eric; Ouma, John; Sharma, Shobhona; Kazura, James W; King, Christopher L

    2005-06-01

    Prenatal immunity to Plasmodium falciparum merozoite proteins involved in erythrocyte invasion may contribute to the partial protection against malaria that is acquired during infancy in areas of stable malaria transmission. We examined newborn and maternal cytokine and antibody responses to merozoite surface protein-1 (MSP-1), ribosomal phosphoprotein P0 (PfP0), and region II of erythrocyte binding antigen-175 (EBA-175) in infant-mother pairs in Kenya. Overall, 82 of 167 (50%), 106 of 176 (60%), and 38 of 84 (45%) cord blood lymphocytes (CBL) from newborns produced one or more cytokines in response to MSP-1, PfP0, and EBA-175, respectively. Newborns of primigravid and/or malaria-infected women were more likely to have antigen-responsive CBL than were newborns of multigravid and/or uninfected women at delivery. Newborn cytokine responses did not match those of their mothers and fell into three distinct categories, Th1 (21 of 55 CBL donors produced only gamma interferon and/or interleukin 2 [IL-2]), Th2 (21 of 55 produced only IL-5 and/or IL-13), and mixed Th1/Th2 (13 of 55). Newborns produced more IL-10 than adults. High and low levels of cord blood IL-12 p70 production induced by anti-CD40 activation were associated with malaria-specific Th1 and Th2 responses, respectively. Antigen-responsive CBL in some newborns were detected only after depletion of IL-10-secreting CD8 cells with enrichment for CD4 cells. These data indicate that prenatal sensitization to blood-stage Plasmodium falciparum occurs frequently in areas where malaria is holoendemic. Modulation of this immunity, possibly by maternal parity and malaria, may affect the acquisition of protective immunity against malaria during infancy.

  13. Apigenin Attenuates Experimental Autoimmune Myocarditis by Modulating Th1/Th2 Cytokine Balance in Mice.

    PubMed

    Zhang, Shouxin; Liu, Xiaoyan; Sun, Chengming; Yang, Jun; Wang, Lihong; Liu, Jie; Gong, Lei; Jing, Yanyan

    2016-04-01

    This study aims to investigate the protective effect of apigenin on the development of experimental autoimmune myocarditis (EAM) and the underlying mechanisms. An EAM model was induced in BALB/c mice by the injection of porcine cardiac myosin. Apigenin was orally administered from day 1 to 21. The severity of myocarditis was assessed by determination of heart weight/body weight ratio (HW/BW) and histopathological evaluation. Echocardiography was conducted to evaluate the cardiac function and heart structure. Antigen-specific T cell proliferation responses to cardiac myosin were evaluated by the lymphocyte proliferation assay. ELISA was used to determine serum levels of type 1 helper (Th1) and Th2 cytokines. Apigenin treatment significantly decreased HW/BW. Histopathologic analysis showed that the infiltration of inflammatory cells was reduced significantly by apigenin treatment. Meanwhile, apigenin administration effectively ameliorated autoimmune myocarditis-induced cardiac hypertrophy and cardiac dysfunction as well as inhibited lymphocyte proliferation in mice immunized with myosin. Furthermore, Th1 cytokines tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) were significantly downregulated, while Th2 cytokines IL-4 and IL-10 were markedly upregulated. The results indicated that apigenin can alleviate EAM due to its immunomodulatory reactions in modification of helper T cell balance.

  14. T-cell clones in human trichinellosis: Evidence for a mixed Th1/Th2 response.

    PubMed

    Della Bella, C; Benagiano, M; De Gennaro, M; Gomez-Morales, M A; Ludovisi, A; D'Elios, S; Luchi, S; Pozio, E; D'Elios, M M; Bruschi, F

    2017-03-01

    In humans, studies on the cellular immune response against Trichinella are scarce. Aim of this study was to characterize the cytokine profile of T cells specific for Trichinella britovi in trichinellosis patients. Peripheral blood mononuclear cells (PBMC) were obtained from five patients involved in a trichinellosis outbreak caused by T. britovi, which occurred in 2013 in Tuscany (Italy). All the patients resulted positive for Trichinella-specific IgG, IgE and presented eosinophilia. T cells were investigated for their proliferation to excretory/secretory antigens from Trichinella spiralis muscle larvae (TsES) and for their cytokine profile. A total of 284 CD4+ and 42 CD8+ T-cell clones were obtained from the TsES-specific T-cell lines from PBMC. All T-cell clones proliferated in response to mitogen. Of the 284 CD4+ T-cell clones generated from TsES-specific T-cell lines, 135 (47%) proliferated significantly to TsES; 26% CD8+ T-cell clones showed proliferation to TsES. In the series of the 135 TsES-specific CD4+ clones, 51% expressed a Th2 profile, 30% a Th0 and 19% Th1. In the series of the 11 TsES-specific CD8+ T-cell clones, 18% were Tc2, 45% Tc0 and 36% Tc1. In human trichinellosis, the cellular immune response is, during the chronic phase, mixed Th1/Th2.

  15. Th1 and Th2 cytokine profiles in sickle cell disease.

    PubMed

    Raghupathy, R; Haider, M Z; Azizieh, F; Abdelsalam, R; D'Souza, T M; Adekile, A D

    2000-01-01

    We have investigated the levels of Th1 (IL-2 and IFN-gamma) and Th2 (IL-4) cytokines in the plasma and supernatants following peripheral blood mononuclear cell culture and mitogen stimulation in a group of 39 patients with sickle cell disease (SCD) made up of 29 SS, 8 Sbeta-thal and 2 Hb SD in steady state. Five SS patients were studied during 7 episodes of vaso-occlusive crisis. Twenty-four control (3 Hb AS and 21 Hb AA) were also studied; 10 were acutely ill while 14 were healthy at the time of the study. The plasma levels of IL-2 and IFN-gamma were similar in the patients and the controls. However, plasma IL-4 was significantly higher among the steady-state SS patients than in the controls. While there was no significant difference in cytokine levels following mitogen stimulation in the different groups, plasma IL-2 to IL-4 and IFN-gamma to IL-4 ratios were significantly lower among the steady-state SS patients, indicating a possible Th2 bias in our sickle cell patients and suggesting a possible mechanism to explain the predisposition of SCD patients to bacterial infections. However, SS patients with good splenic function showed a relative Th1 bias, which may be an additional explanation for the protection against bacterial infections in such patients.

  16. Effect of ultra violet irradiation on the interplay between Th1 and Th2 lymphocytes

    PubMed Central

    Abo Elnazar, Salma Y.; Ghazy, Amany A.; Ghoneim, Hossam E.; Taha, Abdul-Rahman M.; Abouelella, Amira M.

    2015-01-01

    Although ultraviolet (UV) radiation is used to treat several types of diseases, including rickets, psoriasis, eczema, and jaundice, the prolonged exposure to its radiation may result in acute and chronic health effects particularly on the skin, eyes, and the immune system. Aim: This study was carried out to show the effect of UV on both of the lymphoproliferative response and their capacity to produce IL-12 and IL-10 in mice. Methods: Mice were exposed to whole body UVB and tested for the effect of recovery times on lymphocyte proliferation and cytokine production. In addition, direct irradiation of spleens and lymphocyte suspension was carried out. Basal and mitogens-stimulated lymphocyte proliferation was assessed by MTT assay while IL-10 and IL-12 were measured using ELISA. Results: There was a significant suppression in lymphocyte proliferation in comparison with control. IL-12 level was significantly reduced while the level of IL-10 was increased. Con A and PWM mitogens had no significant changes in IL-10 while Con A caused a highly significant increase in IL-12 at day 6 of recovery in UVB body irradiation. Conclusion: Exposure to UVB radiation could cause a state of immune suppression and shifts Th1/Th2 cell response. This effect is closely associated with the reduction of Th1 cytokines’ expression and increase in Th2 cytokines’ levels. PMID:25852558

  17. CD4 T-Cell Subsets in Malaria: TH1/TH2 Revisited

    PubMed Central

    Perez-Mazliah, Damian; Langhorne, Jean

    2015-01-01

    CD4+ T-cells have been shown to play a central role in immune control of infection with Plasmodium parasites. At the erythrocytic stage of infection, IFN-γ production by CD4+ T-cells and CD4+ T-cell help for the B-cell response are required for control and elimination of infected red blood cells. CD4+ T-cells are also important for controlling Plasmodium pre-erythrocytic stages through the activation of parasite-specific CD8+ T-cells. However, excessive inflammatory responses triggered by the infection have been shown to drive pathology. Early classical experiments demonstrated a biphasic CD4+ T-cell response against erythrocytic stages in mice, in which T helper (Th)1 and antibody-helper CD4+ T-cells appear sequentially during a primary infection. While IFN-γ-producing Th1 cells do play a role in controlling acute infections, and they contribute to acute erythrocytic-stage pathology, it became apparent that a classical Th2 response producing IL-4 is not a critical feature of the CD4+ T-cell response during the chronic phase of infection. Rather, effective CD4+ T-cell help for B-cells, which can occur in the absence of IL-4, is required to control chronic parasitemia. IL-10, important to counterbalance inflammation and associated with protection from inflammatory-mediated severe malaria in both humans and experimental models, was originally considered be produced by CD4+ Th2 cells during infection. We review the interpretations of CD4+ T-cell responses during Plasmodium infection, proposed under the original Th1/Th2 paradigm, in light of more recent advances, including the identification of multifunctional T-cells such as Th1 cells co-expressing IFN-γ and IL-10, the identification of follicular helper T-cells (Tfh) as the predominant CD4+ T helper subset for B-cells, and the recognition of inherent plasticity in the fates of different CD4+ T-cells. PMID:25628621

  18. Both Th1 and Th2 Cells Require P-Selectin Glycoprotein Ligand-1 for Optimal Rolling on Inflamed Endothelium

    PubMed Central

    Mangan, Paul R.; O’Quinn, Darrell; Harrington, Laurie; Bonder, Claudine S.; Kubes, Paul; Kucik, Dennis F.; Bullard, Daniel C.; Weaver, Casey T.

    2005-01-01

    The acquisition of homing receptors that redirect lymphocyte trafficking to nonlymphoid tissues after antigen encounter is a fundamental aspect of effector T-cell development. Although a role for selectins and their ligands has been well characterized for trafficking of Th1 cells to nonlymphoid sites, mechanisms responsible for Th2 trafficking are not well understood. Using a flow chamber system in which the endothelial interactions of two distinct T-cell populations could be examined simultaneously, we directly compared the requirements for Th1 and Th2 cell tethering and rolling. We found that although Th2 cells expressed significantly lower levels of selectin ligands than Th1 cells, activation of the endothelium by Th2-derived factors induced rolling interactions that were comparable for both Th1 and Th2 populations. Further, in the absence of PSGL-1, no other adhesion molecule could effectively compensate for lack of PSGL-1 to mediate rolling of either Th1 or Th2 cells. Thus, both Th1 and Th2 populations express functional PSGL-1-based selectin ligands for tethering and rolling on activated endothelium, and both effector populations can use PSGL-1 as the dominant scaffold for functional selectin ligand expression. PMID:16314478

  19. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm

    PubMed Central

    Hirahara, Kiyoshi

    2016-01-01

    CD4+ T cells are crucial for directing appropriate immune responses during host defense and for the pathogenesis of inflammatory diseases. In addition to the classical biphasic model of differentiation of T-helper 1 (Th1) and Th2 cells, unexpected increases in the numbers of CD4+ T-cell subsets, including Th17, Th9, T follicular-helper (Tfh) and T-regulatory (Treg) cells, have been recognized. In the present review, we focus on how these various T-helper cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. In particular, we focus on multiple sclerosis, psoriasis and asthma as typical model diseases in which multiple T-helper cell subsets have recently been suggested to play a role. We will also discuss various unique sub-populations of T-helper cells that have been identified. First, we will introduce the heterogeneous T-helper cell subsets, which are classified by their simultaneous expression of multiple key transcription factors. We will also introduce different kinds of memory-type Th2 cells, which are involved in the pathogenesis of chronic type-2 immune-related diseases. Finally, we will discuss the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T-helper cell subsets. The latest progress in the study of T-helper cell subsets has forced us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the Th1/Th2 balance. To this end, we propose another model—the pathogenic T-helper population disease-induction model—as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases. PMID:26874355

  20. Analysis of Serum Th1/Th2 Cytokine Levels in Patients with Acute Mumps Infection

    PubMed Central

    Malaiyan, Jeevan; Ramanan, Padmasani Venkat; Subramaniam, Dinesh; Menon, Thangam

    2016-01-01

    Background: The mumps virus is frequently the causative agent of parotitis. There has been no study on serum cytokine levels of acute mumps parotitis except for a few which document cytokine levels in cerebrospinal fluid of mumps meningitis. It is with this notion, our study aimed to find Th1/Th2 cytokine levels from patients with acute mumps parotitis. Materials and Methods: Concentrations of mumps-specific IgM, mumps, measles, rubella-specific IgG antibody, and Th1/Th2 cytokines, namely interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, and IL-10 were measured simultaneously in serum from 74 patients (42 pediatric and 32 adult cases), 40 healthy subjects (20 pediatric and 20 adults) and in the supernatant of peripheral blood mononuclear cells stimulated with mumps virus genotype C which served as the positive control. Statistical significance was analyzed between each group by means of Mann–Whitney U-test, Kruskal–Wallis test, and Spearman's rank correlation coefficient test. Results: IgM positivity confirmed acute infection in all 74 patients and of these 67 were vaccinated cases; however, very few of them (10/67) were positive for mumps IgG. We found that IFN-γ, IL-2, and IL-10 showed a statistically significant increase in both pediatric and adult patients with acute mumps infection when compared to healthy controls and values were comparable to the positive control. Conclusion: The Th1 cells play important roles during the acute phase of mumps parotitis. PMID:27293364

  1. Differential chemokine expression following respiratory virus infection reflects Th1- or Th2-biased immunopathology.

    PubMed

    Culley, Fiona J; Pennycook, Alasdair M J; Tregoning, John S; Hussell, Tracy; Openshaw, Peter J M

    2006-05-01

    Respiratory syncytial virus (RSV) is a major viral pathogen of infants that also reinfects adults. During RSV infection, inflammatory host cell recruitment to the lung plays a central role in determining disease outcome. Chemokines mediate cell recruitment to sites of inflammation and are influenced by, and influence, the production of cytokines. We therefore compared chemokine production in a mouse model of immunopathogenic RSV infection in which either Th1 or Th2 immunopathology is induced by prior sensitization to individual RSV proteins. Chemokine expression profiles were profoundly affected by the nature of the pulmonary immunopathology: "Th2" immunopathology in BALB/c mice was associated with increased and prolonged expression of CCL2 (MCP-1), CXCL10 (IP-10), and CCL11 (eotaxin) starting within 24 h of challenge. C57BL/6 mice with "Th2" pathology (enabled by a deficiency of CD8+ cells) also showed increased CCL2 production. No differences in chemokine receptor expression were detected. Chemokine blockers may therefore be of use for children with bronchiolitis.

  2. CD30 antigen: not a physiological marker for TH2 cells but an important costimulator molecule in the regulation of the balance between TH1/TH2 response.

    PubMed

    Pellegrini, Patrizia; Berghella, Anna Maria; Contasta, Ida; Adorno, Domenico

    2003-01-01

    Understanding the physiological role of CD30 would be an important step forward in transplants because CD30+ T cells can be induced by alloantigens even in the presence of immunosuppressives such as cyclosporine (Csa) and hence can act as regulatory cells in allograft. The results of functional studies on purified T CD30+ cell populations led us to hypothesize that the CD30 costimulator molecule is not a specific marker for TH2 cells in normal conditions, as has been suggested, but rather a marker for an important immunoregulatory subpopulation that regulates the balance between TH1 and TH2 (TH1/TH2) type response. To substantiate this hypothesis we studied the TH1/TH2 cytokine network in peripheral whole blood cultures stimulate with M44 CD30 ligand (CD30L), an agonistic monoclonal antibody (mAb). Four types of whole blood culture were used: the first had been stimulated with anti-CD3 mAb which generates a CD30 cytokine profile similar to alloreactive stimulation; the second with anti-CD3 mAb+M81 (an anti-CD30L mAb) to inhibit CD30/CD30L interaction; the third with anti-CD3+anti-interleukin (IL)4 mAbs to counteract IL4 activity and the fourth with anti-CD3+anti-interferon (IFN)gamma mAbs to counteract IFNgamma activity. Network interactions between soluble CD30 (sCD30, a maker of CD30 expression), sBcl2 (a marker of cell survival) and TH1/TH2 cytokines (IFNgamma, IL2, IL12p70, IL12p40, IL4, IL5 and IL10) were then studied in the supernatants obtained. Our results confirm the hypothesis above by showing that CD30 signals trigger functional mechanisms responsible for changes in levels of production of several important TH1 and TH2 cytokines involved in the regulation of the physiological balance between TH1/TH2 functions. The CD30-stimulated network, in fact, induces IFNgamma production linked to TH1 activity (-->TH1) which is subsequently integrated by IL4 production linked to TH2 activity (-->TH2). This production appears to be regulated, respectively, by IL12p40

  3. Effect of Th1/Th2 cytokine administration on proinflammatory SKOV-3 cell activation

    PubMed Central

    Sikora, Justyna; Kondera-Anasz, Zdzisława; Mickiewicz, Patrycja; Mickiewicz, Adam

    2015-01-01

    Introduction Interleukin(IL)-1β, IL-6 and IL-12 might associate with inflammatory processes in a tumor progression and create a specific microenvironment for tumor growth. The aim of the study was to assess whether the Th1 and Th2 type cytokines, such as IL-2 and IL-10, affect ovarian carcinoma continuous cell line (SKOV-3) pro-inflammatory activation. Material and methods SKOV-3 ovarian cells and peripheral blood mononuclear cells (PBMCs) were stimulated by IL-2 and IL-10. Additionally, SKOV-3 ovarian cells and PBMCs were co-cultured together. Proinflammatory activation of cancer cells was evaluated by measurement of IL-1β and IL-6 levels in culture fluid after 72 h of incubation. Results SKOV-3 cells and PBMCs secreted IL-1β and IL-6. After stimulation by IL-2 and IL-10, secretion of studied parameters was changed in a dose-dependent manner. The addition of a higher IL-2 level gave rise to an increase of IL-1β, IL-6 and IL-12 secretion in SKOV-3 cells. Stimulation by IL-10 increased only IL-1β secretion in SKOV-3 cells. However, IL-6 secretion decreased after stimulation with 25 ng/ml IL-10. Activatory effects of IL-2 and inhibitory effects of IL-10 in co-culture of SKOV-3 and PBMCs were observed. Conclusions Our results suggested that Th1/Th2 type of cytokines might influence pro-inflammatory activation of SKOV-3 ovarian cells. Co-cultures of SKOV-3 and PBMCs showed significant changes in cross-talk between cancer and immune cells. PMID:27904527

  4. Blood myeloid and lymphoid dendritic cells reflect Th1/Th2 balance in sarcoidosis and extrinsic allergic alveolitis.

    PubMed

    Buczkowski, Jarosław; Krawczyk, Paweł; Chocholska, Sylwia; Tabarkiewicz, Jacek; Kieszko, Robert; Michnar, Marek; Milanowski, Janusz; Roliński, Jacek

    2003-01-01

    Dendritic cells play a specific regulatory role in the immune system. In this paper, the significance of myeloid and lymphoid dendritic cells in sarcoidosis and extrinsic allergic alveolitis (EAA) was evaluated. Myeloid dendritic cells are connected with Th1 type of immunological response, whereas lymphoid ones--with Th2 type. The latest findings indicate that both diseases are characterized by serious disturbances of Th1/Th2 response to Th1 dominance. Our studies seem to confirm these suggestions. In the peripheral blood of patients with sarcoidosis as well as with EAA, myeloid dendritic cells outnumbered lymphoid ones.

  5. The influence of leptin on Th1/Th2 balance in obese children with asthma*

    PubMed Central

    Youssef, Doaa Mohammed; Elbehidy, Rabab Mohamed; Shokry, Dina Mahamoud; Elbehidy, Eman Mohamed

    2013-01-01

    OBJECTIVE: In individuals with asthma, obesity induces the production of leptin and is associated with disease severity. Our objective was to evaluate the levels of serum leptin and their effect on Th1/Th2 balance in obese and non-obese children with asthma, as well as to investigate the association between serum leptin levels and clinical outcomes. METHODS: We evaluated 50 atopic children with physician-diagnosed moderate-to-severe persistent asthma and 20 controls. The children with asthma were divided into two groups, by body mass index percentile: obese (n = 25) and non-obese (n = 25). From all subjects, we collected peripheral blood samples in order to determine the levels of leptin, IFN-γ, and IL-4. Asthma severity was assessed by an asthma symptom score, and the results were correlated with the parameters studied. RESULTS: Serum leptin levels were significantly higher in the obese asthma group than in the non-obese asthma group, as well as being significantly higher in the children with asthma than in the controls, whereas IFN-γ levels were significantly higher and IL-4 levels were significantly lower in the obese asthma group than in the non-obese asthma group. In addition, the obese asthma group showed higher asthma symptom scores and significantly lower FEV1 (% of predicted) than did the non-obese asthma group. There was a significant positive correlation between leptin and IFN-γ levels only in the obese asthma group. CONCLUSIONS: Although leptin is involved in the pathogenesis of asthma in obese and non-obese children, its effect is more pronounced in the former. In the presence of high leptin levels, only obese children with asthma exhibited Th1 polarization, with higher IFN-γ levels and greater asthma severity. PMID:24310629

  6. CD4+/CD25+ T-Lymphocytes and Th1/Th2 regulation in dilated cardiomyopathy

    PubMed Central

    Efthimiadis, I; Skendros, P; Sarantopoulos, A; Boura, P

    2011-01-01

    Objective: Autoimmune mechanisms are often involved in the pathogenesis of Dilated Cardiomyopathy (DCM) and Th1 immune response against cardiac antigens plays a pivotal role in disease development. Methods: IL-2 receptor (CD4+/CD25+) and cytokines IL-2, IFN-γ, IL-10 were studied in 42 patients (17 with DCM - DCM group, 10 patients with hypertrophic cardiac disease - HCD group, and 15 healthy volunteers - Control group). DCM group was subdivided in: DCM-1 (9 patients with recent disease onset) and DCM-2 (8 patients with chronic DCM). The % CD4+/CD25+ T-lymphocytes were analyzed by double fluorescence flow cytometry both ex vivo and after phytohaemagglutinin (PHA)-cultures with/without 5 and 10 microgr of human cardiac myosin. The cytokines were measured using Enzyme-Linked Immunosorbant Assay (ELISA) method. Results: Ex vivo analysis: In DCM group, CD4+/CD25+ T-cells significantly increased compared to other groups (p<0.05), due exclusively to DCM-2 subgroup (p=0.019). In PHA cultures in DCM-2 subgroup CD4+/CD25+ T-lymphocytes were significantly increased compared to all other groups (p<0.001). The addition of myosin in the cultures of DCM-2 subgroup maintained the same result. In cultures supernatants in DCM-2 subgroup, IL-2 levels were impressively increased compared to DCM-1 subgroup (p=5.91x10-6), HCD and Control groups (p<0.001). Addition of antigen decreased significantly IL-2 levels in DCM-2 subgroup (p=0.01). IFN-γ levels followed the same pattern of alterations. IL-10 levels were significantly increased in both DCM subgroups compared to HCD and Control groups (p<0.05). Conclusions: Increased peripheral CD4+/CD25+ T-cells found in chronic DCM could be a useful prognostic marker in DCM progress. Increased synthesis of IL-2 and IFN-γ and varying IL-10 levels reflects a Th1 pattern of immune response during chronic disease and implies active cellular immunity process, related to poor prognosis. Thus, analysis of the Th1/Th2 phenotype may be useful in disease

  7. Molecular cloning and characterization of Th1 and Th2 cytokines of African buffalo (Syncerus caffer).

    PubMed

    Suzuki, S; Konnai, S; Okagawa, T; Githaka, N W; Kariuki, E; Gakuya, F; Kanduma, E; Shirai, T; Ikebuchi, R; Ikenaka, Y; Ishizuka, M; Murata, S; Ohashi, K

    2012-04-01

    The African buffalo (Syncerus caffer) has been implicated as the reservoir of several bovine infectious agents. However, there is insufficient information on the protective immune responses in the African buffalo, particularly in infected animals. In this study, we analysed Th1 cytokines IL-2 and IFN-γ, and Th2 cytokines IL-4 and IL-10. The cloned cDNA of IL-2, IL-4, IL-10 and IFN-γ contained an open reading frame of 468, 501, 408 and 540 nucleotides, encoding polypeptides of 155, 166, 135 and 179 amino acids, respectively. Nucleotide sequence homology of IL-2, IFN-γ and IL-4 was more than 98% between the African buffalo and cattle, which resulted in identical polypeptides. Meanwhile, IL-10 gene of African buffalo and cattle had 95% homology in nucleotide sequence, corresponding to thirteen amino acid residues substitution. Cysteine residues and potential glycosylation sites were conserved within the family Bovinae. Phylogenetic analyses including cytokines of the African buffalo placed them within a cluster comprised mainly of species belonging to the order Artiodactyla, including cattle, water buffalo, sheep, goat, pig and artiodactyl wildlife. A deeper understanding of the structure of these cytokines will shed light on their protective role in the disease-resistant African buffalo in comparison with other closely related species.

  8. Effects of strenuous exercise on Th1/Th2 gene expression from human peripheral blood mononuclear cells of marathon participants.

    PubMed

    Xiang, Lianbin; Rehm, Kristina E; Marshall, Gailen D

    2014-08-01

    Physical stressors, such as strenuous exercise, can have numerous effects on the human body including the immune system. The aim of this study was to evaluate the gene expression profile of Th1/Th2 cytokines and related transcription factor genes in order to investigate possible immune imbalances before and after a marathon. Blood samples were collected from 16 normal volunteers 24-48 h before and one week after completing a marathon race. Gene expression of Th1 and Th2 related cytokines from human peripheral blood mononuclear cells (PBMC) was analyzed using Human Th1-Th2-Th3 RT(2) Profiler PCR Array and qRT-PCR that measured the transcript levels of 84 genes related to T cell activation. We found that PBMC express a characteristic Th2-like gene profile one week post-marathon compared to pre-marathon. The majority of genes up-regulated one week post-marathon such as IL-4, GATA3, and CCR4 were Th2 associated. For Th1-related genes, CXCR3 and IRF1 were up-regulated one week post-marathon. There was a trend of down-regulation of two Th1 related genes, T-bet and STAT1. Th3-related gene expression patterns did not change in the study. The ratios of both IFN-γ/IL-4 and T-bet/GATA3 gene expressions were significantly lower one week after marathon. These findings suggest that a Th1/Th2 immune imbalance persisted at least 1 week after completion of a marathon which offers a mechanistic rationale for the increased risk of upper respiratory tract infections often reported after strenuous exercise.

  9. Modulation of Th1/Th2 immune responses to HIV-1 Tat by new pro-GSH molecules.

    PubMed

    Fraternale, Alessandra; Paoletti, Maria Filomena; Dominici, Sabrina; Buondelmonte, Costantina; Caputo, Antonella; Castaldello, Arianna; Tripiciano, Antonella; Cafaro, Aurelio; Palamara, Anna Teresa; Sgarbanti, Rossella; Garaci, Enrico; Ensoli, Barbara; Magnani, Mauro

    2011-09-16

    We have previously demonstrated that in Ova-immunized mice the increase in intra-macrophage thiol pool induced by pro-GSH molecules modulates the Th1/Th2 balance in favour of a Th1-type immune response. We show now that the same molecules can support a Th1-type over Th2-type immunity against Tat, which is an early HIV-1 regulatory protein and a Th1 polarizing immunomodulator that is increasingly considered in new anti-HIV vaccination strategies. Our results indicate that Tat-immunized mice pre-treated with the C4 (n-butanoyl) derivative of reduced glutathione (GSH-C4) or a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (MEA) (I-152), have decreased levels of anti-Tat IgG1 as well as increased levels of anti-Tat IgG2a and IgG2b isotypes suggesting a Th1-type response. Moreover, Th1-(IFN-γ and IL-2) Ag-specific cellular responses were detected by ELISPOT assay in splenocytes of the same animals as well as an increase of IL-12 levels in the plasma. These findings suggest that the Th1 immune response to HIV-1 Tat could be further polarized by these molecules. These results together with those previously reported suggest that pro-GSH molecules could be used to modulate the immune response towards different antigens and may be further exploited for inducing specific Th1 immune responses against other HIV antigens as well as other intracellular pathogens in new Tat-based vaccination protocols.

  10. Sexual activity modulates shifts in Th1/Th2 cytokine profile across the menstrual cycle: An observational study

    PubMed Central

    Lorenz, Tierney K.; Heiman, Julia R.; Demas, Gregory E.

    2015-01-01

    Objective To investigate if sexual activity moderated menstrual cycle-related shifts in cytokines associated with helper-T type 1 (Th1) cells (e.g., interferon-γ, IFN-γ) and helper T type 2 (Th2) cells (e.g., interleukin-4, IL-4). Immune activity shifts across the menstrual cycle, with higher follicular-phase Th1 cell activity, but higher luteal-phase Th2 cell activity There is little known about how social behaviors alter Th1/Th2 ratios, despite evidence that psychosocial factors can influence immunity. Of particular interest is how sexual activity influences immune responses that may support conception, such as the Th1/Th2 balance. Design Participants provided saliva samples at four timepoints (menstrual, follicular, ovulatory, and luteal), which were assayed using enzyme-linked immunosorbent assays (ELISA). Setting Academic laboratory. Participants Thirty healthy premenopausal women (16 sexually abstinent, 14 sexually active), not taking hormonal or immunoactive medications. Interventions None. Main outcome measures Salivary estradiol (E2), progesterone (P4), IFN-γ, IL-4. Results Sexually active, but not abstinent, women were significantly more likely to express Th2-like cytokine ratios (IFN-γ < IL-4) in the luteal phase than other phases. Similarly, sexually active women had significantly higher P4, and higher P4 to E2 (P/E) ratios, in the luteal phase than did abstinent women. The P/E ratio mediated menstrual variations in cytokine ratios in sexually active women. Conclusion These results support the hypothesis that shifts in immune response across the menstrual cycle may reflect tradeoffs between reproduction and immunity. These findings point to the need for further research on the interaction between sexual behavior, the menstrual cycle, and immune response. PMID:26385401

  11. Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma.

    PubMed

    Harada, Takeshi; Ozaki, Shuji; Oda, Asuka; Fujii, Shiro; Nakamura, Shingen; Miki, Hirokazu; Kagawa, Kumiko; Takeuchi, Kyoko; Matsumoto, Toshio; Abe, Masahiro

    2013-06-01

    Transient inflammatory reactions have been reported in a subpopulation of patients with multiple myeloma (MM) during lenalidomide (Len) plus dexamethasone (DEX) therapy. Here, we examined serum levels of Th1 (IL-2 and IFN-γ) and Th2 cytokines (IL-6 and TNF-α) in nine refractory or relapsed MM patients treated with Len plus low-dose DEX. Six patients showed elevation of C-reactive protein (CRP) after the initiation of therapy. In these patients, IFN-γ and IL-6 were also elevated in two and three patients, respectively. The remaining three patients showed no appreciable changes in CRP or these cytokines. Furthermore, Len enhanced the production of both Th1 and Th2 cytokines in normal peripheral blood mononuclear cells and in patient bone marrow mononuclear cells containing primary myeloma cells and lymphocytes. These results suggest that the modulation of the Th1 and Th2 cytokine production by Len may contribute to transient inflammatory reaction in MM patients.

  12. Host Th1/Th2 immune response to Taenia solium cyst antigens in relation to cyst burden of neurocysticercosis.

    PubMed

    Tharmalingam, J; Prabhakar, A T; Gangadaran, P; Dorny, P; Vercruysse, J; Geldhof, P; Rajshekhar, V; Alexander, M; Oommen, A

    2016-10-01

    Neurocysticercosis (NCC), Taenia solium larval infection of the brain, is an important cause of acquired seizures in endemic countries, which relate to number, location and degenerating cysts in the brain. Multicyst infections are common in endemic countries although single-cyst infection prevails in India. Single-cyst infections in an endemic country suggest a role for host immunity limiting the infection. This study examined ex vivo CD4(+) T cells and in vitro Th1 and Th2 cytokine responses to T. solium cyst antigens of peripheral blood mononuclear cells of healthy subjects from endemic and nonendemic regions and of single- and multicyst-infected patients for association with cyst burden of NCC. T. solium cyst antigens elicited a Th1 cytokine response in healthy subjects of T. solium-endemic and T. solium-non-endemic regions and those with single-cyst infections and a Th2 cytokine response from subjects with multicyst neurocysticercosis. Multicyst neurocysticercosis subjects also exhibited low levels of effector memory CD4(+) T cells. Th1 cytokine response of T. solium exposure and low infectious loads may aid in limiting cyst number. Th2 cytokines and low effector T cells may enable multiple-cyst infections to establish and persist.

  13. Study of Th1/Th2 balance in peripheral blood mononuclear cells of patients with alopecia areata.

    PubMed

    Sadeghi, Soha; Sanati, Mohammad Hossein; Taghizadeh, Morteza; Mansouri, Parvine; Jadali, Zohreh

    2015-09-01

    Alopecia areata represents an autoimmune pathological process driven primarily by cellular aberrations contained within the immune system, which activates various humoral and cellular elements of the immune response. The aim of this study was to determine the mRNA expression levels of T-bet and GATA-3 as potential inducers of T helper (Th)1 and Th2 differentiation, respectively, as well as Th1(IFN-γ) and Th2(IL-4) cytokine mRNA expression in patients with alopecia areata. Using real-time reverse transcriptase PCR (RT-PCR), the relative amounts of T-bet, GATA-3, IFN-γ, and IL-4 mRNA transcripts were determined in PBMCs from 20 Iranian patients with alopecia areata and compared with those of 20 healthy control subjects. In comparison with the normal group, T-bet and IFN-γ mRNA expression levels were significantly up-regulated in the alopecia areata patients, while GATA-3 and IL-4 mRNA expression levels were down-regulated. Notably, positive correlation (P < 0.05) was found between IFN-γ and T-bet levels in patients and controls. In addition, significant positive correlations existed between GATA-3 and IL-4 (P < 0.05). These results indicate that a Th1/Th2 imbalance exists in alopecia areata, and it may be implicated in the pathogenesis of disease.

  14. MicroRNA-138 regulates the balance of Th1/Th2 via targeting RUNX3 in psoriasis.

    PubMed

    Fu, Dandan; Yu, Wenfa; Li, Min; Wang, Huimin; Liu, Dong; Song, Xiangfeng; Li, Zhanguo; Tian, Zhongwei

    2015-07-01

    Psoriasis is a common chronic inflammatory and T cell-meditated autoimmune skin disease. A recent study found that Runt-related transcription factor 3 (RUNX3) is a susceptibility gene for psoriasis; however, its biological role in the disease has not been studied. RUNX3 was predicted to be the target gene of microRNA-138 (miR-138). The current research was designed to delineate the mechanism of miR-138 in regulating psoriasis via targeting RUNX3. In this study, we found that the expression of RUNX3 is increased significantly while the expression of miR-138 decreased significantly in CD4(+) T cells from psoriasis patients. Moreover, the luciferase report confirmed the targeting reaction between miR-138 and RUNX3. After transfection with the miR-138 inhibitor into CD4(+) T cells from healthy controls, we found that the inhibition of miR-138 increases RUNX3 expression and increased the ratio of Th1/Th2. Furthermore, the miR-138 mimic was transfected into CD4(+) T cells from psoriasis patients. The results showed that the overexpression of miR-138 inhibits RUNX3 expression and decreased the ratio of Th1/Th2 in CD4(+) T cells. Taken together, our study suggests that increased miR-138 regulates the balance of Th1/Th2 through inhibiting RUNX3 expression in psoriasis, providing a potential therapeutic target for psoriasis.

  15. Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection.

    PubMed

    Pereira-Manfro, Wânia F; Ribeiro-Gomes, Flávia L; Filardy, Alessandra Almeida; Vellozo, Natália S; Guillermo, Landi V C; Silva, Elisabeth M; Siegel, Richard M; Dosreis, George A; Lopes, Marcela F

    2014-02-01

    We investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to Leishmania major parasites. Splenic CD4 T cells undergo activation-induced apoptosis, and blockade of FasL-Fas interaction increased IFN-γ and IL-4 cytokine responses to L. major antigens. To block death receptor-induced death, we used mice expressing a T cell-restricted transgene for vFLIP. Inhibition of caspase-8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. major infection, even in the Th1-prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. major infection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti-IL-4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase-8 activity in T cells improves immunity to L. major infection by promoting increased Th1 and Th2 responses.

  16. Th1 and Th2 immune response to P30 and ROP18 peptides in human toxoplasmosis.

    PubMed

    Torres-Morales, Elizabeth; Taborda, Laura; Cardona, Nestor; De-la-Torre, Alejandra; Sepulveda-Arias, Juan Carlos; Patarroyo, Manuel Alfonso; Gomez-Marin, Jorge Enrique

    2014-10-01

    We determined the specific lymphocyte proliferative response and cytokine profile production regarding Toxoplasma P30 (2017 from virulent and non-virulent strain) and ROP18 protein-derived peptides (from clonal lineages I, II and III) in 19 patients having ocular toxoplasmosis, five suffering chronic asymptomatic infection, nine with congenital toxoplasmosis and eight Toxoplasma negative people. A Beckman Coulter FC500 flow cytometer was used for determining antigen-specific T cells (CD3+ CD4+ or CD3+ CD8+ cells) in peripheral blood culture. IFN γ and IL10 levels were determined in culture supernatants. Specific CD4+ and CD8+ T cell response to total antigen and P30- and ROP18-derived peptides was observed in infected people. Ocular toxoplasmosis patients had a preferential Th2 response after antigenic stimulation. Non-virulent peptide 2017 was able to shift response toward Th1 in congenitally infected children and virulent peptide 2017 induced a Th2 response in chronically infected, asymptomatic people. An immune response in human toxoplasmosis after ex vivo antigenic stimulation was Th1- or Th2-skewed, depending on a patient's clinical condition. Colombian ocular toxoplasmosis patients' immune response was Th2-skewed, regardless of the nature of antigen stimulus.

  17. Relationships between Th1/Th2 cytokine profiles and chest radiographic manifestations in childhood Mycoplasma pneumoniae pneumonia

    PubMed Central

    Zhao, Jiu-ling; Wang, Xin; Wang, Yu-shui

    2016-01-01

    Background Mycoplasma pneumoniae pneumonia (MPP) is one of the most common childhood community-acquired pneumonias, and the chest radiograph usually shows bronchial pneumonia, segmental/lobar pneumonia, or segmental/lobar pneumonia with pleural effusion. The imbalance of Th1/Th2 function after Mycoplasma pneumoniae infection is an important immunological mechanism of MPP. In this study, we aimed to evaluate the correlations between Th1/Th2 cytokine profiles and chest radiographic manifestations in MPP children. Patients and methods A total of 87 children with MPP were retrospectively reviewed in this study. According to the chest radiographic manifestations, they were divided into the following three groups: bronchial MPP group, segmental/lobar MPP group, and segmental/lobar MPP with pleural effusion group. Clinical features and changes in Th1/Th2 cytokines were further analyzed. Results The incidence of tachypnea and cyanosis was higher in children with segmental/lobar MPP with pleural effusion than in those with segmental/lobar or bronchial MPP. The peak body temperature of segmental/lobar MPP was higher than that of bronchial MPP, and the duration of fever and hospitalization was positively correlated with the severity of MPP. MPP children’s chest radiograph showed a relationship with the changes in Th1/Th2 cytokines. Serum interleukin-4, interleukin-10 (IL-10), interferon-γ, and tumor necrosis factor-α (TNF-α) of segmental/lobar MPP were significantly higher than those of bronchial MPP, and serum IL-10 (cutoff value: 27.25 pg/mL) can be used as a diagnostic predictor for segmental/lobar MPP. Serum TNF-α and interleukin-6 of segmental/lobar MPP with pleural effusion were significantly higher than those of segmental/lobar MPP without pleural effusion. Serum TNF-α (cutoff value: 60.25 pg/mL) can be used as a diagnostic predictor for segmental/lobar MPP with pleural effusion. Conclusion There were significant correlations between Th1/Th2 cytokine profiles

  18. Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer.

    PubMed

    Pichler, Renate; Gruenbacher, Georg; Culig, Zoran; Brunner, Andrea; Fuchs, Dietmar; Fritz, Josef; Gander, Hubert; Rahm, Andrea; Thurnher, Martin

    2016-12-22

    Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary (p = 0.003) and serum neopterin (p = 0.012), kynurenine (p = 0.015), KTR (p = 0.005), IFN-γ (p = 0.005) and IL-12 (p = 0.003) during therapy, whereas levels of IL-10 decreased significantly (p < 0.001) compared to non-responders. GATA3/T-bet ratio correlated positively with serum neopterin (p = 0.008), IFN-γ (p = 0.013) and KTR (p = 0.018) after the first BCG instillation. We observed a significant increase in CD4 expression in the Th cell population (p < 0.05), with only a modest tendency toward higher frequency in responders compared to non-responders (p = 0.303). The combined assessment of GATA3/T-bet ratio, neopterin and KTR may be a useful biomarker in predicting BCG response. Th2-promoting factors such as GATA3 may trigger Th1-type immune responses and thus contribute to the BCG success.

  19. Peptide dose, affinity, and time of differentiation can contribute to the Th1/Th2 cytokine balance.

    PubMed

    Rogers, P R; Croft, M

    1999-08-01

    Opposing viewpoints exist regarding how Ag dose and affinity modulate Th1/Th2 differentiation, with data suggesting that both high and low level stimulation favors Th2 responses. With transgenic T cells bearing a single TCR, we present novel data, using peptides differing in affinity for the TCR, that show that the time period of differentiation can determine whether Th1 or Th2 responses predominate as the level of initial stimulation is altered. Over the short term, IFN-gamma-producing cells were induced by lower levels of stimulation than IL-4-producing cells, although optimal induction of both was seen with the same high level of stimulation. Over the long term, however, high doses of high affinity peptides led selectively to IFN-gamma-secreting cells, whereas IL-4- and IL-5-secreting cells predominated with lower levels of initial signaling, brought about by moderate doses of high affinity peptides. In contrast, too low a level of stimulation at the naive T cell stage, with low affinity peptides at any concentration, promoted only IL-2-secreting effectors or was not sufficient for long term T cell survival. These results demonstrate that the level of signaling achieved through the TCR is intimately associated with the induction of distinct cytokine-secreting T cells. We show that dose, affinity, time over which differentiation occurs, and initial production of IL-4 and IFN-gamma all can contribute to which T cell subset will predominate. Furthermore, these data reconcile the two opposing views on the effects of dose and affinity and provide a unifying model of Th1/Th2 differentiation based on strength of signaling and length of response.

  20. Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

    SciTech Connect

    Fukuyama, Yoshiko; Tokuhara, Daisuke; Sekine, Shinichi; Kataoka, Kosuke; Markham, Jonathan D.; Irwin, Allyson R.; Moon, Grace H.; Tokuhara, Yuka; Fujihashi, Keiko; Davydova, Julia; Yamamoto, Masato; Gilbert, Rebekah S.; Fujihashi, Kohtaro

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Nasal Ad-FL effectively up-regulates APC function by CD11c{sup +} DCs in mucosal tissues. Black-Right-Pointing-Pointer Nasal Ad-FL induces Notch ligand (L)-expressing CD11c{sup +} DCs. Black-Right-Pointing-Pointer Notch L-expressing DCs support the induction of Th1- and Th2-type cytokine responses. -- Abstract: Our previous studies showed that an adenovirus (Ad) serotype 5 vector expressing Flt3 ligand (Ad-FL) as nasal adjuvant activates CD11c{sup +} dendritic cells (DCs) for the enhancement of antigen (Ag)-specific IgA antibody (Ab) responses. In this study, we examined the molecular mechanism for activation of CD11c{sup +} DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FL activated CD11c{sup +} DCs expressed increased levels of the Notch ligand (L)-expression and specific mRNA. When CD11c{sup +} DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4{sup +} T cells isolated from non-immunized OVA TCR-transgenic (OT II) mice, significantly increased levels of T cell proliferative responses were noted. Furthermore, Ad-FL activated DCs induced IFN-{gamma}, IL-2 and IL-4 producing CD4{sup +} T cells. Of importance, these APC functions by Ad-FL activated DCs were down-regulated by blocking Notch-Notch-L pathway. These results show that Ad-FL induces CD11c{sup +} DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses.

  1. Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes.

    PubMed

    Ghazy, Amany A; Abu El-Nazar, Salma Y; Ghoneim, Hossam E; Taha, Abdul-Rahman M; Abouelella, Amira M

    2015-01-01

    Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of γ-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of γ-rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of γ-rays and found that the exposure to low dose γ-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of γ-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of γ-rays.

  2. Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes

    PubMed Central

    Ghazy, Amany A.; Abu El-Nazar, Salma Y.; Ghoneim, Hossam E.; Taha, Abdul-Rahman M.; Abouelella, Amira M.

    2015-01-01

    Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of γ-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of γ-rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of γ-rays and found that the exposure to low dose γ-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of γ-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of γ-rays. PMID:25914644

  3. Myrrh and artesunate modulate some Th1 and Th2 cytokines secretion in Schistosoma mansoni infected mice

    PubMed Central

    Abdelaziz, Mohamed M.

    2016-01-01

    The effects of artesunate and myrrh on S. mansoni infection and the levels of some Th1 and Th2 cytokines were evaluated in the present study. Six weeks after infection, a group of mice was treated with 4 mg/kg of artesunate and other group was treated with 10 mg/kg of myrrh for 3 successive days. Worm burden was reduced with a percentage of 53.7% and 58.78% after treatment with myrrh and artesunate respectively as well as the levels of IgG antibodies were significantly reduced compared with infected group. No obvious changes were observed in the level of interferon γ after treatment. After treatment with artesunate, interleukin 2 (IL-2) level was significantly decreased, while no significant difference was observed in myrrh-treated group compared with the infected group. On the other hand, the level of IL-10 was not significantly decreased after treatment with artesunate, but it was significantly increased after treatment with myrrh. However, IL-12 levels were significantly decreased after treatment with artesunate. The results demonstrated that, artesunate or myrrh treatment could give a level of protection against S. mansoni infection and modulate the levels of some Th1 and Th2 cytokines in mice infected with S. mansoni. PMID:27536198

  4. Amelioration of adjuvant-induced arthritis by ursolic acid through altered Th1/Th2 cytokine production.

    PubMed

    Ahmad, Sheikh Fayaz; Khan, Beenish; Bani, Sarang; Suri, K A; Satti, N K; Qazi, G N

    2006-03-01

    The objective of the study was to investigate the activity of ursolic acid (UA) on proinflammatory (Th1) and anti-inflammatory (Th2) cytokines in the peripheral blood of arthritic balb/c mice. Ursolic acid is ubiquitous in the plant kingdom and is a constituent of numerous plants which are having diversified phylogenetic origin and taxonomic position. We applied Cytometric bead array (CBA) technology for simultaneously measurement of these cytokines in adjuvant inflammatory arthritis induced mice treated with ursolic acid in graded oral doses. Cytometric bead array uses the sensitivity of amplified fluorescence detection by flowcytometer to measure soluble analytes in a particle based immune assay. This assay can accurately quantitate five cytokines in a 50 microl sample volume. The T-helper (Th1) deviated cells produce detectable level of tumor necrosis factor (TNF-alpha), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), while the Th2 deviated cells produce significant amount of interleukin-4 (IL-4) and interleukin-5 (IL-5). Oral administration of UA at doses of 10, 20, 40, 80 and 160 mg kg(-1) per oral dose inhibited the presence of IL-2, IFN-gamma and TNF-alpha in the peripheral blood.

  5. CD80 and CD86 knockdown in dendritic cells regulates Th1/Th2 cytokine production in asthmatic mice

    PubMed Central

    LI, JIAN-GUO; DU, YU-MO; YAN, ZHI-DONG; YAN, JIA; ZHUANSUN, YONG-XUN; CHEN, RUI; ZHANG, WEI; FENG, SU-LING; RAN, PI-XIN

    2016-01-01

    Dendritic cells (DCs) are associated with the activation and differentiation of T helper (Th) cells. Cluster of differentiation (CD)80 and CD86, the co-stimulatory molecules highly expressed in DCs, have are prominent in promoting the differentiation of Th cells toward Th2 cells. However, little is known about the effect of CD80 and CD86 knockdown on Th1/Th2 cytokine production in mature DCs (mDCs). The aim of the present study was to investigate whether small-interfering RNA (siRNA) could suppress the surface expression of CD80 and CD86 in mDCs. The effects of CD80 and CD86 knockdown in mDCs on Th1/Th2 cytokine expression were examined using an asthmatic murine model. DCs were isolated, separated and cultured in vitro. Flow cytometry was used to examine the expression of CD11c, CD80 and CD86 on the DCs. The DCs were transfected with CD80- and CD86-specific siRNA, while non-siRNA and negative siRNA controls were also designed. Then, the mRNA and protein expression levels of CD80 and CD86 were determined by reverse transcription-quantitative polymerase chain reaction and flow cytometry, respectively. The levels of interferon (IFN)-γ and interleukin (IL)-4 produced by T cells co-cultured with mDCs were measured by enzyme-linked immunosorbent assay. Substantial downregulation of CD80 and CD86 mRNA and protein levels were observed in the mDCs following transfection with siRNA. The level of IFN-γ produced by T cells co-cultured with mDCs was significantly increased in the siRNA group, while IL-4 production was significantly decreased. These results show that specific targeting of CD80 and CD86 with siRNA is able to suppress CD80/CD86 expression and consequently regulate Th1/Th2 cytokine levels by increasing IFN-γ production and decreasing IL-4 levels in an asthmatic murine model. PMID:26998006

  6. Increased Fetal Thymocytes Apoptosis Contributes to Prenatal Nicotine Exposure-induced Th1/Th2 Imbalance in Male Offspring Mice

    PubMed Central

    Chen, Ting; Yan, You-e; Liu, Sha; Liu, Han-xiao; Yan, Hui-yi; Hou, Li-fang; Qu, Wen; Ping, Jie

    2016-01-01

    Nicotine, a definite risk factor during pregnancy, is an immunomodulator. This study was designed to investigate the effects of prenatal nicotine exposure (PNE) on the balance of Th1/Th2 in offspring, and further explore the developmental origin mechanisms from the perspective of fetal thymocytes apoptosis. Pregnant Balb/c mice were administered 1.5 mg/kg nicotine subcutaneously twice per day from gestational day (GD) 9 to GD18. Results showed that PNE could cause a Th2 shift in male offspring, manifested as increased ratio of IgG1/IgG2a, IL-4 production in serum, and IL-4/IFN-γ expression ratio in spleen. Increased apoptosis of total thymocytes and CD4SP and reduced cell proportion of CD4SP were found in PNE male offspring on postnatal day (PND) 14 and PND 49. In the fetuses, decreased body weight and organ index of fetal thymus, histological changes in fetal thymus, reduced CD4SP proportion and increased fetal thymocyte apoptosis were observed in nicotine group. The increased mRNA expression of genes involved in Fas-mediated apoptotic pathway and protein expression of Fas were also detected. In conclusion, PNE could cause a Th2 shift in male offspring mediated by reduced CD4+ T cells output, which may result from the increasing apoptosis of total thymocytes and CD4SP. PMID:27976742

  7. CD4+ Th17 Cells Discriminate Clinical Types and Constitute a Third Subset of Non Th1, Non Th2 T Cells in Human Leprosy

    PubMed Central

    Saini, Chaman; Ramesh, V.; Nath, Indira

    2013-01-01

    Background Patients with localized tuberculoid and generalized lepromatous leprosy show respectively Th1 and Th2 cytokine profile. Additionally, other patients in both types of leprosy also show a non discriminating Th0 cytokine profile with both interferon-γ and IL-4. The present study investigated the role of Th17 cells which appear to be a distinct subtype of Th subtypes in 19 tuberculoid and 18 lepromatous leprosy patients. Five healthy subjects with long term exposure to infection and 4 skin biopsies from healthy subjects undergoing cosmetic surgery were used as controls. Methodology/Principle Findings An array of Th17 related primers for cytokines, chemokines and transcription factors was used in real time reverse transcribed PCR to evaluate gene expression, ELISA for cytokine secretion in the supernatants of antigen stimulated PBMC cultures and flow cytometry for establishing the phenotype of the IL-17, IL-21 producing cells. Conclusions/Significance IL-17 isoforms showed significantly higher expression and release in supernatants of antigen stimulated PBMC cultures and dermal lesions of healthy contacts and tuberculoid leprosy as compared to lepromatous leprosy (p<0.003). This was further confirmed by Th17 associated transcription factor RORC, cytokines IL-21, IL-22, and IL-23, chemokines MMP13, CCL20, CCL22. Of interest was the association of IL-23R and not IL-6R with IL-17+ cells. The Th17 cells were CD4+ CCR6+ confirming their effector cell lineage. Polarized Th1 cytokines were seen in 3/7 tuberculoid and Th2 cytokines in 5/10 lepromatous leprosy patients. Of importance was the higher association of Th17 pathway factors with the non-polarized Th0 types as compared to the polarized Th1 and Th2 (p<0.01). Our study draws attention to a third type of effector Th cell that may play a role in leprosy. PMID:23936569

  8. Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non-Hodgkin lymphoma.

    PubMed

    Chen, Yingtai; Zheng, Tongzhang; Lan, Qing; Foss, Francine; Kim, Christopher; Chen, Xuezhong; Dai, Min; Li, Yumin; Holford, Theodore; Leaderer, Brian; Boyle, Peter; Chanock, Stephen J; Rothman, Nathaniel; Zhang, Yawei

    2011-01-13

    We conducted a population-based, case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared with those with BMI less than 25 kg/m(2), women with BMI more than or equal to 25 kg/m(2) had 50% to 90% increased risk of NHL among women who carried IFNGR2 (rs9808753) AA, IL5 (rs2069812) CT/TT, IL7R (rs1494555) AA, and TNF (rs1799724) CC genotypes, but no increased risk among women with IFNGR2 AG/GG, IL5 CC, IL7R AG/GG, and TNF CT/TT genotypes. A significant interaction with BMI was only observed for IFNGR2 (rs9808753 P(forinteraction) = .034) and IL7R (rs1494555 P(forinteraction) = .016) for NHL overall; IL7R (rs1494555 P(forinteraction) = .016) and TNF (1799724 P(forinteraction) = .031) for B-cell lymphoma; and IL5 (rs2069812 P(forinteraction) = .034) for T-cell lymphoma. After stratification by common B-cell lymphoma subtypes, a significant interaction was observed for IFNGR2 (rs9808753 P(forinteraction) = .006), IL13 (rs20541 P(forinteraction) = .019), and IL7R (rs1494555 P(forinteraction) = .012) for marginal zone B-cell lymphoma; IL7R (rs1494555 P(forinteraction) = .017) for small lymphocytic lymphoma/chronic lymphocytic leukemia; and IL12A (rs568408 P(forinteraction) = .013) and TNF (1799724 P(forinteraction) = .04) for follicular lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between BMI and NHL risk.

  9. The effect of size-segregated ambient particulate matter on Th1/Th2-like immune responses in mice

    PubMed Central

    Liu, Szu-Yuan; Chou, Charles C. K.; Lee, Yi-Hsin; Cheng, Tsun-Jen

    2017-01-01

    Background Particulate matter (PM) has been associated with increased pulmonary and cardiovascular mortality and morbidity. Additionally, PM is known to exacerbate asthma. However, whether ambient PM exposure contributes to the onset of asthma, especially in non-atopic children and adults, is less conclusive. The current study aimed to evaluate the effects of size-fractioned PM on lung immune responses in healthy BALB/c mice. Methods and principal findings We collected PM10, PM2.5, PM1 and PM0.1 samples from October 2012 to August 2013 in the Taipei Basin. These PM samples were representative of urban traffic pollution. The samples were extracted and sonicated in phosphate-buffered saline (PBS). Female BALB/c mice were exposed to the samples via intratracheal instillation at three different doses: 1.75 mg/kg (35 μg/per mouse), 5 mg/kg (100 μg/per mouse), and 12.5 mg/kg (250 μg/per mouse). The mice were exposed on days 0 and 7, and PBS alone was used as a control. Following the exposures, the expression profiles of inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were assessed. Exposure to PM10 resulted in inflammatory responses, including the recruitment of neutrophils and the induction of T helper 1 (Th1) cell-related cytokine release, such as TNF-α and IFN-γ. Furthermore, an allergic immune response, including the recruitment of eosinophils and the up-regulation of T helper 2 (Th2) cell-related cytokine release, such as IL-5 and IL-13, was also observed in the BALF of mice exposed to PM10. Conclusions Our study showed that exposure to PM alone caused mixed Th1/Th2 inflammatory responses in healthy mice. These findings support the hypothesis that PM may contribute to the onset of asthma. PMID:28245275

  10. Changes in peripheral blood Th1 and Th2 cells in rat liver transplantation under different immune statuses.

    PubMed

    Yang, Z-L; Cheng, K; Sun, H G; Zou, W W; Wu, M M

    2013-12-19

    In this study, early expressions of peripheral blood Th1 and Th2 cells were documented following rat liver transplantation and related to immune status. Rats were divided into 3 groups: group A (control): syngeneic transplantation (Brown Norway (BN) → BN); group B: allogeneic transplantation + cyclosporine A (CsA); group C: allogeneic transplantation (Lewis → BN). Flow cytometry was used to analyze peripheral blood CD4(+)CD45RC percentage on days 1, 3, 5, 7, and 14 following transplantation, and were compared to graft rejection pathological grades and receptor survival times. The average survival of groups A and B exceeded 100 days, which was significantly longer than that of group C (3.56 ± 34.3 days). With the exception of the first day, rejection grades were significantly higher in groups C and B compared to group A, and group C rejection grades were significantly higher than those of group B. Three days after transplantation, the CD4(+)CD45RC(+) to CD4(+)CD45RC(-) ratio of group C was significantly higher than that of groups A and B. In group B, the CD4(+)CD45RC(+) to CD4(+)CD45RC(-) ratio was negatively correlated to the rejection grade (r = -0.565, P < 0.01), whereas this relationship was positive in group C (r = 0.745, P < 0.01). In conclusion, peripheral blood Th1 was highly expressed during rejection in rat liver grafts. Peripheral blood Th2 tended to increase early under rejection inhibition with CsA, and its high expression level may correlate with long-term acceptance or tolerance of transplanted livers.

  11. Comparison of Th1 and Th2 responses in non-healing and healing patients with cutaneous leishmaniasis

    PubMed Central

    Shahi, Maryam; Mohajery, Masoud; Shamsian, Seyyed Ali Akbar; Nahrevanian, Hossein; Yazdanpanah, Seyyed Mohammad Javad

    2013-01-01

    Background: Cutaneous leishmaniasis is an endemic disease in many regions of Iran, including the city of Mashhad. In recent years, some cases have not responded to Glucantime, the usual treatment for this disease. The cellular immune response caused by T-helper type 1 (Th1) cells has an important role in protection against leishmaniasis, and activation of the T-helper type 2 (Th2) response causes progression of the disease. By analyzing these responses we hope to find a more effective treatment than that currently in use for leishmaniasis patients. Methods: The cellular immune responses in 60 cases of non-healing and healing cutaneous leishmaniasis, and individuals in a control group, were analyzed by measuring cytokines released by peripheral blood mononuclear cells (PBMCs) when stimulated with Leishmania major antigens by Enzyme Linked Immuno Sorbent Assay (ELISA). Results: Subjects from the healing group secreted more interleukin-12 (IL-12) and interferon gamma (IFN-γ) (p<0.05) and less interleukins -4, -5, -10 (IL-4, IL-5, and IL-10) (p<0.005) and -18 (IL-18) (p=0.003) than the non-healing group. Conclusions: The results demonstrate that secretion of cytokines that activate Th2 response including IL-4, IL-5 and IL-10 in non-healing subjects was higher than healing subjects and secretion of cytokines that activate Th1 response including IL-12 and IFN-γ in healing subjects was higher relative to the non-healing subjects. In this study it has been shown that the level of IL-18 progresses disease in non-healing patients when the level of IL-12 gets decreased. PMID:26989708

  12. Traditional Korean medicine (SCRT) modulate Th1/Th2 specific cytokine production in mice CD4+ T cell.

    PubMed

    Ko, Eunjung; Rho, Samwoong; Lee, Eui-Joon; Seo, Young-Ho; Cho, Chongwoon; Lee, Yongwon; Min, Byung-Il; Shin, Min-Kyu; Hong, Moo-Chang; Bae, Hyunsu

    2004-05-01

    Traditional Korea medicine, So-Cheong-Ryong-Tang (SCRT) also called as Xiao-qing-long-tang or Sho-seiru-to, contains eight species of medicinal plants and has been used for treating allergic diseases, such as allergic rhinitis and asthma, for hundreds of years in Asian countries. CD4+ T cells were highly purified by using magnetic bead from splenocytes of BALB/c mice. SCRT treatment slightly decreased the expression of cell surface protein CD69 on CD4+ T cell in the flow cytometry analysis. In RT-PCR analysis, SCRT increases the expression of IL-2 and IL2R-alpha mRNA, and decreases the expression of IL-4 mRNA, which is an important cytokine of Th2 cell development. On the other hand, SCRT treatment increases IFN-gamma expression, which is one of the key cytokines for Th1 cell development. Present study implies that SCRT can correct Th2 dominant condition directly affecting to the CD4+ T cell without significantly depressing general T cell activities. These results also suggest that the effect on CD4+ T cell may be the one of key pharmacological effect point for treating IgE medicated allergic asthma by SCRT.

  13. Berberine down-regulates the Th1/Th2 cytokine gene expression ratio in mouse primary splenocytes in the absence or presence of lipopolysaccharide in a preventive manner.

    PubMed

    Lin, Wei-Chi; Lin, Jin-Yuarn

    2011-12-01

    Berberine is a natural isoquinoline alkaloid. This study investigated the effects of berberine on cytokine gene expression in mouse primary splenocytes in the absence or presence of lipopolysaccharide (LPS) using 4 different experimental models in vitro. The relative expression of the following cytokine genes was determined using a real-time quantitative polymerase chain reaction assay: pro-inflammatory tumor necrosis factor (TNF)-α, anti-inflammatory interleukin (IL)-10, T-helper type 1 (Th1) (IL-2), and Th2 (IL-4) cytokines. The results showed that berberine down-regulated ratios of the relative Th1 (IL-2)/Th2 (IL-4) cytokines expression fold in mouse primary splenocytes in the absence or presence of LPS in a preventive manner. This study suggests that berberine may possess anti-inflammatory potential by shifting the Th1/Th2 balance toward Th2 polarization.

  14. Correlation between the kinetics of Th1, Th2 cells and pathology in a murine model of experimental pulmonary tuberculosis.

    PubMed Central

    Hernández-Pando, R; Orozcoe, H; Sampieri, A; Pavón, L; Velasquillo, C; Larriva-Sahd, J; Alcocer, J M; Madrid, M V

    1996-01-01

    T-helper 1 (Th1) Th2 kinetics were studied by immunohistochemistry and molecular biology techniques (reverse transcriptase polymerase chain reaction. RT PCR, Southern-blot) during the course of pulmonary tuberculosis induced in BALB/c mice by the intratracheal instillation of the live and virulent strain H-37Rv. The histopathological study clearly showed two phases of the disease. The first one was an acute phase which was characterized by inflammatory infiltrate in the alveolar capillary interstitium, blood vessel and bronchial wall with formation of granulomas. In this acute phase which lasted from 1 to 28 days, a clear predominance of Th1 cells was observed, manifested by a high percentage of interleukin-2 (IL-2) positive cells in the inflammatory infiltrate and granulomas demonstrated by immunohistology, as well as a gradual increment of interferon-gamma (INF-gamma) m-RNA. This was followed by a chronic or advanced phase characterized by pneumonia, focal necrosis and fibrosis, with a Th0 balance due to an equivalent proportion of IL-2 and IL-4 positive cells in the lung lesions, that coincided with the highest level of INF-gamma and IL-4 mRNA. The cytofluorometric analysis of bronchial lavage cells, showed a predominance of CD4 T cells during the acute phase and CD8 T lymphocytes in the chronic phase, gamma-delta T lymphocytes showed two peaks, at the beginning (3 days) and at the end (4 months) of the infection. These results suggest that T-lymphocyte subset kinetics and the pattern of cytokines produced in the lung during tuberculosis infection changed over time and correlate with the type and magnitude of tissue injury. Images Figure 1 Figure 3 Figure 5 PMID:8911136

  15. Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells.

    PubMed Central

    Rincón, M; Flavell, R A

    1997-01-01

    Transcriptional factors of the NFAT family play an important role in regulating the expression of several cytokine genes during the immune response, such as the genes for interleukin 2 (IL-2) and IL-4, among others. Upon antigen stimulation, precursor CD4+ T helper (pTh) cells proliferate and differentiate into two populations of effector cells (eTh1 and eTh2), each one expressing a specific pattern of cytokines that distinguishes them from their precursors. eTh2 cells are the major source of IL-4, while gamma interferon is produced by eTh1 cells. Here we have used reporter transgenic mice to show that DNA binding and transcriptional activities of NFAT are transiently induced during the differentiation of pTh cells into either eTh1 or eTh2 cells to mediate the expression of IL-2 as a common growth factor in both pathways. However, although NFAT DNA binding is similarly induced in both eTh1 and eTh2 cells upon antigen stimulation, only the NFAT complexes present in eTh2 cells are able to mediate high-level transcription, and relatively little NFAT transcriptional activity was induced in eTh1 cells. In contrast to activated pTh cells, neither eTh1 nor eTh2 cells produced significant IL-2 upon stimulation, but the high levels of NFAT transcriptional activities directly correlate with the IL-4 production induced in response to antigen stimulation in eTh2 cells. These data suggest that activated NFAT is involved in the effector function of eTh2 cells and that the failure of eTh1 cells to produce IL-4 in response to an antigen is due, at least partially, to a failure to induce high-level transcription of the IL-4 gene by NFAT. Regulation of NFAT could be therefore a critical element in the polarization to eTh1 or eTh2. PMID:9032280

  16. Haptoglobin genotype modulates the balance of Th1/Th2 cytokines produced by macrophages exposed to free hemoglobin.

    PubMed

    Guetta, Julia; Strauss, Merav; Levy, Nina S; Fahoum, Lana; Levy, Andrew P

    2007-03-01

    The haptoglobin genotype has been demonstrated to be an independent risk factor for CVD in multiple epidemiological studies. The primary function of haptoglobin is to mitigate the deleterious effects of extracorpuscular hemoglobin. We sought to determine if the protein products of the two haptoglobin alleles differed in their ability to modulate the cytokine profile produced by macrophages in response to hemoglobin. Peripheral blood mononuclear cells were isolated from normal human volunteers and cultured in the presence of complexes formed by the protein products of the two different haptoglobin alleles with hemoglobin. The release of specific cytokines in the conditioned media of these cells was assessed by ELISA. We found that the haptoglobin 1 allele protein product-hemoglobin complex stimulated the secretion of significantly more Il-6 and Il-10 than the haptoglobin 2 allele protein product-hemoglobin complex. We demonstrate that the release of these cytokines is dependent on the liganding of the haptoglobin-hemoglobin complex to the CD163 receptor and the activity of casein kinase II. Haptoglobin genotype modulates the balance of inflammatory (Th1) and anti-inflammatory (Th2) cytokines produced by macrophages exposed to free hemoglobin. This may have implications in understanding inter-individual differences in the inflammatory response to hemorrhage.

  17. Suppression of allergic reactions by dehulled adlay in association with the balance of TH1/TH2 cell responses.

    PubMed

    Hsu, Hsin-Yi; Lin, Bi-Fong; Lin, Jin-Yuarn; Kuo, Ching-Chuan; Chiang, Wenchang

    2003-06-18

    Dehulled adlay is known as a natural Chinese medicine having antiallergic activity, although its mechanism remains unclear. This study examined the effects of dehulled adlay on antigen-specific antibody and cytokine production. Mice were immunized three times with ovalbumin (OVA) in alum adjuvant. It was found that oral administration of dehulled adlay in mice suppressed the production of IgE against OVA antigen. Serum anti-OVA IgG(2a) antibody levels were significantly increased in mice after oral administration of dehulled adlay. Furthermore, the production of IL-2 by OVA-stimulated splenocytes was augmented in dehulled adlay-fed mice. Although dehulled adlay had no effect on the serum anti-OVA IgG(1) antibody levels, it had a great capacity to reduce IL-5 secretion by means of OVA-stimulated splenocytes. Hydrothermal processes, including steaming and extrusion cooking, did not change the capacity of dehulled adlay to suppress IgE production. Three fractions of dehulled alday, including methanolic extract, warm water extract, and residue, were obtained. The methanolic extract exhibited the greatest capacity to reduce anti-OVA IgE production. These results suggest that dehulled adlay has a modulating ability to shift the balance from Th2 to Th1 dominance in the T cell mediated immune system and may be beneficial for the treatment of allergic disorders.

  18. Th1/Th2 balance in mouse delayed-type hypersensitivity model with mercuric chloride via skin and oral mucosa.

    PubMed

    Ukichi, Kenichirou; Okamura, Taito; Fukushima, Daihei; Morimoto, Mitsuaki; Yamane, Gen-Yuki; Takahashi, Shinichi

    2011-01-01

    In order to compare delayed-type hypersensitivity (DTH) among different exposure sites, we evaluated the sensitization potency of mercuric chloride (HgCl(2)) via exposure to the skin, or oral or esophageal mucosa using the mouse ear swelling test. Furthermore, we investigated in vitro splenocyte proliferation reaction and cytokine profile in HgCl(2)-exposed and control mice. Sensitization with HgCl(2) was established via the skin and oral mucosa but not via the esophageal mucosa. The splenocyte proliferation reaction was significantly enhanced to a similar degree in skin and oral mucosa-sensitized mice compared with in the control mice. IL-10 levels from cultured splenocytes were significantly increased in skin and oral mucosa-sensitized mice compared with those in control mice, whilst IFN-γ significantly increased only in splenocytes from skin-sensitized mice. These results suggest that exposure of the skin or oral mucosa to HgCl(2) can induce DTH, but that Th1/Th2 balance differs according to the site of antigen exposure.

  19. Multiparameter fluorescence imaging for quantification of TH-1 and TH-2 cytokines at the single-cell level

    NASA Astrophysics Data System (ADS)

    Fekkar, Hakim; Benbernou, N.; Esnault, S.; Shin, H. C.; Guenounou, Moncef

    1998-04-01

    Immune responses are strongly influenced by the cytokines following antigenic stimulation. Distinct cytokine-producing T cell subsets are well known to play a major role in immune responses and to be differentially regulated during immunological disorders, although the characterization and quantification of the TH-1/TH-2 cytokine pattern in T cells remained not clearly defined. Expression of cytokines by T lymphocytes is a highly balanced process, involving stimulatory and inhibitory intracellular signaling pathways. The aim of this study was (1) to quantify the cytokine expression in T cells at the single cell level using optical imaging, (2) and to analyze the influence of cyclic AMP- dependent signal transduction pathway in the balance between the TH-1 and TH-2 cytokine profile. We attempted to study several cytokines (IL-2, IFN-(gamma) , IL-4, IL-10 and IL-13) in peripheral blood mononuclear cells. Cells were prestimulated in vitro using phytohemagglutinin and phorbol ester for 36h, and then further cultured for 8h in the presence of monensin. Cells were permeabilized and then simple-, double- or triple-labeled with the corresponding specific fluorescent monoclonal antibodies. The cell phenotype was also determined by analyzing the expression of each of CD4, CD8, CD45RO and CD45RA with the cytokine expression. Conventional images of cells were recorded with a Peltier- cooled CCD camera (B/W C5985, Hamamatsu photonics) through an inverted microscope equipped with epi-fluorescence (Diaphot 300, Nikon). Images were digitalized using an acquisition video interface (Oculus TCX Coreco) in 762 by 570 pixels coded in 8 bits (256 gray levels), and analyzed thereafter in an IBM PC computer based on an intel pentium processor with an adequate software (Visilog 4, Noesis). The first image processing step is the extraction of cell areas using an edge detection and a binary thresholding method. In order to reduce the background noise of fluorescence, we performed an opening

  20. Streptococcus pneumoniae fructose-1,6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokine responses in mice.

    PubMed

    Elhaik Goldman, Shirin; Dotan, Shahar; Talias, Amir; Lilo, Amit; Azriel, Shalhevet; Malka, Itay; Portnoi, Maxim; Ohayon, Ariel; Kafka, Daniel; Ellis, Ronald; Elkabets, Moshe; Porgador, Angel; Levin, Ditza; Azhari, Rosa; Swiatlo, Edwin; Ling, Eduard; Feldman, Galia; Tal, Michael; Dagan, Ron; Mizrachi Nebenzahl, Yaffa

    2016-04-01

    Streptococcus pneumoniae (S. pneumoniae) is a major pathogen worldwide. The currently available polysaccharide-based vaccines significantly reduce morbidity and mortality. However, the inherent disadvantages of the currently available polysaccharide-based vaccines have motivated the search for other bacterial immunogens capable of eliciting a protective immune response against S. pneumoniae. Fructose-1,6-bisphosphate aldolase (FBA) is a glycolytic enzyme, which was found to localize to the bacterial surface, where it functions as an adhesin. Previously, immunizing mice with recombinant FBA (rFBA) in the presence of alum elicited a protective immune response against a lethal challenge with S. pneumoniae. Thus, the aim of the present study was to determine the cytokine responses that are indicative of protective immunity following immunization with rFBA. The protective effects against pneumococcal challenge in mice immunized with rFBA with complete Freund's adjuvant (CFA) in the initial immunization and with incomplete Freund's adjuvant (IFA) in booster immunizations surpassed the protective effects observed following immunization with either rFBA + alum or pVACfba. CD4+ T-cells obtained from the rFBA/CFA/IFA/IFA-immunized mice co-cultured with rFBA-pulsed antigen-presenting cells (APCs), exhibited a significantly greater proliferative ability than CD4+ T-cells obtained from the adjuvant-immunized mice co-cultured with rFBA‑pulsed APCs. The levels of the Th1-type cytokines, interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α and IL-12, the Th2-type cytokines, IL-4, IL-5 and IL-10, and the Th17-type cytokine, IL-17A, significantly increased within 72 h of the initiation of co-culture with CD4+ T-cells obtained from the rFBA‑immunized mice, in comparison with the co-cultures with CD4+ T-cells obtained from the adjuvant-immunized mice. Immunizing mice with rFBA resulted in an IgG1/IgG2 ratio of 41, indicating a Th2 response with substantial Th1

  1. Upregulation of Tim-3 on CD4(+) T cells is associated with Th1/Th2 imbalance in patients with allergic asthma.

    PubMed

    Tang, Fei; Wang, Fukun; An, Liyun; Wang, Xianling

    2015-01-01

    T cell Ig and mucin domain-containing molecule-3 (Tim-3) is a negative regulator preferentially expressed on Th1 cells. Allergic asthma is a clinical syndrome well characterized by Th1/Th2 imbalance. To investigate the role of Tim-3 in the pathogenesis of asthma and its relationship with Th1/Th2 imbalance, a total of 40 patients with allergic asthma and 40 healthy controls were enrolled. Expression of Tim-3 and Th1/Th2 imbalance as well as the relationship between them was analyzed by flow cytometry and real-time PCR. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro and anti-Tim-3 was used to block Tim-3 signaling; Th1/Th2 cytokines in the culture supernatant were detected by enzyme linked immunosorbent assay (ELISA). CD4(+) T cells and B cells were sorted and co-cultured in vitro, and anti-Tim-3 was used to block Tim-3 signaling; Total IgG/IgE in the culture supernatant was detected by ELISA. The mRNA level of T-bet and IFN-γ were significantly decreased in allergic asthma patients, while GATA-3 and IL-4 were significantly increased. Expression of Tim-3 on CD4(+) T cells was much higher in allergic asthma patients and it was negatively correlated with T-bet/GATA-3 ratio or IFN-γ/IL-4 ratio. Blocking of Tim-3 significantly increased Th1 cytokines (TNF-α and IFN-γ) and decreased Th2 cytokines (IL-4, IL-5, IL-13) in the culture supernatant of PBMCs. Blocking of Tim-3 dramatically reduced the production of IgG and IgE in the co-culture supernatant of CD4(+) T cells and B cells. In conclusion, Tim-3 was up-regulated in allergic asthma patients and related with the Th1/Th2 imbalance. Blocking of Tim-3 may be of therapeutic benefit by enhancing the Th1 cytokines response, down-regulating the Th2 cytokines response, and reducing IgG/IgE production.

  2. On the mechanism determining the TH1/TH2 phenotype of an immune response, and its pertinence to strategies for the prevention, and treatment, of certain infectious diseases.

    PubMed

    Bretscher, P A

    2014-06-01

    It is well recognized that the physiological/pathological consequences of an immune response, against a foreign or a self-antigen, are often critically dependent on the class of immunity generated. Here we focus on how antigen interacts with the cells of the immune system to determine whether antigen predominantly generates Th1 or Th2 cells. We refer to this mechanism as the 'decision criterion' controlling the Th1/Th2 phenotype of the immune response. A plausible decision criterion should account for the variables of immunization known to affect the Th1/Th2 phenotype of the ensuing immune response. Documented variables include the nature of the antigen, in terms of its degree of foreignness, the dose of antigen and the time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. These are quantitative variables made at the level of the system. In addition, the route of immunization is also critical. I describe a quantitative hypothesis as to the nature of the decision criterion, referred to as the Threshold Hypothesis. This hypothesis accounts for the quantitative variables of immunization known to affect the Th1/Th2 phenotype of the immune response generated. I suggest and illustrate how this is not true of competing, contemporary hypotheses. I outline studies testing predictions of the hypothesis and illustrate its potential utility in designing strategies to prevent or treat medical situations where a predominant Th1 response is required to contain an infection, such as those caused by HIV-1 and by Mycobacterium tuberculosis, or to contain cancers.

  3. Anisakis simplex allergy: a murine model of anaphylaxis induced by parasitic proteins displays a mixed Th1/Th2 pattern

    PubMed Central

    Baeza, M L; Conejero, L; Higaki, Y; Martín, E; Pérez, C; Infante, S; Rubio, M; Zubeldia, J M

    2005-01-01

    The study of the singular hypersensitivity reactions to Anisakis simplex (A.s) proteins, may help us to undestand many of the unknown immune interactions between helmiths infections and allergy. We have developed a murine model of allergy to A. simplex, that mimics human A. simplex allergy to study the specific aspects of anaphylaxis induced by parasites. Male C3H/HeJ mice were intraperitoneally sensitized to A. simplex. Mice were then intravenous or orally challenged with A. simplex. Antigen-specific immunoglobulins, polyclonal IgE, anaphylactic symptoms, plasma histamine levels and cytokine profiles were determined. Comparative IgE immunoblot analyses were also performed. Specific IgE, IgG1 and IgG2a were detected in sensitized mice since week 3. Polyclonal IgE raised and peaked with different kinetics. Intravenous A. simplex challenge produced anaphylaxis in mice, accompanied by plasma histamine release. Oral A. simplex challenge in similarly sensitized mice did not caused symptoms nor histamine release. Numerous A. simplex allergens were recognized by sensitized mouse sera, some of them similar to human serum. The A. simplex stimulated splenocytes released IL-10, IFN-γ, IL-4, IL-13 and IL-5. We describe a new animal model of anaphylaxis. It exhibits characteristics of type I hypersensitivity reactions to Anisakis simplex similar to those observed in allergic humans. Different responses to i.v. or oral A. simplex challenges emerged, which did not reflect a window tolerization period. The cytokine profile developed (mixed Th1/Th2 pattern) differed from the observed in classical models of anaphylaxis or allergy to food antigens. This model may permit to investigate the peculiar allergic reactions to parasitic proteins. PMID:16297154

  4. Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-β-dependent manner.

    PubMed

    Kumar, Nathella Pavan; Moideen, Kadar; George, Parakkal Jovvian; Dolla, Chandrakumar; Kumaran, Paul; Babu, Subash

    2016-02-01

    Type 2 diabetes mellitus (DM) is a risk factor for the development of active tuberculosis (TB), although its role in the TB-induced responses in latent TB (LTB) is not well understood. Since Th1, Th2, and Th17 responses are important in immunity to LTB, we postulated that coincident DM could alter the function of these CD4(+) T-cell subsets. To this end, we examined mycobacteria-induced immune responses in the whole blood of individuals with LTB-DM and compared them with responses of individuals without DM (LTB-NDM). T-cell responses from LTB-DM are characterized by diminished frequencies of mono- and dual-functional CD4(+) Th1, Th2, and Th17 cells at baseline and following stimulation with mycobacterial antigens-purified protein derivative, early secreted antigen-6, and culture filtrate protein-10. This modulation was at least partially dependent on IL-10 and TGF-β, since neutralization of either cytokine resulted in significantly increased frequencies of Th1 and Th2 cells but not Th17 cells in LTB-DM but not LTB individuals. LTB-DM is therefore characterized by diminished frequencies of Th1, Th2, and Th17 cells, indicating that DM alters the immune response in latent TB leading to a suboptimal induction of protective CD4(+) T-cell responses, thereby providing a potential mechanism for increased susceptibility to active disease.

  5. Serum Cytokines Th1, Th2, and Th17 Expression Profiling in Active Lupus Nephritis-IV: From a Southern Chinese Han Population

    PubMed Central

    Wang, Yin; Hu, Weiping; Wang, Ning; Sun, Qingyi; Liu, Qingyan; Liu, Xiaocong; Hou, Xianghua; Cheng, Ao

    2016-01-01

    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant T cell immune response. Diffuse proliferative lupus nephritis (LN-IV) is the most common, severe, and active form of lupus nephritis. In this study, we investigated the production of Th1, Th2, and Th17 cytokines in prediction of active form of LN-IV. ProcartaPlex multiplex immunoassays panels were used for detection of serum Th1, Th2, and Th17 cytokines profiling. Th1 and Th17 cytokines (IL-18, IFN-γ, IL-12p70, IL-6, and IL-17A) were considerably expressed in the serum of lupus nephritis IV patients in comparison to the healthy control. However, only IL18 and IL6 were higher in class IV versus class III lupus nephritis. Importantly, the ratios of Th1/Th2 (IL-18/IL-4) and Th17/Th2 (IL-17A/IL-4) were significantly elevated in LN-IV when compared with LN-III, LN-V, and healthy controls. Consistently, the serum cytokines IL-18, IL-17A, and IFN-γ were markedly expressed in LN-IV patient glomeruli and interstitial tissue compared to other classes of LN by IHC. ROC further suggests that IL-18 was a potential marker for LN-IV. The data from our study suggests that the early detection and quantification of these cytokines may help in prediction of active form of LN-IV. PMID:27738386

  6. Electro-acupuncture at Acupoint ST36 Ameliorates Inflammation and Regulates Th1/Th2 Balance in Delayed-Type Hypersensitivity.

    PubMed

    Wang, Zhigang; Chen, Tao; Long, Man; Chen, Longyun; Wang, Lei; Yin, Nina; Chen, Zebin

    2017-04-01

    Increasing evidence indicates anti-allergic and anti-inflammatory effects of electro-acupuncture (EA) therapy. However, its underlying mechanism on delayed-type hypersensitivity (DTH), a classic allergic inflammatory disease, still remains unclear. In this study, we aimed to explore the immunomodulatory mechanism of EA intervention in a mouse model of ovalbumin (OVA)-induced DTH. Mice were randomly divided into four groups: Control, OVA-DTH, DTH + EA, DTH + Sham. "Zusanli" acupoint (ST36) was used for DTH + EA, whereas a non-acupoint (localized 5 mm below the "Zusanli" acupoint) was selected for DTH + Sham. Footpad thickness was checked, and the infiltration of inflammatory cells was estimated by hematoxylin and eosin staining. Levels of IgG and IgE in serum of different groups and inflammatory cytokines in the supernatants from homogenized footpads, including IFN-γ, TNF-α, IL-4, and IL-5, were determined by ELISA. Cell proliferation of spleen lymphocytes was assayed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT). The frequency of CD4(+)IFN-γ(+) and CD4(+)IL-4(+) T cells was analyzed with flow cytometry. In addition, the mRNA and protein expression of T-bet and GATA-3 were evaluated by real-time PCR and Western blotting, respectively. Our data showed EA treatment at acupoint ST36 relieved the pathological progression of DTH responses via reduction in footpad swelling, infiltration of inflammatory cells, levels of IgG and IgE as well as decreased production of IFN-γ and TNF-α in homogenized footpad tissue. Moreover, detailed studies were performed revealing that EA attenuated the percentage of CD4(+)IFN-γ(+) T cells and prevented Th cells differentiation into Th1 cells, and this results from inhibiting secretion of IFN-γ and suppressing expression of T-bet, an IFN-γ transcription factor. The results indicated that EA treatment improved Th1-mediated allergic skin inflammation via restoring Th1/Th2 balance by curbing Th1

  7. Suppression of Th1 and Th2 immune responses in mice by Sinomenine, an alkaloid extracted from the chinese medicinal plant Sinomenium acutum.

    PubMed

    Feng, Huang; Yamaki, Kouya; Takano, Hirohisa; Inoue, Ken-ichiro; Yanagisawa, Rie; Yoshino, Shin

    2006-12-01

    The present study was designed to investigate the effect of sinomenine (SIN), an alkaloid extracted from Sinomenium acutum, on Th1 and Th2 immune responses in mice. For this investigation, mice were S. C. immunized with ovalbumin (OVA) emulsified with complete Freund's adjuvant (day 0). Varying doses of SIN were orally administered daily over a period of 21 days, commencing on day 0. On day 21, anti-OVA IgG and proliferative responses of spleen cells to the antigen were measured. Anti-OVA IgG2a and IFN-gamma were measured as indicators of Th1 immune responses and anti-OVA IgG1, IgE, and IL-5 as those of Th2 responses. TGF-beta was measured as an indicator of Th3 immune responses. The results showed that treatment with SIN was followed by decreases in anti-OVA IgG and the antigen-specific splenocyte proliferation. Production of all isotypes of antibodies including anti-OVA IgG2a, IgG1 and IgE as well as secretion of cytokines such as IFN-gamma and IL-5 was suppressed by SIN, although the suppression of anti-OVA IgG2a and IFN-gamma by the alkaloid appeared to be greater than that of anti-OVA IgG1, IgE, and IL-5. In addition, SIN enhanced the secretion of TGF-beta. These results suggest that SIN appears to have suppressive effects on both Th1 and Th2 immune responses. The results also suggest that Th1 responses may be more preferentially suppressed by the Sinomenium acutum-derived alkaloid compared to Th2 responses. TGF-beta may at least in part contribute to the suppression of Th1 as well as Th2 immune responses.

  8. Arabinosylated Lipoarabinomannan Skews Th2 Phenotype towards Th1 during Leishmania Infection by Chromatin Modification: Involvement of MAPK Signaling

    PubMed Central

    Bhattacharya, Parna; Gupta, Gaurav; Majumder, Saikat; Adhikari, Anupam; Banerjee, Sayantan; Halder, Kuntal; Bhattacharya Majumdar, Suchandra; Ghosh, Moumita; Chaudhuri, Shubho; Roy, Syamal; Majumdar, Subrata

    2011-01-01

    The parasitic protozoan Leishmania donovani is the causative organism for visceral leishmaniasis (VL) which persists in the host macrophages by deactivating its signaling machinery resulting in a critical shift from proinflammatory (Th1) to an anti-inflammatory (Th2) response. The severity of this disease is mainly determined by the production of IL-12 and IL-10 which could be reversed by use of effective immunoprophylactics. In this study we have evaluated the potential of Arabinosylated Lipoarabinomannan (Ara-LAM), a cell wall glycolipid isolated from non pathogenic Mycobacterium smegmatis, in regulating the host effector response via effective regulation of mitogen-activated protein kinases (MAPK) signaling cascades in Leishmania donovani infected macrophages isolated from BALB/C mice. Ara-LAM, a Toll-like receptor 2 (TLR2) specific ligand, was found to activate p38 MAPK signaling along with subsequent abrogation of extracellular signal–regulated kinase (ERKs) signaling. The use of pharmacological inhibitors of p38MAPK and ERK signaling showed the importance of these signaling pathways in the regulation of IL-10 and IL-12 in Ara-LAM pretreated parasitized macrophages. Molecular characterization of this regulation of IL-10 and IL-12 was revealed by chromatin immunoprecipitation assay (CHIP) which showed that in Ara-LAM pretreated parasitized murine macrophages there was a significant induction of IL-12 by selective phosphorylation and acetylation of histone H3 residues at its promoter region. While, IL-10 production was attenuated by Ara-LAM pretreatment via abrogation of histone H3 phosphorylation and acetylation at its promoter region. This Ara-LAM mediated antagonistic regulations in the induction of IL-10 and IL-12 genes were further correlated to changes in the transcriptional regulators Signal transducer and activator of transcription 3 (STAT3) and Suppressor of cytokine signaling 3 (SOCS3). These results demonstrate the crucial role played by Ara-LAM in

  9. Effect of vitamin D supplementation during pregnancy on the Th1/Th2 cell balance of rat offspring.

    PubMed

    Chen, Wen-Jia; Hou, Xue-Jing; Yang, Shu-Fen; Yin, Xin-Hua; Ren, Lihong

    2014-05-01

    Vitamin D has important functions in the immune system, and it may suppress the proliferation of T helper (Th) cells and modulate their cytokine production. In this study, we aimed to investigate the effects of maternal supplementation with different doses of vitamin D on the allergy status of the offspring. We gave pregnant female rats a low dose (48000IU/kg, equal to 800IU/d in human) and a high dose (240000IU/kg,equal to 4000IU/d in human) of vitamin D3 intramuscular injection on gestation day (GD)17, and we used an enzyme-linked immunosorbent assay (ELISA) to determine the levels of immune responsive cytokines including IL-4, IgE, and interferon gamma (IFN-gamma) in the offspring. On postnatal day (PND) 21, plasma IL-4 levels were elevated by 10.43% (p < 0.01) in the offspring from the high dose vitamin D3 group compared with the control group. And offspring plasma IL-4 levels in the low dose group decreased by 7.27% (p < 0.05) compared with the control dose group. We found that the offspring of mothers given a low dose of vitamin D3 had a 6.17% (p < 0.01) decrease in their plasma IgE levels compared to control animals, but the high dose of vitamin D3 showed no effect. The serum 25(OH)D3 levels were negatively correlated with the IL-4 (r = -0.561, p < 0.01) and IgE (r = -0.421, p < 0.05) levels of the offspring from the low dose group. In the lung tissues of the offspring of the high dose group, we observed thickening of the alveolar septa and more inflammatory cells compared with the control group and low dose group. Thickened alveolar septa were also found in the lung tissues of the offspring from the control group. We conclude that high dose vitamin D3 maternal supplementation during pregnancy induced an imbalance of Th1 and Th2 cells in their offspring resulting allergic and inflammatory response.

  10. Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

    PubMed Central

    Ferraz-de-Paula, Viviane; Palermo-Neto, Joao; Castro, Carla N.; Druker, Jimena; Holsboer, Florian; Perone, Marcelo J.; Gerlo, Sarah; De Bosscher, Karolien; Haegeman, Guy; Arzt, Eduardo

    2012-01-01

    Background Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-γ and an increase in IL-5 production, respectively. Conclusions Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders. PMID:22496903

  11. Comparison of Th1- and Th2-associated immune reactivities stimulated by single versus multiple vaccination of mice with irradiated Schistosoma mansoni cercariae

    SciTech Connect

    Caulada-Benedetti, Z.; Al-Zamel, F.; Sher, A.; James, S. )

    1991-03-01

    Mice immunized against Schistosoma mansoni by a single percutaneous exposure to radiation-attenuated parasite larvae demonstrate partial resistance to challenge infection that has been shown to correlate with development of cell-mediated immunity, whereas mice hyperimmunized by multiple exposure to attenuated larvae produce antibodies capable of transferring partial protection to naive recipients. Measurement of Ag-specific lymphokine responses in these animals suggested that the difference in resistance mechanisms may be due to the differential induction of Th subset response by the two immunization protocols. Thus, upon Ag stimulation, singly immunized mice predominantly demonstrated responses associated with Th1 reactivity, including IL-2 and IFN-gamma production, whereas multiply immunized animals showed increased IL-5, IL-4, and IgG1 antibody production associated with enhanced Th2 response. These responses demonstrated some degree of organ compartmentalization, with splenocytes demonstrating higher Th1-related lymphokine production and cells from draining lymph nodes showing stronger proliferation and Th2 type reactivity. However, hyperimmunized mice also continued to demonstrate substantial Th1-associated immune reactivity. Moreover, in vivo Ag challenge elicited activated larvacidal macrophages in hyperimmunized animals. These observations indicate that protective cell-mediated mechanisms associated with induction of CD4+ Th1 cell reactivity predominate in singly vaccinated mice. Further vaccination stimulates Th2 responses, such as enhanced IgG1 production, that may also contribute to protective immunity.

  12. Expression of Th1, Th2, lymphocyte trafficking and activation markers on CD4+ T-cells of Hymenoptera allergic subjects and after venom immunotherapy.

    PubMed

    Cabrera, Carmen M; Urra, José M; Alfaya, Teresa; Roca, Federico De La; Feo-Brito, Francisco

    2014-11-01

    Systemic reactions to Hymenoptera stings can be fatal and represent a reduction in the quality of life. The immune mechanisms involved in venom allergic subjects are barely known. Nevertheless, a shift towards a Th1-type response with an increase in IFNγ levels has been observed after venom immunotherapy (VIT). There is currently no information available about the expression of markers on CD4+ T-cells or their involvement in venom allergy, nor following VIT. For this, we have studied the expression of Th1 and Th2-cell markers, homing receptors and activation markers on CD4+ T-cells of subjects who presented systemic allergic reactions, mainly to Polistes dominulus, and after receiving a 4-month conventional VIT protocol. The markers studied were: CD26 (Th1), CD30 (Th2), CXCR4, CXCR3 (Th1), CCR4 (Th2), CD154 (CD40L), CD152 (CTLA-A), and ICOS. We also determined the IL-4 (Th2) and IFNγ (Th1) intracellular cytokine levels in T-cells and carried out a basophil activation test (BAT). Comparing venom allergic subjects with non-allergic healthy controls, we have found up-regulation of CD26, CXCR4, CXCR3, CD154 and ICOS. Conversely, a down-regulation of CD30, CD154 and CD152 occurred upon immune intervention, whereas the remaining markers were not affected. Equally, VIT has been shown to be effective, as evidenced by the decrease of basophil degranulation and increase of IFNγ levels in T-cells after the fourth month of treatment. These new findings highlight the possible application of these surface molecules as markers to distinguish between symptomatic and asymptomatic subjects sensitized to Hymenoptera venom, as well as revealing information about the immune changes associated with VIT.

  13. Coupling Peptide Antigens to Virus-Like Particles or to Protein Carriers Influences the Th1/Th2 Polarity of the Resulting Immune Response

    PubMed Central

    Pomwised, Rattanaruji; Intamaso, Uraiwan; Teintze, Martin; Young, Mark; Pincus, Seth H.

    2016-01-01

    We have conjugated the S9 peptide, a mimic of the group B streptococcal type III capsular polysaccharide, to different carriers in an effort to elicit an optimal immune response. As carriers, we utilized the soluble protein keyhole limpet hemocyanin and virus-like particles (VLPs) from two plant viruses, Cowpea Chlorotic Mottle Virus and Cowpea Mosaic Virus. We have found that coupling the peptide to the soluble protein elicits a Th2 immune response, as evidenced by the production of the peptide-specific IgG1 antibody and IL-4/IL-10 production in response to antigen stimulation, whereas the peptide conjugated to VLPs elicited a Th1 response (IgG2a, IFN-γ). Because the VLPs used as carriers package RNA during the assembly process, we hypothesize that this effect may result from the presence of nucleic acid in the immunogen, which affects the Th1/Th2 polarity of the response. PMID:27164150

  14. Coupling Peptide Antigens to Virus-Like Particles or to Protein Carriers Influences the Th1/Th2 Polarity of the Resulting Immune Response.

    PubMed

    Pomwised, Rattanaruji; Intamaso, Uraiwan; Teintze, Martin; Young, Mark; Pincus, Seth H

    2016-05-05

    We have conjugated the S9 peptide, a mimic of the group B streptococcal type III capsular polysaccharide, to different carriers in an effort to elicit an optimal immune response. As carriers, we utilized the soluble protein keyhole limpet hemocyanin and virus-like particles (VLPs) from two plant viruses, Cowpea Chlorotic Mottle Virus and Cowpea Mosaic Virus. We have found that coupling the peptide to the soluble protein elicits a Th2 immune response, as evidenced by the production of the peptide-specific IgG1 antibody and IL-4/IL-10 production in response to antigen stimulation, whereas the peptide conjugated to VLPs elicited a Th1 response (IgG2a, IFN-γ). Because the VLPs used as carriers package RNA during the assembly process, we hypothesize that this effect may result from the presence of nucleic acid in the immunogen, which affects the Th1/Th2 polarity of the response.

  15. Dysfunction of Th1 and th2 lymphocytes and change in blood cytokine concentration at various stages of chronic intoxication with organophosphorus compounds.

    PubMed

    Zabrodskii, P F; Gromov, M S; Yafarova, I Kh

    2014-04-01

    Experiments on noninbred albino rats showed that a chronic exposure to organophosphorus compounds (carbophos and metaphos, 30 days, total dose 0.3 LD50) is primarily followed by a decrease in the immune reactions and IFN-γ associated with Th1 lymphocyte function (in comparison with the immune response due to activation of Th2 cells by IL-4). The concentrations of IL-2, IL-6, and IL-10 in the blood decreased after 30-day intoxication. The immune reactions associated with functional activity of Th1 and Th2 lymphocytes were shown to decrease similarly after chronic treatment with organophosphorus compounds for 60 days (total dose 0.6 LD50). This exposure was accompanied by a decrease in the concentrations of IFN-γ, IL-4, IL-2, and IL-6, but had no effect on the level of IL-10 in the blood.

  16. A CpG-containing oligodeoxynucleotide as an efficient adjuvant counterbalancing the Th1/Th2 immune response in diphtheria-tetanus-pertussis vaccine.

    PubMed

    Sugai, Toshiyuki; Mori, Masaaki; Nakazawa, Masatoshi; Ichino, Motohide; Naruto, Takuya; Kobayashi, Naoki; Kobayashi, Yoshinori; Minami, Mutsuhiko; Yokota, Shumpei

    2005-11-16

    Adjuvants in vaccines are immune stimulants that play an important role in the induction of effective and appropriate immune responses to vaccine component(s). Diphtheria-tetanus-pertussis (DPT) vaccine contains not only aluminum hydrate (alum) to enhance the immune response to the vaccine ingredients, but also, both for that purpose and as a principal ingredient, pertussis toxin (PT). However, both adjuvants strongly promote T helper (Th) 2 type immune responses. Th1 and Th2 type immune responses are counterbalanced in vivo, and a Th2-prone immune response is not effective against intracellular infections but promotes IgE production, which is related to allergic disease. In this study, we used the CpG motif contained in oligodeoxynucleotide (CpG-ODN), which has an adjuvant effect and also induces the Th1 response, as an adjuvant to this vaccine, and we investigated its adjuvanticity and its potential to modulate immune responses to DPT vaccine. Administration of DPT vaccine with CpG-ODN (DPT-alum/ODN) to mice significantly reduced the total IgE levels and increased the anti-PT specific IgG2a titer in serum, in comparison with ordinary DPT vaccine (DPT-alum). Moreover, we investigated the antibody response to orally administrated ovalbumin (OVA) after vaccine administration. In the DPT-alum/ODN-administered group, the OVA specific IgE production in serum greatly decreased in comparison with that in the DPT-alum-administered group. These data indicate that CpG-ODN was not useful only as an efficient vaccine adjuvant but also shifted the immune responses substantially toward Th1 and modulated the Th1/Th2 immune response in DPT vaccine. These data suggested new applications of CpG-ODN as adjuvants in DPT vaccine.

  17. A differential interplay between the expression of Th1/Th2/Treg related cytokine genes in Teladorsagia circumcincta infected DRB1*1101 carrier lambs

    PubMed Central

    2011-01-01

    Substantial debate exists on whether the immune response between sheep resistant and susceptible to gastrointestinal nematodes can be differentiated into a Th1 and Th2 phenotype. The present study addresses the hypothesis that variation in resistance to Teladorsagia circumcincta between DRB1*1101 (associated with reduced faecal egg count and worm burden) carriers and non-carriers is due to a differential interplay in the expression of Th1/Th2 and regulatory T (Treg) related cytokine genes. Lambs from each genotype were either slaughtered at day 0 (un-infected control) or infected with 3 × 104 Teladorsagia circumcincta L3 and slaughtered at 3, 7, 21, and 35 days later. Lambs carrying the DRB1*1101 allele had a significantly lower worm burden (P < 0.05) compared to the non-carriers. Abomasal mucosal cytokine gene expression was evaluated by quantitative real-time PCR and comparison made for time and genotype effects. The response generated varied through the course of infection and was affected by genotype. DRB1*1101 carriers had an up-regulated expression of the Th1-related cytokine genes (IL-1β, TNFα, and IFN-γ) at day 3, but this was replaced by an up-regulated expression of Th2-related cytokine genes (IL-10 and IL-13) and Treg-related cytokine genes (IL-2RA-CD25, TGFα, TGFβ, Arg2, MIF and FOXP3) by day 7. Conversely, in the non-carriers these changes in gene expression were delayed until days 7 and 21 post infection (pi), respectively. It is concluded that resistance to Teladorsagia circumcincta in animals carrying the DRB1*1101 allele is influenced by an earlier interplay between Th1, Th2 and T regulatory immune response genes. PMID:21385411

  18. A differential interplay between the expression of Th1/Th2/Treg related cytokine genes in Teladorsagia circumcincta infected DRB1*1101 carrier lambs.

    PubMed

    Hassan, Musa; Hanrahan, James P; Good, Barbara; Mulcahy, Grace; Sweeney, Torres

    2011-03-08

    Substantial debate exists on whether the immune response between sheep resistant and susceptible to gastrointestinal nematodes can be differentiated into a Th1 and Th2 phenotype. The present study addresses the hypothesis that variation in resistance to Teladorsagia circumcincta between DRB1*1101 (associated with reduced faecal egg count and worm burden) carriers and non-carriers is due to a differential interplay in the expression of Th1/Th2 and regulatory T (Treg) related cytokine genes. Lambs from each genotype were either slaughtered at day 0 (un-infected control) or infected with 3 × 10(4) Teladorsagia circumcincta L3 and slaughtered at 3, 7, 21, and 35 days later. Lambs carrying the DRB1*1101 allele had a significantly lower worm burden (P < 0.05) compared to the non-carriers. Abomasal mucosal cytokine gene expression was evaluated by quantitative real-time PCR and comparison made for time and genotype effects. The response generated varied through the course of infection and was affected by genotype. DRB1*1101 carriers had an up-regulated expression of the Th1-related cytokine genes (IL-1β, TNFα, and IFN-γ) at day 3, but this was replaced by an up-regulated expression of Th2-related cytokine genes (IL-10 and IL-13) and Treg-related cytokine genes (IL-2RA-CD25, TGFα, TGFβ, Arg2, MIF and FOXP3) by day 7. Conversely, in the non-carriers these changes in gene expression were delayed until days 7 and 21 post infection (pi), respectively. It is concluded that resistance to Teladorsagia circumcincta in animals carrying the DRB1*1101 allele is influenced by an earlier interplay between Th1, Th2 and T regulatory immune response genes.

  19. Mycophenolate Mofetil Modulates Differentiation of Th1/Th2 and the Secretion of Cytokines in an Active Crohn’s Disease Mouse Model

    PubMed Central

    Lv, Qing-Kang; Liu, Ju-Xiong; Li, Su-Nan; Gao, Ying-Jie; Lv, Yan; Xu, Zi-Peng; Huang, Bing-Xu; Xu, Shi-Yao; Yang, Dong-Xue; Zeng, Ya-Long; Liu, Dian-Feng; Wang, Wei

    2015-01-01

    Mycophenolate mofetil (MMF) is an alternative immunosuppressive agent that has been reported to be effective and well tolerated for the treatment of refractory inflammatory bowel disease (IBD). The aim of this study was to investigate the therapeutic effect of MMF on intestinal injury and tissue inflammation, which were caused by Crohn’s disease (CD). Here, trinitrobenzene sulfonic acid-relapsing (TNBS) colitis was induced in mice; then, we measured the differentiation of Th1/Th2 cells in mouse splenocytes by flow cytometry and the secretion of cytokines in mice with TNBS-induced colitis by real-time polymerase chain reaction and/or enzyme-linked immunosorbent assay (RT-PCR/ELISA). The results show that MMF significantly inhibited mRNA expression of pro-inflammatory cytokines IFN-γ, TNF-α, IL-12, IL-6, and IL-1β in mice with TNBS-induced colitis; however, MMF did not inhibit the expression of IL-10 mRNA. Additionally, ELISA showed that the serum levels of IFN-γ, TNF-α, IL-12, IL-6, and IL-1β were down-regulated in a TNBS model of colitis. Flow cytometric analysis showed MMF markedly reduced the percentages of Th1 and Th2 splenocytes in the CD mouse model. Mycophenolic acid (MPA) also significantly decreased the percentages of splenic Th1 and Th2 cells in vitro. Furthermore, MMF treatment not only significantly ameliorated diarrhea, and loss of body weight but also abrogated the histopathologic severity and inflammatory response of inflammatory colitis, and increased the survival rate of TNBS-induced colitic mice. These results suggest that treatment with MMF may improve experimental colitis and induce inflammatory response remission of CD by down-regulation of pro-inflammatory cytokines via modulation of the differentiation of Th1/Th2 cells. PMID:26561804

  20. Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes.

    PubMed

    Messi, Mara; Giacchetto, Isabella; Nagata, Kinya; Lanzavecchia, Antonio; Natoli, Gioacchino; Sallusto, Federica

    2003-01-01

    CD4+ T cell priming under T helper type I (T(H)1) or T(H)2 conditions gives rise to polarized cytokine gene expression. We found that in these conditions human naive T cells acquired stable histone hyperacetylation at either the Ifng or Il4 promoter. Effector memory T cells showed polarized cytokine gene acetylation patterns in vivo, whereas central memory T cells had hypoacetylated cytokine genes but acquired polarized acetylation and expression after appropriate stimulation. However, hypoacetylation of the nonexpressed cytokine gene did not lead to irreversible silencing because most T(H)1 and T(H)2 cells acetylated and expressed the alternative gene when stimulated under opposite T(H) conditions. Such cytokine flexibility was absent in a subset of T(H)2 cells that failed to up-regulate T-bet and to express interferon-gamma when stimulated under T(H)1 conditions. Thus, most human CD4+ T cells retain both memory and flexibility of cytokine gene expression.

  1. Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice

    PubMed Central

    Lee, Chen-Chen; Wang, Ching-Chiung; Huang, Huei-Mei; Lin, Chu-Lun; Leu, Sy-Jye; Lee, Yueh-Lun

    2015-01-01

    This study investigated the immunomodulatory effects of ferulic acid (FA) on antigen-presenting dendritic cells (DCs) in vitro and its antiallergic effects against ovalbumin- (OVA-) induced Th2-mediated allergic asthma in mice. The activation of FA-treated bone marrow-derived DCs by lipopolysaccharide (LPS) stimulation induced a high level of interleukin- (IL-) 12 but reduced the expression levels of the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor- (TNF-) α. Compared to control-treated DCs, FA significantly enhanced the expressions of Notch ligand Delta-like 4 (Dll4), MHC class II, and CD40 molecules by these DCs. Furthermore, these FA-treated DCs enhanced T-cell proliferation and Th1 cell polarization. In animal experiments, oral administration of FA reduced the levels of OVA-specific immunoglobulin E (IgE) and IgG1 and enhanced IgG2a antibody production in serum. It also ameliorated airway hyperresponsiveness and attenuated eosinophilic pulmonary infiltration in dose-dependent manners. In addition, FA treatment inhibited the production of eotaxin, Th2 cytokines (IL-4, IL-5, and IL-13), and proinflammatory cytokines but promoted the Th1 cytokine interferon- (IFN-) γ production in bronchoalveolar lavage fluid (BALF) and the culture supernatant of spleen cells. These findings suggest that FA exhibits an antiallergic effect via restoring Th1/Th2 imbalance by modulating DCs function in an asthmatic mouse model. PMID:26495021

  2. Effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4+ CD25+ Foxp3+ Treg in asthma Balb/c mouse

    PubMed Central

    Yun, Xiang; Shang, Yunxiao; Li, Miao

    2015-01-01

    Background: Bronchial asthma is a chronic airway inflammatory disease that involves T lymphocytes. Methods: In order to explore the effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4+ CD25+ Foxp3+ Treg in asthma Balb/c mouse, we constructed acute asthma model with ovalbumin to observe the mouse behavior change in Balb/c mice. The expression of GATA-3 mRNA and T-bet mRNA was measured by real-time PCR. The proportion of CD4+ CD25+ Foxp3+ Treg/CD4+ was determined by flow cytometry. Results: The results demonstrated that oral gavage with Lactobacillus salivarius before sensitization could alleviate the clinical symptoms, airway hyper-reactivity and airway inflammation in asthma mouse to some extent; Lactobacillus salivarius may improve the imbalance of Th1/Th2 in asthma mouse through increasing the expression of T-bet mRNA at the transcriptional level and inhibiting the expression of GATA-3 mRNA simultaneously. Conclusion: CD4+ CD25+ Foxp3+ Treg cells may be involved in the pathogenesis of bronchial asthma, and may be the upstream regulatory mechanism of the improvement of Th1/Th2 imbalance by Lactobacillus salivarius. PMID:26339333

  3. Th1, Th2 and Th17 Effector T Cell-Induced Autoimmune Gastritis Differs in Pathological Pattern and in Susceptibility to Suppression by Regulatory T Cells

    PubMed Central

    Stummvoll, Georg H.; DiPaolo, Richard J.; Huter, Eva N.; Davidson, Todd S.; Glass, Deborah; Ward, Jerrold M.; Shevach, Ethan M.

    2008-01-01

    Th cells can be subdivided into IFNγ-secreting Th1, IL-4/IL-5 secreting Th2, and IL-17 secreting Th17 cells. We have evaluated the capacity of fully differentiated Th1, Th2, and Th17 cells derived from a mouse bearing a transgenic TCR specific for the gastric parietal cell antigen, H/K ATPase, to induce autoimmune gastritis after transfer to immunodeficient recipients. We have also determined the susceptibility of the disease induced by each of the effector T cell types to suppression by polyclonal regulatory T cells (Treg) in vivo. Each type of effector cell induced autoimmune gastritis with distinct histological patterns. Th17 cells induced the most destructive disease with cellular infiltrates composed primarily of eosinophils accompanied by high levels of serum IgE. Polyclonal Treg could suppress the capacity of Th1 cells, moderately suppress Th2 cells, but could only suppress Th17 induced disease at early time points. The major effect of the Treg was to inhibit the expansion of the effector T cells. However, effector cells isolated from protected animals were not anergic and were fully competent to proliferate and produce effector cytokines ex vivo. The strong inhibitory effect of polyclonal Treg on the capacity of some types of differentiated effector cells to induce disease provides an experimental basis for the clinical use of polyclonal Treg in the treatment of autoimmune disease in man. PMID:18641328

  4. Th1, Th2, and Th17 effector T cell-induced autoimmune gastritis differs in pathological pattern and in susceptibility to suppression by regulatory T cells.

    PubMed

    Stummvoll, Georg H; DiPaolo, Richard J; Huter, Eva N; Davidson, Todd S; Glass, Deborah; Ward, Jerrold M; Shevach, Ethan M

    2008-08-01

    Th cells can be subdivided into IFN-gamma-secreting Th1, IL-4/IL-5-secreting Th2, and IL-17-secreting Th17 cells. We have evaluated the capacity of fully differentiated Th1, Th2, and Th17 cells derived from a mouse bearing a transgenic TCR specific for the gastric parietal cell antigen, H(+)K(+)-ATPase, to induce autoimmune gastritis after transfer to immunodeficient recipients. We have also determined the susceptibility of the disease induced by each of the effector T cell types to suppression by polyclonal regulatory T cells (Treg) in vivo. Each type of effector cell induced autoimmune gastritis with distinct histological patterns. Th17 cells induced the most destructive disease with cellular infiltrates composed primarily of eosinophils accompanied by high levels of serum IgE. Polyclonal Treg could suppress the capacity of Th1 cells, could moderately suppress Th2 cells, but could suppress Th17-induced disease only at early time points. The major effect of the Treg was to inhibit the expansion of the effector T cells. However, effector cells isolated from protected animals were not anergic and were fully competent to proliferate and produce effector cytokines ex vivo. The strong inhibitory effect of polyclonal Treg on the capacity of some types of differentiated effector cells to induce disease provides an experimental basis for the clinical use of polyclonal Treg in the treatment of autoimmune disease in humans.

  5. Cytokine mRNA expression in hepatitis C virus infection: TH1 predominance in patients with chronic hepatitis C and TH1-TH2 cytokine profile in subjects with self-limited disease.

    PubMed

    Gigi, E; Raptopoulou-Gigi, M; Kalogeridis, A; Masiou, S; Orphanou, E; Vrettou, E; Lalla, T H; Sinakos, E; Tsapas, V

    2008-02-01

    Many determinants of the immune response have been implied in the pathogenesis of chronic hepatitis C. TH1 and TH2 cytokines play a prominent role in viral infections and a dysregulation of these cytokines could account for viral persistence and evolution of chronic disease. To explore a possible TH1 and TH2 cytokine dysregulation resulting in the inability to terminate hepatitis C virus (HCV) infection, we studied TH1 [interferon (IFN)-gamma, interleukin (IL)-2] and TH2 (IL-4, IL-10) mRNA expression of peripheral blood mononuclear cells (PBMC) in response to NS3 HCV antigen stimulation, in 31 untreated patients with chronic hepatitis C and 29 subjects with self-limited disease. After a 48 h culture of PBMC, total RNA isolation was performed and complementary DNA was prepared by reverse transcription. mRNA levels were quantified by real-time polymerase chain reaction using a standard curve formed after cloning each cytokine gene and a reference gene using recombinant DNA technology in a specific plasmid vector. In the patients group, mRNA expression of IFN-gamma, IL-2 and IL-4 but not IL-10 was detected, IFN-gamma being the predominant cytokine expressed. All four cytokines were expressed in subjects with self limited disease, however levels of IFN-gamma were lower and a significant higher expression of IL-10 compared to patients was found. There was a significant correlation between IFN-gamma mRNA expression levels and stage of fibrosis. Our findings show that in chronic hepatitis C, TH1 cytokines predominate and correlate to liver immunopathology. Furthermore, subjects with self-limited disease, maintain the ability to respond to HCV antigens for a long time after disease resolution.

  6. Passage from normal mucosa to adenoma and colon cancer: alteration of normal sCD30 mechanisms regulating TH1/TH2 cell functions.

    PubMed

    Contasta, Ida; Berghella, Anna Maria; Pellegrini, Patrizia; Adorno, Domenico

    2003-08-01

    The pathogenesis of cancer is currently under intensive investigation to identify reliable prognostic indices for the early detection of disease. Adenomas have been identified as precursors of colorectal cancer and tumor establishment, and disease progression has been found to reflect a malfunction of the immune system. On the basis of the role of the CD30 molecule in the regulation of TH1/TH2 functions and our previous results, strongly suggesting the validity of serum TH1/TH2 cytokines in the study of tumor progression, we studied network interaction between the production of soluble (s) CD30/sBCl2 in whole blood culture [in basic conditions and after PHA, LPS, and anti-CD3 monoclonal antibody (mAb) stimulation] and levels of TH1/TH2 cytokines (IL2, IFN gamma, IL12, IL4, IL5, IL10). Peripheral blood from a group of healthy subjects, as well as from patients with adenoma and colorectal cancer was used. Our objective was to gain a better insight into the role of the CD30 molecule in the passage from normal mucosa to adenoma and tumor and identify specific disease markers. Our results suggest that the decrease in CD30 expression and the abnormal increase in Bcl2 expression, observed in the peripheral cells of both adenoma and tumor groups determine an imbalance between TH1/TH2 functions. Consequently, changes in sCD30/sBcl2 culture production and TH1/TH2 cytokine serum levels may be reliable markers for tumor progression. In fact, our overall data show that a decrease of sCD30 levels in basic and PHA conditions and an increase of IFN gamma, IL4, IL5, and IL12 serum levels and sBcl2 in all activation condition are indicative of the passage from normal mucosa to adenoma; whilst a decrease of sBcl2 level in basic, LPS and anti-CD3 conditions and of IL2, IFN gamma serum levels, together with an increase of IL5 are indicative of the passage from adenoma to tumor.

  7. Resting Respiratory Tract Dendritic Cells Preferentially Stimulate T Helper Cell Type 2 (Th2) Responses and Require Obligatory Cytokine Signals for Induction of  Th1 Immunity

    PubMed Central

    Stumbles, Philip A.; Thomas, Jennifer A.; Pimm, Carolyn L.; Lee, Peter T.; Venaille, Thierry J.; Proksch, Stephen; Holt, Patrick G.

    1998-01-01

    Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the “default” T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2–3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-γ by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing– associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor α or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli. PMID:9841916

  8. Amelioration of skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice by oral administration of Agaricus blazei extracts.

    PubMed

    Takimoto, Hiroaki; Kato, Hanano; Kaneko, Masahiro; Kumazawa, Yoshio

    2008-01-01

    We showed in a previous study that hot-water extracts of Agaricus blazei (Agaricus extracts) had anti-tumor activity to Meth A fibrosarcoma, but it remains unclear whether the Agaricus extracts ameliorate the skewed balance of type-1 T helper (Th1) and type-2 T helper (Th2) cells. We examined whether Agaricus extracts effect the skewed Th1/Th2 balance in tumor-bearing and asthma-induced mice. When Meth A-bearing mice were given orally either Agaricus extracts or water once a day starting 5 days after tumor implantation, spleen T cells, prepared from tumor-bearing mice treated with Agaricus extracts, in response to anti-CD3 monoclonal antibody produced significantly higher levels of interferon gamma (IFN-gamma) than that of controls. The mRNA expression of IFN-gamma-inducing protein 10 and the frequency of CD69(+) or CD49d(+) cells, among activated T cells infiltrated into tumors, significantly increased in Agaricus-treated mice, compared with those of tumor-controls. In asthma-induced mice, treatment with the Agaricus extracts caused significant downregulation of OVA-specific antibody responses of IgG1 and IgE but not of IgG2a, and significantly decreased total cell numbers, levels of interleukin 5, and eosinophil numbers in bronchial alveolar lavage fluids. IFN-gamma production by anti-CD3-stimulated spleen cells, obtained from Agaricus-treated mice, significantly increased. Our results strongly suggest that oral administration of Agaricus extracts ameliorates the Th1/Th2 balance from the Th2-skewed conditions.

  9. Testosterone-Mediated Endocrine Function and TH1/TH2 Cytokine Balance after Prenatal Exposure to Perfluorooctane Sulfonate: By Sex Status

    PubMed Central

    Zhong, Shou-Qiang; Chen, Zan-Xiong; Kong, Min-Li; Xie, Yan-Qi; Zhou, Yang; Qin, Xiao-Di; Paul, Gunther; Zeng, Xiao-Wen; Dong, Guang-Hui

    2016-01-01

    Little information exists about the evaluation of potential developmental immunotoxicity induced by perfluorooctane sulfonate (PFOS), a synthetic persistent and increasingly ubiquitous environmental contaminant. To assess potential sex-specific impacts of PFOS on immunological health in the offspring, using male and female C57BL/6 mice, pups were evaluated for developmental immunotoxic effects after maternal oral exposure to PFOS (0.1, 1.0 and 5.0 mg PFOS/kg/day) during Gestational Days 1–17. Spontaneous TH1/TH2-type cytokines, serum levels of testosterone and estradiol were evaluated in F1 pups at four and eight weeks of age. The study showed that male pups were more sensitive to the effects of PFOS than female pups. At eight weeks of age, an imbalance in TH1/TH2-type cytokines with excess TH2 cytokines (IL-4) was found only in male pups. As for hormone levels, PFOS treatment in utero significantly decreased serum testosterone levels and increased estradiol levels only in male pups, and a significant interaction between sex and PFOS was observed for serum testosterone at both four weeks of age (pinteraction = 0.0049) and eight weeks of age (pinteraction = 0.0227) and for estradiol alternation at four weeks of age (pinteraction = 0.0351). In conclusion, testosterone-mediated endocrine function may be partially involved in the TH1/TH2 imbalance induced by PFOS, and these deficits are detectable among both young and adult mice and may affect males more than females. PMID:27626407

  10. Ribavirin exerts differential effects on functions of Cd4+ Th1, Th2, and regulatory T cell clones in hepatitis C.

    PubMed

    Langhans, Bettina; Nischalke, Hans Dieter; Arndt, Simone; Braunschweiger, Ingrid; Nattermann, Jacob; Sauerbruch, Tilman; Spengler, Ulrich

    2012-01-01

    Ribavirin improves outcomes of therapy in chronic hepatitis C but its mode of action has still remained unclear. Since ribavirin has been proposed to modulate the host's T cell responses, we studied its direct effects on CD4(+) T cell clones with diverse functional polarization which had been generated from patients with chronic hepatitis C. We analysed in vitro proliferation ([(3)H] thymidine uptake) and cytokine responses (IL-10, IFN-gamma) at varying concentrations of ribavirin (0-10 µg/ml) in 8, 9 and 7 CD4(+) TH1, TH2 and regulatory T cell (Treg) clones, respectively. In co-culture experiments, we further determined effects of ribarivin on inhibition of TH1 and TH2 effector cells by Treg clones. All clones had been generated from peripheral blood of patients with chronic hepatitis C in the presence of HCV core protein. Ribavirin enhanced proliferation of T effector cells and increased production of IFN-gamma in TH1 clones, but had only little effect on IL-10 secretion in TH2 clones. However, ribavirin markedly inhibited IL-10 release in Treg clones in a dose dependent fashion. These Treg clones suppressed proliferation of T effector clones by their IL-10 secretion, and in co-culture assays ribavirin reversed Treg-mediated suppression of T effector cells. Our in vitro data suggest that--in addition to its immunostimulatory effects on TH1 cells--ribavirin can inhibit functions of HCV-specific Tregs and thus reverses Treg-mediated suppression of T effector cells in chronic hepatitis C.

  11. Improvement in Th1/Th2 immune homeostasis, antioxidative status and resistance to pathogenic E. coli on consumption of probiotic Lactobacillus rhamnosus fermented milk in aging mice.

    PubMed

    Sharma, Rohit; Kapila, Rajeev; Dass, Gulshan; Kapila, Suman

    2014-01-01

    Imbalance in Th1/Th2 immune pathways and cellular antioxidant systems with progressive aging are among the leading causes of increased risk of morbidity and mortality in elderly. Although probiotics have been considered to boost immune system, there is a lack of comprehensive analysis of probiotic effects on aging physiology. The present study aimed at determining anti-immunosenescence potential of milk fermented with probiotic Lactobacillus rhamnosus (LR) in 16 months old mice by concurrent analysis of immunosenescence markers associated with Th1/Th2 profile of splenocytes, inflamm-aging in plasma, neutrophil functions and antibody response in intestine along with analysis of antioxidant enzymes in liver and red blood cells (RBCs) after feeding trials of 1 and 2 months, respectively. An enteropathogenic Escherichia coli (ATCC 14948)-based infection model in aging mice was also designed to validate protective attributes of LR. Splenocytes registered increased IFN-γ and decreased IL-4 and IL-10 production in LR-fed animals. Neutrophil respiratory burst enzymes and phagocytosis increased significantly while no aggravation in plasma levels of MCP-1 and TNF-α was observed. Further, owing to increased Th1 response, antibodies registered a decrease in IgG1/IgG2a ratio and IgE levels in LR groups. No significant variations were observed in secretory IgA and IgA + cells in the intestine. Antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in LR-fed groups recorded increased activities which were more pronounced in the liver than in RBCs. LR supplementation significantly reduced E. coli translocation to organs (intestine, liver, spleen, peritoneal fluid) by enhancing E. coli-specific antibodies (IgA and IgG1) and inflammatory proteins. In conclusion, LR supplementation alleviated immunosenescence-associated Th1/Th2 imbalance, improved antioxidant capacity, and enhanced resistance of aged mice to E. coli infection thereby signifying its potential

  12. Role of NF-κB activation and Th1/Th2 imbalance in pulmonary toxicity induced by nano NiO.

    PubMed

    Chang, Xuhong; Zhu, An; Liu, Fangfang; Zou, Lingyue; Su, Li; Li, Sheng; Sun, Yingbiao

    2017-04-01

    With the progress of nanotechnology, nano nickel oxide (NiO) has been extensively used as sensors, battery electrodes, catalysts, and cosmetics. Previous researches verified that nano NiO could exert pulmonary toxicity, but its mechanism was unclear. To shed light upon this, the role of nuclear factor-κB (NF-κB) activation and Th1/Th2 imbalance were to explore in pulmonary damage induced by nano NiO. Male Wistar rats were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg kg(-1) ) and micro NiO group (0.024 mg kg(-1) ) and treated by intratracheal instillation twice a week for 6 weeks. The results showed that the abnormal changes induced by nano NiO were found on indicators of nitrative stress (NO, TNOS, and iNOS), inflammatory cytokines (TNF-α, IL-2, and IL-10) and cytokine-induced neutrophil chemoattractants (CINC-1, CINC-2αβ, and CINC-3) in lung tissue. In addition, nano NiO instillation induced the upregulated mRNA and protein expression of NF-κB, inhibitor of κB kinase-α (IKK-α) and nuclear factor-inducing kinase (NIK). The protein content of GATA-3 increased as well as T-bet decreased in nano NiO groups, and the ratio of T-bet/GATA-3, as a key evaluation indicator of Th1/Th2 balance, was lower than the control group. The findings indicated that nano NiO could enhance the nitrative stress and inflammatory response in lung tissue, and its mechanism was related to the NF-κB activation and Th1/Th2 imbalance. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1354-1362, 2017.

  13. Relationship between NADPH and Th1/Th2 ratio in patients with non-Hodgkin lymphoma who have been exposed to pesticides.

    PubMed

    Zahzeh, Meriem Rabia; Loukidi, Bouchra; Meziane, Warda; Haddouche, Mustapha; Mesli, Naima; Zouaoui, Zahia; Aribi, Mourad

    2015-01-01

    The effect of pesticides on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), including its level and relationship with the T helper 1 (Th1)/Th2 ratio, in patients suffering from non-Hodgkin lymphoma (NHL) was investigated. One hundred newly diagnosed patients with aggressive NHL (53 men, 47 women) and 40 healthy age-, sex-, and body mass index-matched controls (23 men, 17 women), exposed or not to pesticides, were recruited for a cross-sectional study conducted at the Clinical Hematology Departments of Tlemcen and Sidi Bel-Abbès University Medical Centers in the northwest of Algeria. NADPH levels were significantly increased in patients compared with controls; and in exposed patients compared with those not exposed, and controls (one-way analysis of variance; P=0.000). Albumin, glutathione peroxidase, superoxide dismutase, catalase activity, and oxygen radical absorbance capacity levels were significantly decreased in patients compared with in the control group. Oxygen radical absorbance capacity levels were significantly decreased in exposed patients compared with in unexposed patients; however, malondialdehyde levels were significantly increased in exposed patients when compared with controls and unexposed patients. Protein carbonyl and xanthine oxidase levels were significantly increased in exposed patients compared with controls; meanwhile, there were no significant differences between the two patient groups or between unexposed patients and controls. The Th1/Th2 ratio was significantly decreased in patients when compared with controls; the neutrophil-to-lymphocyte ratio was significantly increased (for both comparisons, P<0.001). In addition, NADPH was strongly associated with NHL (Mantel-Haenszel common odds ratio estimate =5.55; 95% confidence interval, 2.22-13.88; P=0.000). Moreover, NADPH levels were significantly negatively related to the Th1/Th2 ratio, either in exposed patients or in unexposed patients (respectively, r=-0.498 [P=0.004] and

  14. Relationship between NADPH and Th1/Th2 ratio in patients with non-Hodgkin lymphoma who have been exposed to pesticides

    PubMed Central

    Zahzeh, Meriem Rabia; Loukidi, Bouchra; Meziane, Warda; Haddouche, Mustapha; Mesli, Naima; Zouaoui, Zahia; Aribi, Mourad

    2015-01-01

    The effect of pesticides on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), including its level and relationship with the T helper 1 (Th1)/Th2 ratio, in patients suffering from non-Hodgkin lymphoma (NHL) was investigated. One hundred newly diagnosed patients with aggressive NHL (53 men, 47 women) and 40 healthy age-, sex-, and body mass index-matched controls (23 men, 17 women), exposed or not to pesticides, were recruited for a cross-sectional study conducted at the Clinical Hematology Departments of Tlemcen and Sidi Bel-Abbès University Medical Centers in the northwest of Algeria. NADPH levels were significantly increased in patients compared with controls; and in exposed patients compared with those not exposed, and controls (one-way analysis of variance; P=0.000). Albumin, glutathione peroxidase, superoxide dismutase, catalase activity, and oxygen radical absorbance capacity levels were significantly decreased in patients compared with in the control group. Oxygen radical absorbance capacity levels were significantly decreased in exposed patients compared with in unexposed patients; however, malondialdehyde levels were significantly increased in exposed patients when compared with controls and unexposed patients. Protein carbonyl and xanthine oxidase levels were significantly increased in exposed patients compared with controls; meanwhile, there were no significant differences between the two patient groups or between unexposed patients and controls. The Th1/Th2 ratio was significantly decreased in patients when compared with controls; the neutrophil-to-lymphocyte ratio was significantly increased (for both comparisons, P<0.001). In addition, NADPH was strongly associated with NHL (Mantel–Haenszel common odds ratio estimate =5.55; 95% confidence interval, 2.22–13.88; P=0.000). Moreover, NADPH levels were significantly negatively related to the Th1/Th2 ratio, either in exposed patients or in unexposed patients (respectively, r=−0.498 [P=0

  15. Fasciola hepatica reinfection potentiates a mixed Th1/Th2/Th17/Treg response and correlates with the clinical phenotypes of anemia

    PubMed Central

    Perez-Crespo, Ignacio; Chillón-Marinas, Carlos; Khoubbane, Messaoud; Quesada, Carla; Reguera-Gomez, Marta; Mas-Coma, Santiago; Fresno, Manuel; Gironès, Núria

    2017-01-01

    Background Fascioliasis is a severe zoonotic disease of worldwide extension caused by liver flukes. In human fascioliasis hyperendemic areas, reinfection and chronicity are the norm and anemia is the main sign. Herein, the profile of the Th1/Th2/Th17/Treg expression levels is analyzed after reinfection, correlating them with their corresponding hematological biomarkers of morbidity. Methodology/Principal findings The experimental design reproduces the usual reinfection/chronicity conditions in human fascioliasis endemic areas and included Fasciola hepatica primo-infected Wistar rats (PI) and rats reinfected at 8 weeks (R8), and at 12 weeks (R12), and negative control rats. In a cross-sectional study, the expression of the genes associated with Th1 (Ifng, Il12a, Il12b, Nos2), Th2 (Il4, Arg1), Treg (Foxp3, Il10, Tgfb, Ebi3), and Th17 (Il17) in the spleen and thymus was analyzed. After 20 weeks of primary infection, PI did not present significant changes in the expression of those genes when compared to non-infected rats (NI), but an increase of Il4, Arg1 and Ifng mRNA in the spleen was observed in R12, suggesting the existence of an active mixed Th1/Th2 systemic immune response in reinfection. Foxp3, Il10, Tgfb and Ebi3 levels increased in the spleen in R12 when compared to NI and PI, indicating that the Treg gene expression levels are potentiated in chronic phase reinfection. Il17 gene expression levels in R12 in the spleen increased when compared to NI, PI and R8. Gene expression levels of Il10 in the thymus increased when compared to NI and PI in R12. Ifng expression levels in the thymus increased in all reinfected rats, but not in PI. The clinical phenotype was determined by the fluke burden, the rat body weight and the hemogram. Multivariate mathematical models were built to describe the Th1/Th2/Th17/Treg expression levels and the clinical phenotype. In reinfection, two phenotypic patterns were detected: i) one which includes only increased splenic Ifng

  16. Proliferation and TH1/TH2 cytokine production in human peripheral blood mononuclear cells after treatment with cypermethrin and mancozeb in vitro.

    PubMed

    Mandarapu, Rajesh; Ajumeera, Rajanna; Venkatesan, Vijayalakshmi; Prakhya, Balakrishna Murthy

    2014-01-01

    In recent times, human cell-based assays are gaining attention in assessments of immunomodulatory effects of chemicals. In the study here, the possible effects of cypermethrin and mancozeb on lymphocyte proliferation and proinflammatory (tumor necrosis factor (TNF-) α) and immunoregulatory cytokine (interferon- (IFN-) γ, interleukins (IL) 2, 4, 6, and 10) formation in vitro were investigated. Human peripheral blood mononuclear cells (PBMC) were isolated and exposed for 6 hr to noncytotoxic doses (0.45-30 µM) of cypermethrin or mancozeb in the presence of activating rat S9 fraction. Cultures were then further incubated for 48 or 72 hr in fresh medium containing phytohemagglutinin (10 µg/mL) to assess, respectively, effects on cell proliferation (BrdU-ELISA method) and cytokine formation (flow cytometric bead immunoassays). Mancozeb induced dose-dependent increases in lymphocyte proliferation, inhibition of production of TNFα and the TH2 cytokines IL-6 and IL-10, and an increase in IFNγ (TH1 cytokine) production (at least 2-fold compared to control); mancozeb also induced inhibition of IL-4 (TH2) and stimulated IL-2 (TH1) production, albeit only in dose-related manners for each. In contrast, cypermethrin exposure did not cause significant effects on proliferation or cytokine profiles. Further studies are needed to better understand the functional significance of our in vitro findings.

  17. The Anti-Allergic Rhinitis Effect of Traditional Chinese Medicine of Shenqi by Regulating Mast Cell Degranulation and Th1/Th2 Cytokine Balance.

    PubMed

    Shao, Yang-Yang; Zhou, Yi-Ming; Hu, Min; Li, Jin-Ze; Chen, Cheng-Juan; Wang, Yong-Jiang; Shi, Xiao-Yun; Wang, Wen-Jie; Zhang, Tian-Tai

    2017-03-22

    Shenqi is a traditional Chinese polyherbal medicine has been widely used for the treatment of allergic rhinitis (AR). The aim of this study was to investigate the anti-allergic rhinitis activity of Shenqi and explore its underlying molecular mechanism. Ovalbumin (OVA)-induced allergic rhinitis rat model was used to evaluate the anti-allergic rhinitis effect of Shenqi. The effect of Shenqi on IgE-mediated degranulation was measured using rat basophilic leukemia (RBL-2H3) cells. Primary spleen lymphocytes were isolated to investigate the anti-allergic mechanism of Shenqi by detecting the expression of transcription factors via Western blot and the level of cytokines (IL-4 and IFN-γ) via ELISA. In OVA-induced AR rat models, Shenqi relieved the allergic rhinitis symptoms, inhibited the histopathological changes of nasal mucosa, and reduced the levels of IL-4 and IgE. The results from the in vitro study certified that Shenqi inhibited mast cell degranulation. Furthermore, the results of GATA3, T-bet, p-STAT6, and SOCS1 expression and production of IFN-γ and IL-4 demonstrated that Shenqi balanced the ratio of Th1/Th2 (IFN-γ/IL-4) in OVA-stimulated spleen lymphocytes. In conclusion, these results suggest that Shenqi exhibits an obvious anti-allergic effect by suppressing the mast cell-mediated allergic response and by improving the imbalance of Th1/Th2 ratio in allergic rhinitis.

  18. A novel lectin from Artocarpus lingnanensis induces proliferation and Th1/Th2 cytokine secretion through CD45 signaling pathway in human T lymphocytes.

    PubMed

    Cui, Bo; Li, Lu; Zeng, Qiyan; Lin, Faquan; Yin, Lijun; Liao, Liejun; Huang, Min; Wang, Jingping

    2017-04-01

    Lectins are carbohydrate-binding proteins and have been used for purification and characterization of glycoproteins. In this study, a novel 58.9-kDa tetrameric lectin from Artocarpus lingnanensis seeds was purified, characterized, and its mitogenic potential was evaluated. The hemagglutination inhibition assay indicated that Artocarpus lingnanensis lectin (ALL) showed specificity toward galactose. ALL was effectively purified in a single-step using affinity chromatography on a galactose-Sepharose column. ALL showed pH optima between 5.0 and 9.0, and optimal temperature between 20 and 40 °C. ALL triggered proliferation and activation of human T lymphocytes (e.g., CD4(+) T lymphocytes). Flow cytometry and laser scanning confocal microscopy revealed binding of ALL to T cells and colocalized with CD45. Affinity chromatography and Western blot suggested that CD45 isolated from human T cell membrane fraction may be the major receptor of ALL. CD45 blocking antibody attenuated the binding and proliferation of T cells induced by ALL. CD45-PTPase inhibitor dephostatin reduced ALL-induced T cells proliferation and expression of CD25 and pZAP-70. Furthermore, secretion of ALL-induced Th1/Th2 cytokines was blocked with dephostatin. Also, dephostatin inhibited phosphorylation of ALL-mediated activation of ERK and p38MAPK. This study demonstrates the involvement of CD45-mediated signaling in ALL-induced T lymphocyte proliferation and Th1/Th2 cytokine secretion through activation of p38 and ERK.

  19. Effectiveness of an immunocastration vaccine formulation to reduce the gonadal function in female and male mice by Th1/Th2 immune response.

    PubMed

    Siel, Daniela; Vidal, Sonia; Sevilla, Rafael; Paredes, Rodolfo; Carvallo, Francisco; Lapierre, Lisette; Maino, Mario; Pérez, Oliver; Sáenz, Leonardo

    2016-10-01

    Immunocastration has emerged as an alternative to surgical castration in different animal species. This study examined the effectiveness of a new vaccine formulation for immunocastration using the biopolymer chitosan as adjuvant. First, female and male mice (n = 4), in three subsequent experiments were vaccinated at Days 1 and 30 of the study, to determine the immune response profile and gonadal alterations due to immunization. The results demonstrated that the vaccine was able to elicit strong antibody responses against native GnRH hormone (P < 0.01), with a T helper (Th) 1/Th2 immune response profile. Along with this, a suppression of gonadal activity with a decrease of luteal bodies (1.08 ± 0.22 and 4.08 ± 0.39) and antral follicles (1.17 ± 0.32 and 4.5 ± 0.38) in the ovaries of immunized females and control, respectively, and a reduction of seminiferous tubules size (142.3 ± 5.58 mm and 198.0 ± 6.11 mm) and germinal cellular layers (3.58 ± 0.26 and 5.08 ± 0.29) of immunized males and control animals, respectively, were observed (P < 0.01). Then, in a study of long-term immune response due to vaccination in female and male mice (n = 4) from two subsequent experiments, a suppression of gonadal function and an induction of a Th1/Th2 immune response was also observed, determined by both, immunoglobulin and cytokine profiles, which lasted until the end of the study (7 months; P < 0.01). The findings of this study have demonstrated that vaccination with a new immunocastration vaccine inducing a Th1/Th2 immune response against GnRH (P < 0.01) elicit a decrease of gonadal function in male and female mice (P < 0.01). Owing to long-term duration of the antibody levels generated, this vaccine formulation appears as a promising alternative for immunocastration of several animal species where long-lasting reproductive block is needed.

  20. [EFFECT OF 4-METHYLPYRAZOLE ON IMMUNE RESPONSE, FUNCTION OF Th1 AND Th2 LYMPHOCYTES, AND CYTOKINE CONCENTRATION IN RAT BLOOD AFTER ACUTE METHANOL POISONING].

    PubMed

    Zabrodskii, P F; Maslyakov, V V; Gromov, M S

    2016-01-01

    It was established in experiments on noninbred albino rats that the acute intoxication with methanol (1.0 LD50) decreased cellular and humoral immune responses, Th2-lymphocyte activity (to a greater extent as compared to the function of Th1 cells), reduced the blood concentration of immunoregulatory (IFN-g, IL-2, IL-4) and proinflammatory (TNF, IL-1b, IL-6) cytokines on the average by 36.5% (p < 0.05), and did not affect the content of anti-inflammatory cytokines (IL-10, IL-13). Methanol antidote 4-methylpyrazole (non-competitive inhibitor of alcohol dehydrogenase) administered upon acute intoxication with methanol at a dose of 1.0 DL50 partially reduces the intoxication-induced suppression of humoral and cellular immune response, activity of T-helper cells, and production of IL-4 and restores blood levels of TNF, IL-1b, IFN-γ, IL-4, IL-2, IL-6 to the control values.

  1. Altered influenza virus haemagglutinin (HA)-derived peptide is potent therapy for CIA by inducing Th1 to Th2 shift.

    PubMed

    Sun, Jian; Jia, Yuan; Li, Ru; Guo, Jianping; Sun, Xiaolin; Liu, Yanying; Li, Yingni; Yao, Haihong; Liu, Xia; Zhao, Jing; Li, Zhanguo

    2011-07-01

    There has been an increase in interest in the use of altered peptides as antigen-specific therapeutic agents in autoimmune diseases. Here we investigated the inhibitory effect and possible mechanism of an altered influenza virus haemagglutinin (HA)-derived peptide in collagen-induced arthritis (CIA). CIA was induced in DBA/1 mice by immunisation with type II collagen (CII). Altered HA308-317, wild-type HA308-317 or irrelevant peptide was administered intranasally beginning from arthritis onset. Clinical and histological scores were assessed, and cytokine levels in the serum or supernatants from splenocytes were determined. The percentages of Th1 and Th2 cells in response to different peptides were analysed by FACS both in vivo and in vitro. Our results showed that intranasal administration of altered HA308-317 peptide significantly ameliorated CIA. The therapeutic effect of altered HA308-317 peptide was associated with a substantial decrease in production of interferon (IFN)-γ, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, anti-CII IgG, IgG1 and IgG2a antibodies, and an markedly increase in production of IL-10 and IL-4 in serum or supernatants from splenocytes treated with altered HA308-317 peptide. The percentage of Th2 (CD4(+)IL-4(+)) cells was upregulated significantly by altered HA308-317 peptide with a decreased percentage of Th1 (T helper 1; CD4(+)INF-γ(+)) cells both in vivo and in vitro. These findings suggest that altered HA308-317 peptide might be a promising candidate for rheumatoid arthritis (RA) treatment.

  2. Kinetics and functional implications of Th1 and Th2 cytokine production following activation of peripheral blood mononuclear cells in primary culture.

    PubMed

    McHugh, S; Deighton, J; Rifkin, I; Ewan, P

    1996-06-01

    The importance of cytokine production in some disease processes is now widely recognized. To investigate temporal relationships between cytokines, we stimulated peripheral blood mononuclear cells (PBMC) in vitro using the T cell mitogen phytohemagglutinin (PHA) and various antigens chosen to induce predominantly Th1 (streptokinase: streptodornase or purified protein derivative) or Th2 (Dermatophagoides pteronyssinus, bee or wasp venom: allergens in sensitive subjects) responses. Cytokine production was measured by sensitive bioassays or enzyme-linked immunosorbent assays. Of the 30 subjects studied, 10 were normal and 20 individuals were allergic to either D. pteronyssinus (n = 10) or bee venom (n = 10) (examined before specific allergen immunotherapy). We examined the temporal profiles of a panel of cytokines produced in primary culture. In PHA-driven cultures, cytokines were found to be sequentially produced in the order interleukin (IL)-2, IL-4, IL-5, IL-3, interferon (IFN)-gamma, IL-10, IL-6, IL-12 and tumor necrosis factor (TNF)-alpha. The response to allergen in allergic patients was predominantly Th2 in nature, with the production of IL-4, IL-5, IL-6 and IL-10, but little or no IFN-gamma. IL-2, IL-3, TNF-alpha and IL-12 were also produced in low amounts. The response of both atopic and normal subjects to recall bacterial antigens was predominantly Th1, with high levels of IFN-gamma, IL-2 and TNF-alpha. The relevance of the order, amount and speed of production, characteristic kinetics (production, consumption, homeostatic regulation) and the cell source of the cytokines are discussed.

  3. CD45-mediated signaling pathway is involved in Rhizoctonia bataticola lectin (RBL)-induced proliferation and Th1/Th2 cytokine secretion in human PBMC

    SciTech Connect

    Pujari, Radha; Eligar, Sachin M.; Kumar, Natesh; Nagre, Nagaraja N.; Inamdar, Shashikala R.; Swamy, Bale M.; Shastry, Padma

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer RBL, a potent mitogenic and complex N-glycan specific lectin binds to CD45 on PBMC. Black-Right-Pointing-Pointer RBL triggers CD45-mediated signaling involved in activation of p38MAPK and STAT-5. Black-Right-Pointing-Pointer Inhibition of CD45 PTPase signaling blocks RBL-induced ZAP70 phosphorylation. Black-Right-Pointing-Pointer RBL-CD45 mediated signaling is crucial for RBL-induced immunodulatory activities. -- Abstract: We earlier reported the mitogenic and immunostimulatory activities of Rhizoctonia bataticola lectin (RBL), purified from phytopathogenic fungus R. bataticola in human PBMC. The lectin demonstrates specificity towards glycoproteins containing complex N-glycans. Since CD45-protein tyrosine phosphatase that abundantly expresses N-glycans is important in T-cell signaling, the study aimed to investigate the involvement of CD45 in the immunomodulatory activities of RBL. Flowcytometry and confocal microscopy studies revealed that RBL exhibited binding to PBMC and colocalized with CD45. The binding was comparable in cells expressing different CD45 isoforms-RA, -RB and -RO. CD45 blocking antibody reduced the binding and proliferation of PBMC induced by RBL. CD45-PTPase inhibitor dephostatin inhibited RBL-induced proliferation, expression of CD25 and pZAP-70. RBL-induced secretion of Th1/Th2 cytokines were significantly inhibited in presence of dephostatin. Also, dephostatin blocked phosphorylation of p38MAPK and STAT-5 that was crucial for the biological functions of RBL. The study demonstrates the involvement of CD45-mediated signaling in RBL-induced PBMC proliferation and Th1/Th2 cytokine secretion through activation of p38MAPK and STAT-5.

  4. Doxycycline and Benznidazole Reduce the Profile of Th1, Th2, and Th17 Chemokines and Chemokine Receptors in Cardiac Tissue from Chronic Trypanosoma cruzi-Infected Dogs

    PubMed Central

    de Paula Costa, Guilherme; Lopes, Laís Roquete; Horta, Aline Luciano; Pontes, Washington Martins; Milanezi, Cristiane M.; Guedes, Paulo Marcos da Mata; de Lima, Wanderson Geraldo; Schulz, Richard

    2016-01-01

    Chemokines (CKs) and chemokine receptors (CKR) promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox) in association, or not, with benznidazole (Bz) on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i) two months after infection, Dox (50 mg/kg) 2x/day for 12 months; (ii) nine months after infection, Bz (3,5 mg/kg) 2x/day for 60 days; (iii) Dox + Bz; and (iv) vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11), Th2 (CCL1, CCL17, CCL24, and CCL26), Th17 (CCL20) CKs, Th1 (CCR5, CCR6, and CXCR3), and Th2/Th17 (CCR3, CCR4, and CCR8) CKR, as well as IL-17. T. cruzi infection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection. PMID:27688600

  5. Mesenchymal stem cell transplantation can restore lupus disease-associated miRNA expression and Th1/Th2 ratios in a murine model of SLE

    PubMed Central

    Choi, Eun Wha; Lee, MinJae; Song, Ji Woo; Shin, Il Seob; Kim, Sung Joo

    2016-01-01

    C3.MRL-Faslpr/J mice spontaneously develop high titers of anti-dsDNA, mild glomerular nephritis, and severe lymphoproliferation symptoms. This study aimed to compare the effects of long-term serial administration of human adipose tissue-derived mesenchymal stem cells (ASCs), and cyclophosphamide treatment in C3.MRL-Faslpr/J mice using a murine SLE model. C3.MRL-Faslpr/J mice were divided into saline (C), cyclophosphamide (Y), and ASC (H) treatment groups. Background-matched control C3H mice treated with saline (N) were also compared. The Y group showed the greatest improvement in disease parameters, but with damaged trabecular integrity. ASC transplantation reduced anti-dsDNA levels, glomerular C3 deposition and CD138 proportion significantly, without trabecular damage. Furthermore, both cyclophosphamide and ASC treatment significantly decreased the ratio of Th1/Th2 compared with the saline-treatment. The expression levels of miR-31-5p, miR-96-5p, miR-182-5p, miR-183-5p, and miR-379-5p were significantly higher, while those of miR150-5p were significantly lower in the C group than in the N group. The expression levels of miR-96-5p, miR-182-5p in the Y and H groups were significantly lower than in the C group. Thus, treatment with cyclophosphamide or ASC can change miRNAs and decrease miR-96-5p and miR-182-5p expression, as well as decreasing the CD138 proportion and the Th1/Th2 ratio, which might be involved in the therapeutic mechanism. PMID:27924862

  6. Hydrogen sulfide protects against bleomycin-induced pulmonary fibrosis in rats by inhibiting NF-κB expression and regulating Th1/Th2 balance.

    PubMed

    Cao, Hua; Zhou, Xiaohong; Zhang, Jianping; Huang, Xinli; Zhai, Yu; Zhang, Xuejing; Chu, Li

    2014-01-30

    Hydrogen sulfide (H2S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. The objective of this study was to evaluate the inhibitory effect of H2S on bleomycin (BLM)-induced pulmonary fibrosis in rats and its possible mechanisms. Fifty-four pathogen-free Male Wistar rats were randomly divided into three groups: control, BLM and H2S treated groups with 18 rats in each group. Each group was then divided into three subgroups based on time of study (7, 14 and 28 day). Pulmonary fibrosis model was established by a single intratracheal instillation of BLM A5 (5 mg/kg). While control rats received saline, rats of the treated group simultaneously were administered intraperitoneal injections of NaHS (the H2S donor, 28 μmol/kg) once daily. BLM induced pulmonary inflammation and fibrosis, increased lung hydroxyproline levels, lung index, total cell counts, neutrophils and eosinophils counts and expression of NF-κB p65 in lung tissue, decreased lymphocytes and macrophages counts. In addition, Th1 response is suppressed as shown by diminished IFN-γ in bronchoalveolar lavage fluid (BALF) after BLM exposure, and enhancement of Th2 response is marked by increased IL-4 in BALF. H2S administration significantly attenuated these effects. The findings reveal the therapeutic potential of H2S for BLM-induced pulmonary fibrosis in male rats, which were at least partly due to inhibition NF-κB p65 expression and regulation of Th1/Th2 balance.

  7. Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy.

    PubMed

    Jung, Unsu; Foley, Jason E; Erdmann, Andreas A; Toda, Yoko; Borenstein, Todd; Mariotti, Jacopo; Fowler, Daniel H

    2006-09-01

    Rapamycin prevention of murine graft-versus-host disease (GVHD) is associated with a shift toward Th2- and Tc2-type cytokines. Recently, we found that use of rapamycin during ex vivo donor Th2 cell generation enhances the ability of adoptively transferred Th2 cells to prevent murine GVHD. In this study, using a method, without antigen-presenting cells, of T-cell expansion based on CD3,CD28 costimulation, we evaluated whether (1) rapamycin preferentially promotes the generation of Th2/Tc2 cells relative to Th1/Tc1 cells, (2) rapamycin-generated T-cell subsets induce cytokine skewing after allogeneic bone marrow transplantation (BMT), and (3) such in vivo cytokine skewing is sensitive to post-BMT rapamycin therapy. Contrary to our hypothesis, rapamycin did not preferentially promote Th2/Tc2 cell polarity, because rapamycin-generated Th1/Tc1 cells secreted type I cytokines (interleukin [IL]-2 and interferon-gamma) did not secrete type II cytokines (IL-4, IL-5, IL-10, or IL-13) and mediated fasL-based cytolysis. Rapamycin influenced T-cell differentiation, because each of the Th1, Th2, Tc1, and Tc2 subsets generated in rapamycin had increased expression of the central-memory T-cell marker, L-selectin (CD62L). Rapamycin-generated Th1/Tc1 and Th2/Tc2 cells were not anergic but instead had increased expansion after costimulation in vitro, increased expansion in vivo after BMT, and maintained full capacity to skew toward type I or II cytokines after BMT, respectively; further, rapamycin-generated Th1/Tc1 cells mediated increased lethal GVHD relative to control Th1/Tc1 cells. Rapamycin therapy after BMT in recipients of rapamycin-generated Th1/Tc1 cells greatly reduced Th1/Tc1 cell number, greatly reduced type I cytokines, and reduced lethal GVHD; in marked contrast, rapamycin therapy in recipients of rapamycin-generated Th2/Tc2 cells nominally influenced the number of Th2/Tc2 cells in vivo and did not abrogate post-BMT type II cytokine skewing. In conclusion, ex vivo and

  8. Administration of TLR7 agonist, resiquimod, in different types of chicken induces a mixed Th1 and Th2 response in the peripheral blood mononuclear cells.

    PubMed

    Annamalai, Arunsaravanakumar; Ramakrishnan, Saravanan; Sachan, Swati; Sharma, Bal Krishan; Anand Kumar, B S; Kumar, Vimal; Badasara, Surendra Kumar; Kumar, Ajay; Saravanan, B C; Krishnaswamy, Narayanan

    2015-06-01

    This study evaluated the variation in immune response in peripheral blood mononuclear cells (PBMCs) of broiler, White Leghorn (WL) and Kadaknath breeds of chicken following administration of TLR7 agonist, resiquimod (R-848). Expression of different immune related genes viz., interferon-β (IFN-β), IFN-γ, IL-1β, IL-4, TLR7 and iNOS was assessed by quantitative real time PCR over a period of 24 h. The results indicated that there was a significant up-regulation in the relative expression of immune response genes post R-848 administration (P < 0.01). In conclusion, the transcriptional expression of IFN-β, IFN-γ, IL-1β, IL-4, iNOS and TLR7 genes in the PBMCs was significantly up-regulated over 24 h in broiler, WL and Kadaknath breeds of birds after the administration of R-848. Overall, R-848 induced a mixed Th1 and Th2 response in PBMCs of chicken origin ex vivo.

  9. VPAC2 (vasoactive intestinal peptide receptor type 2) receptor deficient mice develop exacerbated experimental autoimmune encephalomyelitis with increased Th1/Th17 and reduced Th2/Treg responses.

    PubMed

    Tan, Yossan-Var; Abad, Catalina; Wang, Yuqi; Lopez, Robert; Waschek, James A

    2015-02-01

    Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two structurally-related neuropeptides with widespread expression in the central and peripheral nervous systems. Although these peptides have been repeatedly shown to exert potent anti-inflammatory actions when administered in animal models of inflammatory disease, mice deficient in VIP and PACAP were recently shown to exhibit different phenotypes (ameliorated and exacerbated, respectively) in response to experimental autoimmune encephalomyelitis (EAE). Therefore, elucidating what are the specific immunoregulatory roles played by each of their receptor subtypes (VPAC1, VPAC2, and PAC1) is critical. In this study, we found that mice with a genetic deletion of VIPR2, encoding the VPAC2 receptor, exhibited exacerbated (MOG35-55)-induced EAE compared to wild type mice, characterized by enhanced clinical and histopathological features, increased proinflammatory cytokines (TNF-α, IL-6, IFN-γ (Th1), and IL-17 (Th17)) and reduced anti-inflammatory cytokines (IL-10, TGFβ, and IL-4 (Th2)) in the CNS and lymph nodes. Moreover, the abundance and proliferative index of lymph node, thymus and CNS CD4(+)CD25(+)FoxP3(+) Tregs were strikingly reduced in VPAC2-deficient mice with EAE. Finally, the in vitro suppressive activity of lymph node and splenic Tregs from VPAC2-deficient mice was impaired. Overall, our results demonstrate critical protective roles for PACAP and the VPAC2 receptor against autoimmunity, promoting the expansion and maintenance of the Treg pool.

  10. Cofactor Independent Phosphoglycerate Mutase of Brugia malayi Induces a Mixed Th1/Th2 Type Immune Response and Inhibits Larval Development in the Host

    PubMed Central

    Singh, Prashant K.; Kushwaha, Susheela; Rana, Ajay K.; Misra-Bhattacharya, Shailja

    2014-01-01

    Lymphatic filariasis is a major debilitating disease, endemic in 72 countries putting more than 1.39 billion people at risk and 120 million are already infected. Despite the significant progress in chemotherapeutic advancements, there is still need for other measures like development of an effective vaccine or discovery of novel drug targets. In this study, structural and immunological characterization of independent phosphoglycerate mutase of filarial parasite Brugia malayi was carried out. Protein was found to be expressed in all major parasite life stages and as an excretory secretory product of adult parasites. Bm-iPGM also reacted to all the categories of human bancroftian patient's sera including endemic normals. In vivo immunological behaviour of protein was determined in immunized BALB/c mice followed by prophylactic analysis in BALB/c mice and Mastomys coucha. Immunization with Bm-iPGM led to generation of a mixed Th1/Th2 type immune response offering 58.2% protection against larval challenge in BALB/c and 65–68% protection in M. coucha. In vitro studies confirmed participation of anti-Bm-iPGM antibodies in killing of B. malayi infective larvae and microfilariae through ADCC mechanism. The present findings reveal potential immunoprotective nature of Bm-iPGM advocating its worth as an antifilarial vaccine candidate. PMID:25061608

  11. As2 O3 combined with leflunomide prolongs heart xenograft survival via suppressing the response of Th1, Th2, and B cells in a rat model.

    PubMed

    Jiao, Zhi-Xing; Leng, Yun; Xia, Jun-Jie; Wu, Hai-Qiao; Jin, Ning; Fu, Jia-Zhao; Cheng, Lian-Na; Wang, Jin-Hua; Ni, Shao-Bin; Qi, Zhong-Quan

    2016-05-01

    Xenotransplantation remits the severe shortage of human organs and tissues for transplantation, which is a problem that severely limits the application of transplantation to the treatment of human disease. However, severe immune rejection significantly limits the efficacy of xenotransplantation. In this study, we systematically investigated the immunosuppressive effect and mechanism of action of As2 O3 and leflunomide using a hamster-to-rat heart xenotransplantation model. We initially examined heart xenograft survival following As2 O3 and leflunomide treatment alone or combined treatment. We found that treatment with As2 O3 combined with leflunomide can significantly prolong the survival of heart xenograft by inhibiting Th1 and Th2 differentiation and reducing the production of IgG and IgM. Interestingly, As2 O3 and leflunomide showed low toxicity to the organs of the recipient. Taken together, these observations indicate that treatment with As2 O3 combined with leflunomide may be a promising immunosuppressive schedule for xenotransplantation.

  12. Effects of salbutamol aerosol combined with magnesium sulfate on T-lymphocyte subgroup and Th1/Th2 cytokines of pediatric asthma

    PubMed Central

    Diao, Min; Min, Jie; Guo, Fei; Zhang, Chong-Lin

    2017-01-01

    The aim of the study was to analyze the effects of the intravenous infusion of salbutamol aerosol combined with magnesium sulfate in the treatment of pediatric asthma and the subsequent effects on the levels of T-lymphocyte subgroups and Th1/Th2 cytokines. A total of 86 patients with pediatric asthma, first diagnosed and treated at the Xuzhou Children's Hospital, were continuously selected and randomly divided into an observation group of 44 cases and control group of 42 cases. The patients in the control group were treated with budesonide atomization inhalation, while the children in the observation group were treated with intravenous infusion of salbutamol aerosol combined with magnesium sulfate. The therapeutic effects in the groups were compared. After treatment, the levels of serum CD3+ and CD8+ decreased when compared to before treatment; the levels of CD4+ and CD4+/CD8+ also increased, but the observation group had more significant improvement. Differences were statistically significant (P<0.05). After treatment, the levels of serum interleukin-2 (IL-2) and interferon-γ (IFN-γ) increased when compared to before, while levels of IL-4 and IL-6 decreased, and the observation group had more significant improvement. The differences were statistically significant (P<0.05). After treatment, the levels of VT, t-PTEF/t-E, MTIF/MTEF and TEF75/PTEF increased when compared to before; the observation group had more significant improvement. The differences were statistically significant (P<0.05). The effective rate and degree of treatment for the observation group were significantly higher than those of the control group and differences were statistically significant (P<0.05). The intravenous infusion of salbutamol aerosol combined with magnesium sulfate in the treatment of pediatric asthma can significantly improve therapeutic effects and lung functions, improve immune functions and relieve inflammatory reactions. Therefore, it indicates better clinical application and

  13. L-Theanine Improves Immunity by Altering TH2/TH1 Cytokine Balance, Brain Neurotransmitters, and Expression of Phospholipase C in Rat Hearts.

    PubMed

    Li, Chengjian; Tong, Haiou; Yan, Qiongxian; Tang, Shaoxun; Han, Xuefeng; Xiao, Wenjun; Tan, Zhiliang

    2016-02-28

    BACKGROUND This study aimed to investigate the regulatory effects of L-theanine on secretion of immune cytokines, hormones, and neurotransmitters, and mRNA expression of phospholipase C (PLC) in rats, and to explore its regulatory mechanism in immune function. MATERIAL AND METHODS Sixty-four Sprague-Dawley rats received daily intragastric infusion of different doses of L-theanine solution [0, 50 (LT), 200 (MT), and 400 (HT) mg/kg BW]. Cytokines, immunoglobulins, and hormones in the serum, neurotransmitters, and mRNA expression of PLC in the relevant tissues were assayed. RESULTS L-theanine administration increased the splenic organ index and decreased the contents of ILs-4/6/10 and the ratio of IL-4/IFN-γ in the serum. High-dose L-theanine administration increased the levels of dopamine and 5-hydroxytryptamine in the pituitary and hippocampus, resulting in decrease in corticosterone level in the serum. L-theanine administration decreased the mRNA expressions of PLC isomers in the liver and PLC-γ1 and PLC-δ1 in the spleen. Interestingly, mRNA expressions of PLC-β1 in the spleen and PLC isomers mRNA in the heart were up-regulated by L-theanine administration. CONCLUSIONS Administration of 400 mg/kg BWL-theanine improved immune function of the rats by increasing the splenic weight, altering the Th2/Th1 cytokine balance, decreasing the corticosterone level in the serum, elevating dopamine and 5-hydroxytryptamine in the brain, and regulating the mRNA expression of PLC isomers in the heart.

  14. L-Theanine Improves Immunity by Altering TH2/TH1 Cytokine Balance, Brain Neurotransmitters, and Expression of Phospholipase C in Rat Hearts

    PubMed Central

    Li, Chengjian; Tong, Haiou; Yan, Qiongxian; Tang, Shaoxun; Han, Xuefeng; Xiao, Wenjun; Tan, Zhiliang

    2016-01-01

    Background This study aimed to investigate the regulatory effects of L-theanine on secretion of immune cytokines, hormones, and neurotransmitters, and mRNA expression of phospholipase C (PLC) in rats, and to explore its regulatory mechanism in immune function. Material/Methods Sixty-four Sprague-Dawley rats received daily intragastric infusion of different doses of L-theanine solution [0, 50 (LT), 200 (MT), and 400 (HT) mg/kg BW]. Cytokines, immunoglobulins, and hormones in the serum, neurotransmitters, and mRNA expression of PLC in the relevant tissues were assayed. Results L-theanine administration increased the splenic organ index and decreased the contents of ILs-4/6/10 and the ratio of IL-4/IFN-γ in the serum. High-dose L-theanine administration increased the levels of dopamine and 5-hydroxytryptamine in the pituitary and hippocampus, resulting in decrease in corticosterone level in the serum. L-theanine administration decreased the mRNA expressions of PLC isomers in the liver and PLC-γ1 and PLC-δ1 in the spleen. Interestingly, mRNA expressions of PLC-βf1 in the spleen and PLC isomers mRNA in the heart were up-regulated by L-theanine administration. Conclusions Administration of 400 mg/kg BWL-theanine improved immune function of the rats by increasing the splenic weight, altering the Th2/Th1 cytokine balance, decreasing the corticosterone level in the serum, elevating dopamine and 5-hydroxytryptamine in the brain, and regulating the mRNA expression of PLC isomers in the heart. PMID:26922362

  15. Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

    SciTech Connect

    Antonelli, Alessandro; Ferrari, Silvia Martina; Frascerra, Silvia; Corrado, Alda; Pupilli, Cinzia; Bernini, Giampaolo; Benvenga, Salvatore; Ferrannini, Ele; Fallahi, Poupak

    2011-07-01

    Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

  16. Mycobacterium avium infection in mice is associated with time-related expression of Th1 and Th2 CD4+ T-lymphocyte response.

    PubMed Central

    Azouaou, N; Petrofsky, M; Young, L S; Bermudez, L E

    1997-01-01

    Disseminated infection caused by organisms of Mycobacterium avium complex is common in acquired immune deficiency syndrome (AIDS) patients. M. avium is an intracellular bacterium that multiplies within macrophages. We examined the effect of M. avium infection on the T-helper cell response in C57/BL/6 black mice. At weekly intervals, CD4+ T-cells were isolated from spleens and lines were created. T-cell lines were exposed to sonicated M. avium in the presence of feeder cells and macrophages and the supernatant were collected to measure the concentrations of interferon-gamma (IFN-gamma and interleukin-10 (IL-10). Production of IFN-gamma in CD4+ T-cells obtained from uninfected mice did not vary significantly during the 5 weeks. Levels of IFN-gamma produced by T-cell lines of infected mice were similar to the control mice during the first 2 weeks but significantly reduced (approximately 30 ng/ml) thereafter. In contrast, production of IL-10 by T-cell lines of infected mice was in a range of 190 to 342 pg/ml in weeks 1, 2 and 3, but increased to an average of 1300 pg/ml at weeks 4 and 5. Pre-immunized mice, when infected with M. avium strain 101, showed a different profile of T-cell cytokines, with high IFN-gamma and low IL-10 production. Proteins purified from a number of disease-associated (D-A) and non-D-A strains of M. avium were tested for the ability to induce IL-10. 65,000 MW and 60,000 MW proteins of M. avium induced significantly more IL-10 than 45,000 MW, 33,000 MW and 27,000 MW proteins. These results showed that M. avium predominantly stimulates either Th1 or Th2 T-helper cells according to the phase of the infection. PMID:9301531

  17. The PorB porin from commensal Neisseria lactamica induces Th1 and Th2 immune responses to ovalbumin in mice and is a potential immune adjuvant.

    PubMed

    Liu, Xiuping; Wetzler, Lee M; Massari, Paola

    2008-02-06

    Porins from pathogenic Neisseriae are among several bacterial products with immune adjuvant activity. Neisseria meningitidis (Nme) PorB, has been shown to induce immune cells activation in a TLR2-dependent manner and acts as a vaccine immune adjuvant. The PorB porin from Neisseria lactamica (Nlac), a common nasopharyngeal commensal, shares significant structural and functional similarities with Nme PorB. In this work we ask whether the immune adjuvant ability of porins from pathogenic Neisserial strains is a characteristic shared with porins from non-pathogenic Neisserial species or whether it is unique for bacterial products derived from microorganisms capable of inducing inflammation and disease. We evaluated the potential immune adjuvant effect of Nlac PorB in mice using ovalbumin (OVA) as a prototype antigen. Immunization with Nlac PorB/OVA induced high OVA-specific IgG and IgM titers compared to OVA alone, similar to other adjuvants such as Nme PorB and alum. High titers of IgG1 and IgG2b were detected as well as production of IL-4, IL-10, IL-12 and INF-gamma in response to Nlac PorB, consistent with induction of both a Th1-type and a Th2-type immune response. OVA-specific proliferation was also determined in splenocytes from Nlac PorB/OVA-immunized mice. In addition, B cell activation in vitro and cytokine production in response to Nlac PorB was found to be mediated by TLR2, in a similar manner to Nme PorB.

  18. TH1/TH2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients

    PubMed Central

    MUÑOZ-VALLE, J F; VÁZQUEZ-DEL MERCADO, M; GARCÍA-IGLESIAS, T; OROZCO-BAROCIO, G; BERNARD-MEDINA, G; MARTÍNEZ-BONILLA, G; BASTIDAS-RAMÍREZ, B E; NAVARRO, A D; BUENO, M; MARTÍNEZ-LÓPEZ, E; BEST-AGUILERA, C R; KAMACHI, M; ARMENDÁRIZ-BORUNDA, J

    2003-01-01

    During the course of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), several immune and neuroendocrine changes associated with pregnancy may exert positive (amelioration) or negative (exacerbation) effects on the clinical outcome. In order to shed light on the mechanisms underlying these responses, we performed a prospective longitudinal study in RA and SLE pregnant women, including healthy pregnant women as a control group. Cytokine messenger RNA (mRNA) expression assessed by quantitative competitive polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC), cytokine levels and lymphocyte proliferation responses (LPR) following phytohaemagglutinin (PHA) stimulation of PBMC, plasma metalloprotease-9 activity (MMP-9) and hormonal status during pregnancy were determined. TNFa was the most abundant cytokine mRNA expressed in PBMC in all groups studied (healthy pregnant women, RA and SLE pregnant patients). However, a general TH2 response reflected by high IL-10 levels was found in RA, as well as SLE, patients. A significant change in IFN-γ was observed in RA patients but only during the first trimester of pregnancy. This compared with a major TH1 response in healthy pregnant women. Interestingly, our study showed a homogeneous hormonal pattern in RA and SLE patients. Although decreased cortisol levels were observed in all patients studied, this is possibly related to the remission of disease activity status brought about by steroid treatment before and during pregnancy. In summary, we suggest that complex immune and hormonal networks are involved in pregnancy and that rheumatic diseases are very dynamic immune processes that cannot be described with a clear-cut cytokine profile. Furthermore, the observations in this study may reflect treatment-related immune effects more than those associated with disease. PMID:12562402

  19. Expression pattern of transcription factors and intracellular cytokines reveals that clinically cured tuberculosis is accompanied by an increase in Mycobacterium-specific Th1, Th2, and Th17 cells.

    PubMed

    da Silva, Marcos V; Massaro Junior, Vladimir J; Machado, Juliana R; Silva, Djalma A A; Castellano, Lúcio R; Alexandre, Patricia B D; Rodrigues, Denise B R; Rodrigues, Virmondes

    2015-01-01

    Tuberculosis (TB) remains a major global health problem and is the second biggest cause of death by infectious disease worldwide. Here, we investigate in vitro the Th1, Th2, Th17, and Treg cytokines and transcriptional factors produced after Mycobacterium-specific antigen stimulation in patients with active pulmonary tuberculosis, clinically cured pulmonary tuberculosis, and healthy donors with a positive tuberculin skin test (TST+). Together, our data indicate that clinical cure after treatment increases the percentages of Mycobacterium-specific Th1, Th2, and Th17 cells compared with those found in active-TB and TST+ healthy donors. These results show that the host-parasite equilibrium in latent TB breaks in favor of the microorganism and that the subsequent clinical recovery posttreatment does not return the percentage levels of such cells to those observed in latent tuberculosis. Additionally, our results indicate that rather than showing an increase in the percentage of Mycobacterium-specific Tregs, active-TB patients display lower Th1 : Treg and Th17 : Treg ratios. These data, together with lower Th1 : Th2 and Th17 : Th2 ratios, may indicate a mechanism by which the breakdown of the host-parasite equilibrium leads to active-TB and changes in the repertoire of Mycobacterium-specific Th cells that are associated with clinical cure after treatment of pulmonary tuberculosis.

  20. The changes in the T helper 1 (Th1) and T helper 2 (Th2) cytokine balance during HIV-1 infection are indicative of an allergic response to viral proteins that may be reversed by Th2 cytokine inhibitors and immune response modifiers--a review and hypothesis.

    PubMed

    Becker, Yechiel

    2004-01-01

    The HIV-1 infection in humans induces an early cellular immune response to react to the viral proteins with a cytotoxic T cell (CTL) response that fails to inhibit virus replication and the spread of the virus. It became evident that the progression of the disease causes chronic changes to the immune system of which a gradual increase in IgE antibodies is one of its features. When the HIV-1 epidemic began, the relation between the gradual increase in IgE content and AIDS was not understood, but later it became a marker for disease prognosis. The advances in the knowledge on T helper 1 (Th1) and T helper 2 (Th2) cells revealed that Th1 cells produce cytokines that stimulate the proliferation of CTLs. Th2 cells produce cytokines that are responsible for the activation of the humoral immune response in healthy people. Studies on both Th1 and Th2 cytokine synthesis revealed an aberration in HIV-1 infected people. Clerici and Shearer presented a hypothesis (1993) whereby Th1 cell activity declines and Th2 activity increases (the Th1 --> Th2 switch hypothesis) in HIV-1 infected people. In fact, experiments concerning this hypothesis ultimately supported the premise that the switch involves a critical change in the cytokine balance, which leads to the contraction of AIDS. However, the research community must still discern why such a Th1 --> Th2 switch takes place in infected people and how it can be reversed. The present review points to the fact that a similar Th1 --> Th2 switch constitutes the response of allergic people to environmental allergens. HIV-1 patients and allergic people that are exposed to allergens respond with an increased synthesis of Th2 cytokines and IgE, together with a decrease in Th1 cytokines. The studies on allergen-induced Th2 cells revealed that the Th2 cytokine IL-4 induces B cells to synthesize IgE, and cytokine IL-5 is the inducer of eosinophilia, just as in HIV-1 infection. The difference between the HIV-1 infection and allergies is the

  1. Relationships between Th1 or Th2 iNKT Cell Activity and Structures of CD1d-Antigen Complexes: Meta-analysis of CD1d-Glycolipids Dynamics Simulations

    PubMed Central

    Laurent, Xavier; Renault, Nicolas; Farce, Amaury; Chavatte, Philippe; Hénon, Eric

    2014-01-01

    A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1. PMID:25376021

  2. The immunodominant T helper 2 (Th2) response elicited in BALB/c mice by the Leishmania LiP2a and LiP2b acidic ribosomal proteins cannot be reverted by strong Th1 inducers.

    PubMed

    Iborra, S; Abánades, D R; Parody, N; Carrión, J; Risueño, R M; Pineda, M A; Bonay, P; Alonso, C; Soto, M

    2007-11-01

    The search for disease-associated T helper 2 (Th2) Leishmania antigens and the induction of a Th1 immune response to them using defined vaccination protocols is a potential strategy to induce protection against Leishmania infection. Leishmania infantum LiP2a and LiP2b acidic ribosomal protein (P proteins) have been described as prominent antigens during human and canine visceral leishmaniasis. In this study we demonstrate that BALB/c mice infected with Leishmania major develop a Th2-like humoral response against Leishmania LiP2a and LiP2b proteins and that the same response is induced in BALB/c mice when the parasite P proteins are immunized as recombinant molecules without adjuvant. The genetic immunization of BALB/c mice with eukaryotic expression plasmids coding for these proteins was unable to redirect the Th2-like response induced by these antigens, and only the co-administration of the recombinant P proteins with CpG oligodeoxynucleotides (CpG ODN) promoted a mixed Th1/Th2 immune response. According to the preponderance of a Th2 or mixed Th1/Th2 responses elicited by the different regimens of immunization tested, no evidence of protection was observed in mice after challenge with L. major. Although alterations of the clinical outcome were not detected in mice presensitized with the P proteins, the enhanced IgG1 and interleukin (IL)-4 response against total Leishmania antigens in these mice may indicate an exacerbation of the disease.

  3. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for glial and neural-related molecules in central nervous system mixed glial cell cultures: neurotrophins, growth factors and structural proteins

    PubMed Central

    Lisak, Robert P; Benjamins, Joyce A; Bealmear, Beverly; Nedelkoska, Liljana; Yao, Bin; Land, Susan; Studzinski, Diane

    2007-01-01

    Background In multiple sclerosis, inflammatory cells are found in both active and chronic lesions, and it is increasingly clear that cytokines are involved directly and indirectly in both formation and inhibition of lesions. We propose that cytokine mixtures typical of Th1 or Th2 lymphocytes, or monocyte/macrophages each induce unique molecular changes in glial cells. Methods To examine changes in gene expression that might occur in glial cells exposed to the secreted products of immune cells, we have used gene array analysis to assess the early effects of different cytokine mixtures on mixed CNS glia in culture. We compared the effects of cytokines typical of Th1 and Th2 lymphocytes and monocyte/macrophages (M/M) on CNS glia after 6 hours of treatment. Results In this paper we focus on changes with potential relevance for neuroprotection and axon/glial interactions. Each mixture of cytokines induced a unique pattern of changes in genes for neurotrophins, growth and maturation factors and related receptors; most notably an alternatively spliced form of trkC was markedly downregulated by Th1 and M/M cytokines, while Th2 cytokines upregulated BDNF. Genes for molecules of potential importance in axon/glial interactions, including cell adhesion molecules, connexins, and some molecules traditionally associated with neurons showed significant changes, while no genes for myelin-associated genes were regulated at this early time point. Unexpectedly, changes occurred in several genes for proteins initially associated with retina, cancer or bone development, and not previously reported in glial cells. Conclusion Each of the three cytokine mixtures induced specific changes in gene expression that could be altered by pharmacologic strategies to promote protection of the central nervous system. PMID:18088439

  4. Clinical association of baseline levels of conjugated dienes in low-density lipoprotein and nitric oxide with aggressive B-cell non-Hodgkin lymphoma and their relationship with immunoglobulins and Th1-to-Th2 ratio

    PubMed Central

    Haddouche, Mustapha; Meziane, Warda; Hadjidj, Zeyneb; Mesli, Naima; Aribi, Mourad

    2016-01-01

    Objective The aim of this study was to highlight the clinical association of baseline levels of conjugated dienes in low-density lipoprotein (LDL-BCD) and nitric oxide (NO) with immunoglobulins (Igs) and T helper (Th)1/Th2 ratio in patients with newly diagnosed B-cell non-Hodgkin lymphoma (NHL). Patients and methods Thirty-two newly diagnosed patients with aggressive B-cell NHL and 25 age-, sex-, and body-mass-index-matched healthy controls were randomly selected for a cross-sectional case–control study conducted at the Hematology Department of Tlemcen Medical Centre University (northwest of Algeria). Results Circulating levels of LDL-BCD and NO and those of IgA and IgM were significantly higher in patients than in controls. The levels of Th1/Th2 ratio and plasma total antioxidant capacity were significantly lower in patients compared with controls, while malondialdehyde and protein carbonyl levels were significantly higher in patients. B-cell NHL was significantly associated with high levels of LDL-BCD from 25th to 75th percentile (25th percentile: relative risk [RR] =2.26, 95% confidence interval [CI] 1.42–3.59, P=0.014; 50th percentile: RR =2.84, 95% CI 1.72–4.68, P<0.001; 75th percentile: RR =5.43, 95% CI 2.58–11.42, P<0.001). Similarly, the disease was significantly associated with high levels of NO production from 25th to 75th percentile (25th percentile: RR =2.07, 95% CI 1.25–3.44, P=0.024; 50th percentile: RR =2.78, 95% CI 1.63–4.72, P<0.001; 75th percentile: RR =4.68, 95% CI 2.21–9.91, P<0.001). Moreover, LDL-BCD levels were positively and significantly correlated with interferon (IFN)-γ, whereas NO levels were inversely and significantly correlated with IFN-γ and Th1/Th2 ratio. Conclusion LDL-BCD and NO production seem to be associated with aggressive B-cell NHL and alteration of Th1/Th2 ratio. Our results have to be examined using ex vivo mechanistic studies leading to further investigations of these parameters, with an interest in the

  5. The progesterone derivative dydrogesterone abrogates murine stress-triggered abortion by inducing a Th2 biased local immune response.

    PubMed

    Joachim, Ricarda; Zenclussen, Ana Claudia; Polgar, Beata; Douglas, Alison J; Fest, Stefan; Knackstedt, Maike; Klapp, Burghard F; Arck, Petra Clara

    2003-11-01

    Stress is known to induce abortions in mice and humans, putatively via increased levels of abortogenic Th1 cytokines and a decrease of progesterone. Adequate levels of progesterone exert an antiabortive response through binding to the progesterone-receptor, which induces the release of progesterone-induced blocking factor (PIBF) from lymphocytes. PIBF is highly pregnancy-protective by induction of a Th2 biased immune activity. The aim of this study was to investigate the effect of the progesterone derivative dydrogesterone (6-dehydro-retroprogesterone) in stress-triggered murine abortion. DBA/2J-mated CBA/J female mice were randomized in different groups: two groups were treated with different dydrogesterone dosages in a single injection before exposure to sound stress on Day 5 of pregnancy, one group was exposed to stress without dydrogesterone treatment, the fourth group received no stress and no dydrogesterone. On gestation Day 13, a highly elevated abortion rate was detected in stressed mice compared to control mice. Stressed animals presented lower levels of progesterone and PIBF in plasma and a reduced staining intensity of progesterone receptor at the feto-maternal interface. Injection of dydrogesterone abrogated the effect of stress on the abortion rate. Further, dydrogesterone increased levels of plasma PIBF in stressed mice, but did not affect progesterone levels. Interestingly, dydrogesterone dramatically increased the percentage of IL-4 positive decidual immune cells in stressed mice. Our data suggest that dydrogesterone abrogates stress-triggered abortion by inducing a Th2 biased local immune response.

  6. The comparison of expression of cutaneous lymphocyte-associated antigen (CLA), and Th1- and Th2-associated antigens in mycosis fungoides and cutaneous lesions of adult T-cell leukemia/lymphoma.

    PubMed

    Yamaguchi, Takahiro; Ohshima, Koichi; Tsuchiya, Takeshi; Suehuji, Hiroaki; Karube, Kennosuke; Nakayama, Juichiro; Suzumiya, Junji; Yoshino, Tadashi; Kikuchi, Masahiro

    2003-01-01

    Mycosis fungoides (MF) is morphologically similar to cutaneous lesions of adult T cell leukemia/lymphoma (ATLL) of human T-cell lymphotropic virus-type I (HTLV-1). In addition, the Th1 or Th2 characteristic of MF and ATLL is still controversial. In the present study, to discriminate MF and cutaneous lesion of ATLL using immunohistochemical markers, and to elucidate Th1 or Th2 dominancy in both disorders, CLA (cutaneous lymphocyte associated antigen) was expressed on epidermotrophic lymphoma cells in all early stage MF. In contrast, all ATLL were negative for CLA. CXCR3 was especially expressed in epidermotropic small lymphoma cells of MF. CCR5 was expressed in both disorders with variable sized lymphoma cells. ST2 was expressed on large transformed lymphoma cells with ATLL, but not in any MF cases. OX40 was expressed in the large transformed cell population in both disorders. These findings suggest that CLA and ST2 could be potentially useful immunohistochemical markers for discrimination of mycosis fungoides and cutaneous lesions of ATLL. And OX40 could be a useful immunohistochemical marker for the histopathological progression of both disorders.

  7. Combined Effects of Circulating Levels of 25-Hydroxyvitamin D and Th1 and Th2 Cytokines on Breast Cancer Estrogen Receptor Status

    PubMed Central

    Yao, Song; Hong, Chi-Chen; McCann, Susan E.; Zirpoli, Gary; Quan, Lei; Gong, Zhihong; Johnson, Candace S.; Trump, Donald L.; Ambrosone, Christine B.

    2014-01-01

    Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44−21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy. PMID:24473087

  8. Combined effects of circulating levels of 25-hydroxyvitamin d and Th1 and th2 cytokines on breast cancer estrogen receptor status.

    PubMed

    Yao, Song; Hong, Chi-Chen; McCann, Susan E; Zirpoli, Gary; Quan, Lei; Gong, Zhihong; Johnson, Candace S; Trump, Donald L; Ambrosone, Christine B

    2014-01-27

    Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNα2, and TNFα, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFα levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44-21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNα2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy.

  9. p(⁷⁰S⁶K¹) in the TORC1 pathway is essential for the differentiation of Th17 Cells, but not Th1, Th2, or Treg cells in mice.

    PubMed

    Sasaki, Carl Y; Chen, Gang; Munk, Rachel; Eitan, Erez; Martindale, Jennifer; Longo, Dan L; Ghosh, Paritosh

    2016-01-01

    The TORC1 pathway is necessary for ribosomal biogenesis and initiation of protein translation. Furthermore, the differentiation of Th1 and Th17 cells requires TORC1 activity. To investigate the role of the TORC1 pathway in the differentiation of Th1 and/or Th17 cells in more detail, we compared the differentiation capacity of naïve T cells from wild type and p70(S6K1) knockout mice. Expression of many of the genes associated with Th17-cell differentiation, such as IL17a, IL17f, and IL-23R, were reduced in p70(S6K1) knockout mice. In contrast, the development of Th1, Th2, and Treg cells was unaffected in the absence of p70(S6K1) . Furthermore, expression of the major transcription factor in Th17-cell differentiation, retinoic acid receptor-related orphan receptor gamma T, remained unchanged. However, the acetylation of histone 3 at the promoters of IL17a and IL17f was reduced in the absence of p70(S6K1) . In accordance with the in vitro data, the kinetics, but not the development, of EAE was affected with the loss of p70(S6K1) expression. Collectively, our findings suggested that both in vitro and in vivo differentiation of Th17 cells were positively regulated by p70(S6K1) .

  10. The Mushroom Agaricus blazei Murill Elicits Medicinal Effects on Tumor, Infection, Allergy, and Inflammation through Its Modulation of Innate Immunity and Amelioration of Th1/Th2 Imbalance and Inflammation

    PubMed Central

    Hetland, Geir; Johnson, Egil; Lyberg, Torstein; Kvalheim, Gunnar

    2011-01-01

    The medicinal mushroom Agaricus blazei Murill from the Brazilian rain forest has been used in traditional medicine and as health food for the prevention of a range of diseases, including infection, allergy, and cancer. Other scientists and we have examined whether there is scientific evidence behind such postulations. Agaricus blazei M is rich in the immunomodulating polysaccharides, β-glucans, and has been shown to have antitumor, anti-infection, and antiallergic/-asthmatic properties in mouse models, in addition to anti-inflammatory effects in inflammatory bowel disease patients. These effects are mediated through the mushroom's stimulation of innate immune cells, such as monocytes, NK cells, and dendritic cells, and the amelioration of a skewed Th1/Th2 balance and inflammation. PMID:21912538

  11. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures

    PubMed Central

    Lisak, Robert P; Benjamins, Joyce A; Bealmear, Beverly; Nedelkoska, Liljana; Studzinski, Diane; Retland, Ernest; Yao, Bin; Land, Susan

    2009-01-01

    Background Cytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS) in multiple sclerosis (MS). Methods We have used gene array analysis to identify the initial direct effects of cytokines on CNS glia by comparing changes in early gene expression in CNS glial cultures treated for 6 hours with cytokines typical of those secreted by Th1 and Th2 lymphocytes and monocyte/macrophages (M/M). Results In two previous papers, we summarized effects of these cytokines on immune-related molecules, and on neural and glial related proteins, including neurotrophins, growth factors and structural proteins. In this paper, we present the effects of the cytokines on molecules involved in metabolism, signaling and regulatory mechanisms in CNS glia. Many of the changes in gene expression were similar to those seen in ischemic preconditioning and in early inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), related to ion homeostasis, mitochondrial function, neurotransmission, vitamin D metabolism and a variety of transcription factors and signaling pathways. Among the most prominent changes, all three cytokine mixtures markedly downregulated the dopamine D3 receptor, while Th1 and Th2 cytokines downregulated neuropeptide Y receptor 5. An unexpected finding was the large number of changes related to lipid metabolism, including several suggesting a switch from diacylglycerol to phosphatidyl inositol mediated signaling pathways. Using QRT-PCR we validated the results for regulation of genes for iNOS, arginase and P glycoprotein/multi-drug resistance protein 1 (MDR1) seen at 6 hours with microarray. Conclusion Each of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter signaling in glia. PMID

  12. Early and Late Extensive Chronic Graft-Versus-Host Disease (cGVHD) In Children Is Characterized By Different Th1/Th2 Cytokine Profiles: Findings Of The Children’s Oncology Group Study (COG), ASCT0031

    PubMed Central

    Rozmus, Jacob; Schultz, Kirk R.; Wynne, Kristin; Kariminia, Amina; Satyanarayana, Preeti; Krailo, Mark; Grupp, Stephan A.; Gilman, Andrew L.; Goldman, Frederick D.

    2011-01-01

    Mechanisms underlying chronic graft-versus-host disease (cGVHD) are numerous, including skewing of Th1/Th2 cytokine expression. cGVHD has biological differences between early and late onset cGVHD. To test whether different Th1/Th2 cytokines are associated with early or late onset cGVHD, peripheral blood was collected from 63 children enrolled on the Children’s Oncology Group phase III trial ASCT0031 evaluating hydroxychloroquine therapy for newly diagnosed extensive cGVHD. mRNA expression of interferon gamma (IFN-γ) and interleukins 2, 4 and 10(IL-2, IL-4 and IL-10) from stimulated peripheral blood mononuclear cells was evaluated by quantitative polymerase chain reaction (Q-PCR). We found that early onset cGVHD (n=33) was characterized by decreased expression of IFN-γ and IL-2 mRNA after non-specific PMA-Ionomycin stimulation. In contrast, late onset cGVHD (n=11) was characterized by decreased expression of IL-4 and IL-2 mRNA after anti-CD3 stimulation of T cells. Receiver Operator Characteristic (ROC) curve analysis revealed that IFN-γ production could determine the absence of early cGVHD (AUC=0.77) and IL-4 (AUC=0.89) and IL-2 (AUC=0.84) the absence of late cGVHD. We did not find any correlation between cytokine expression and a specific immune cell subset. We also showed an increased expression of Foxp3 mRNA in early onset cGVHD and late controls. The different time-dependent cytokine profiles in newly-diagnosed cGVHD suggests that mechanisms underlying cGVHD are temporally regulated. While larger validation studies are needed our data suggests cytokine profiles could potentially be used as biomarkers for the diagnosis of cGVHD. PMID:21669298

  13. An immunosuppressive murine leukaemia virus induces a Th1-->Th2 switch and abrogates the IgM antibody response to sheep erythrocytes by suppressing the production of IL-2.

    PubMed Central

    Faxvaag, A; Espevik, T; Dalen, A

    1995-01-01

    Many retroviruses have tropism for cells in the immune system and have a propensity to induce immunosuppression in the host. Some of the effects of retroviruses on immune cell function are thought to be mediated through cytokines. Friend ImmunoSuppressive virus-2 (FIS-2) is a low oncogenic murine leukaemia virus (MuLV) that induces lymphadenopathy and immunosuppression in NMRI mice. The role of T cell cytokines during the generation of a primary antibody response in healthy and FIS-2-infected mice was studied following the antibody response to sheep erythrocytes by an in vitro immunization (IVI) technique. In cultures from FIS-2-infected mice, the antibody response was reduced compared with cultures from uninfected mice and the production of the Th2 cytokines IL-4 and IL-6 was elevated, whereas the Th1 cytokines IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) were reduced. The suppressed anti-sheep erythrocyte antibody response in cultures from mice infected with FIS-2 seemed to be caused by an insufficient production of IL-2, since addition of recombinant IL-2 stimulated the antibody response. This effect was also observed in cultures depleted of T cells, indicating a direct effect of IL-2 on B cells. A switch to a Th2 cell response and suppression of IL-2 production might play a central role in the immune cell dysfunction induced by FIS-2. PMID:8536362

  14. Induction of a balanced Th1/Th2 immune responses by co-delivery of PLGA/ovalbumin nanospheres and CpG ODNs/PEI-SWCNT nanoparticles as TLR9 agonist in BALB/c mice.

    PubMed

    Ebrahimian, Mahboubeh; Hashemi, Maryam; Maleki, Mohsen; Abnous, Khalil; Hashemitabar, Gholamreza; Ramezani, Mohammad; Haghparast, Alireza

    2016-10-29

    To develop effective and safe vaccines with reduced dose of antigen and adjuvant, intelligent delivery systems are required. Many delivery systems have been developed to enhance the biological activity of cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODN) as both immunotherapeutic agents and vaccine adjuvants. In this study we designed a novel CpG ODN delivery system based on single-walled carbon nanotube (SWCNT) functionalized with polyethylenimine (PEI) and alkylcarboxylated PEI (AL-PEI). The physicochemical characteristics, cytotoxicity and cellular uptake studies of these carriers were performed. All carriers were conjugated with CpG ODN followed by co-delivery with ovalbumin (OVA) encapsulated into poly (lactic-co-glycolic acid) nanospheres (PLGA NSs) to enhance the induction of immune responses. The effect of these formulations on antibody (IgG1, IgG2a) and cytokine (IL-1β, IFN-γ, IL-4) production was evaluated in an in vivo experiment. The results showed that all nano-adjuvant formulations had a strong influence in up-regulation of IFN-γ and IL-4 in parallel with high IgG1-IgG2a isotype antibody titers in mice. In particular, SWCNT-AL-PEI nano-adjuvant formulation generated a balanced Th1 and Th2 immune response with more biased toward Th1 response without exhibiting any inflammatory and toxic effects. Therefore this nano-adjuvant formulation could be used as an efficient prophylactic immune responses agent.

  15. Prophylaxis with a Respiratory Syncytial Virus (RSV) Anti-G Protein Monoclonal Antibody Shifts the Adaptive Immune Response to RSV rA2-line19F Infection from Th2 to Th1 in BALB/c Mice

    PubMed Central

    Boyoglu-Barnum, Seyhan; Chirkova, Tatiana; Todd, Sean O.; Barnum, Thomas R.; Gaston, Kelsey A.; Jorquera, Patricia; Haynes, Lia M.; Tripp, Ralph A.; Moore, Martin L.

    2014-01-01

    ABSTRACT Respiratory syncytial virus (RSV) is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. In the present study, we investigated the effect of prophylactic treatment with the intact and F(ab′)2 forms of an anti-G protein monoclonal antibody (MAb), 131-2G, on the humoral and cellular adaptive immune responses to RSV rA2-line19F (r19F) challenge in BALB/c mice. The F(ab′)2 form of 131-2G does not decrease virus replication, but intact 131-2G does. The serum specimens for antibodies and spleen cells for memory T cell responses to RSV antigens were analyzed at 30, 45, 75, and 95 days postinfection (p.i.) with or without prior treatment with 131-2G. The ratios of Th2 to Th1 antibody isotypes at each time p.i indicated that both forms of MAb 131-2G shifted the subclass response from a Th2 (IgG1 and IgG2b) to a Th1 (IgG2A) bias. The ratio of IgG1 to IgG2A antibody titer was 3-fold to 10-fold higher for untreated than MAb-treated mice. There was also some increase in IgG (22% ± 13% increase) and neutralization (32% increase) in antibodies with MAb 131-2G prophylaxis at 75 days p.i. Treatment with 131-2G significantly (P ≤ 0.001) decreased the percentage of interleukin-4 (IL-4)-positive CD4 and CD8 cells in RSV-stimulated spleen cells at all times p.i., while the percentage of interferon gamma (IFN-γ) T cells significantly (P ≤ 0.001) increased ≥75 days p.i. The shift from a Th2- to a Th1-biased T cell response in treated compared to untreated mice likely was directed by the much higher levels of T-box transcription factor (T-bet) (≥45% versus <10%) in CD4 and CD8 T cells and lower levels of Gata-3 (≤2% versus ≥ 6%) in CD4 T cells in peptide-stimulated, day 75 p.i. spleen cells. These data show that the RSV G protein affects both humoral and cellular adaptive immune responses, and induction of 131-2G-like antibodies might improve the safety and

  16. Efficient Immuno-Modulation of TH1/TH2 Biomarkers in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis: Nanocarrier-Mediated Transcutaneous Co-Delivery of Anti-Inflammatory and Antioxidant Drugs

    PubMed Central

    Hussain, Zahid; Katas, Haliza; Mohd Amin, Mohd Cairul Iqbal; Kumolosasi, Endang

    2014-01-01

    The present study was conducted with the aim to investigate the immuno-modulatory and histological stabilization effects of nanocarrier–based transcutaneous co-delivery of hydrocortisone (HC) and hydroxytyrosol (HT). In this investigation, the clinical and pharmacological efficacies of nanoparticle (NP)-based formulation to alleviate 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis (AD) was explored by using an NC/Nga mouse model. Ex vivo visual examination of AD induction in experimental mice indicated remarkable control of NP-based formulations in reducing pathological severity of AD-like skin lesions. Therapeutic effectiveness of NP-based formulations was also evaluated by comparing skin thickness of AD-induced NP-treated mice (456±27 µm) with that of atopic mice (916±37 µm). Analysis of the immuno-spectrum of AD also revealed the dominance of NP-based formulations in restraining immunoglobulin-E (IgE), histamine, prostaglandin-E2 (PGE2), vascular endothelial growth factor-α (VEGF-α), and T-helper cells (TH1/TH2) producing cytokines in serum and skin biopsies of tested mice. These anti-AD data were further supported by histological findings that revealed alleviated pathological features, including collagen fiber deposition, fibroblasts infiltration, and fragmentation of elastic fibers in experimental mice. Thus, NP-mediated transcutaneous co-delivery of HC and HT can be considered as a promising therapy for managing immunological and histological spectra associated with AD. PMID:25396426

  17. Correlation of TLR2 and TLR4 expressions in peripheral blood mononuclear cells to Th1- and Th2-type immune responses in children with henoch-schönlein purpura.

    PubMed

    Chang, Hong; Zhang, Qiu-Ye; Lin, Yi; Cheng, Na; Zhang, Shou-Qing

    2015-01-01

    We discussed the correlation of TLR2 (Toll-like receptor) and TLR4 expressions in peripheral blood mononuclear cells (PBMCs) to Th1- and Th2-type immune responses in children with Henoch-Schönlein Purpura (HSP). The role of TLR2 and TLR4 in the pathogenesis of HSP was analyzed. Sixty-four HSP children treated at our hospital from October 2011 to November 2012 were enrolled and divided into NHSPN group (complicated by renal impairment, 36 cases) and HSPN group (not complicated by renal impairment, 28 cases). In the meantime, 30 normal children receiving physical examination at our hospital were recruited as controls. Peripheral blood T cell subgroups and TLR2 and TLR4 expressions in PBMCs were detected by using flow cytometry; relative expression levels of TLR2 and TLR4 mRNA in PBMCs by real-time quantitative fluorescence PCR, and plasma levels of IFN-γ, IL-4 and IL-6 by ELISA method. Relative expression levels of TLR2 and TLR4 mRNAs in PBMCs and TLR2 and TLR4 protein expressions in children with HSP were significantly higher than those of the controls (P<0.01). The relative expression levels of TLR2 and TLR4 mRNAs in PBMCs and TLR2 and TLR4 protein expressions in HSPN group were obviously higher than those in NHSPN group (P<0.05; P<0.01; P<0.01; P<0.01); CD3(+) T cells and CD3(+)CD4(+) T cells in HSP group were significantly decreased, while CD3(+)CD8(+) T cells and CD3(+)HLADR(+) T activated cells were considerably increased (P<0.01); The plasma levels of IL-4 and IL-6 in HSP group were significantly higher than those of the normal controls (P<0.01, P<0.01); IFN-γ level in the former was much lower than in the control group (P<0.05); IFN-γ/IL-4 ratio in the former was also lower than that in the control (P<0.01); TLR2 and TLR4 expressions in HSP group showed significantly positive correlation with the plasma levels of IL-4 and IL-6 (P<0.01, P<0.05; P<0.01, P<0.01) and significantly negative correlation with IFN-γ/IL-4 ratio (P<0.01; P<0.01). TLR2 and TLR4

  18. A VLP Library of C-Terminally Truncated Hepatitis B Core Proteins: Correlation of RNA Encapsidation with a Th1/Th2 Switch in the Immune Responses of Mice

    PubMed Central

    Sominskaya, Irina; Skrastina, Dace; Petrovskis, Ivars; Dishlers, Andris; Berza, Ieva; Mihailova, Maria; Jansons, Juris; Akopjana, Inara; Stahovska, Irina; Dreilina, Dzidra; Ose, Velta; Pumpens, Paul

    2013-01-01

    An efficient pBR327- and Ptrp-based E. coli expression system was used to generate a large-scale library of virus like particles (VLP) formed by recombinant hepatitis B virus (HBV) core (HBc) protein derivatives. To construct the library, the gene of HBc protein of the genotype D/subtype ayw2 virus was gradually truncated from the 3`-end and twenty-two HBc variants (with truncation up to 139 aa) were expressed at high levels. The proteins were purified by salt precipitation and gel filtration. Background RNA binding was observed for VLPs formed by HBc1-149, which lacked all C-terminal Arg blocks, and the addition of three Arg residues (HBc1-152) only slightly increased RNA binding. The presence of two Arg blocks (proteins HBc1-162 and HBc1-163) resulted in approximately half of the typical level of RNA binding, and the presence of three blocks (protein HBc1-171) led to approximately 85% of the typical level of binding. Only a small increase in the level of RNA binding was found for the HBc1-175 VLPs, which contained all four Arg blocks but lacked the last 8 aa of the full-length HBc protein. VLPs containing high levels of RNA had higher antigenicity according to an ELISA with anti-HBc mAbs than the VLPs formed by HBc variants without C-terminal Arg blocks and lacking RNA. The results indicate that the VLPs were stabilised by nucleic acids. The immunogenicity in BALB/c mice was comparable for VLPs formed by different HBc proteins, but a clear switch from a Th1 response to a Th2 response occurred after the loss of encapsidated RNA. We did not observe significant differences in lymphocyte proliferation in vitro for the tested VLP variants; however, the loss of RNA encapsidation correlated with a decreased level of IFN-γ induction, which is a measure of the potential CTL activity of immunogens. PMID:24086668

  19. Plasticity of Migrating CD1b+ and CD1b- Lymph Dendritic Cells in the Promotion of Th1, Th2 and Th17 in Response to Salmonella and Helminth Secretions

    PubMed Central

    Olivier, Michel; Foret, Benjamin; Le Vern, Yves; Kerboeuf, Dominique; Guilloteau, Laurence A.

    2013-01-01

    Dendritic cells (DCs) are pivotal in the development of specific T-cell responses to control pathogens, as they govern both the initiation and the polarization of adaptive immunity. To investigate the capacities of migrating DCs to respond to pathogens, we used physiologically generated lymph DCs (L-DCs). The flexible polarization of L-DCs was analysed in response to Salmonella or helminth secretions known to induce different T cell responses. Mature conventional CD1b+ L-DCs showed a predisposition to promote pro-inflammatory (IL-6), pro-Th1 (IL-12p40) and anti-inflammatory (IL-10) responses which were amplified by Salmonella, and limited to only IL-6 induction by helminth secretions. The other major population of L-DCs did not express the CD1b molecule and displayed phenotypic features of immaturity compared to CD1b+ L-DCs. Salmonella infection reduced the constitutive expression of TNF-α and IL-4 mRNA in CD1b- L-DCs, whereas this expression was not affected by helminth secretions. The cytokine response of T cells promoted by L-DCs was analysed in T cell subsets after co-culture with Salmonella or helminth secretion-driven CD1b+ or CD1b- L-DCs. T cells preferentially expressed the IL-17 gene, and to a lesser extent the IFN-γ and IL-10 genes, in response to Salmonella-driven CD1b+ L-DCs, whereas a preferential IL-10, IFN-γ and IL-17 gene expression was observed in response to Salmonella-driven CD1b- L-DCs. In contrast, a predominant IL-4 and IL-13 gene expression by CD4+ and CD8+ T cells was observed after stimulation of CD1b+ and CD1b- L-DCs with helminth secretions. These results show that mature conventional CD1b+ L-DCs maintain a flexible capacity to respond differently to pathogens, that the predisposition of CD1b- L-DCs to promote a Th2 response can be oriented towards other Th responses, and finally that the modulation of migrating L-DCs responses is controlled more by the pathogen encountered than the L-DC subsets. PMID:24223964

  20. Simultaneous analysis of T helper subsets (Th1, Th2, Th9, Th17, Th22, Tfh, Tr1 and Tregs) markers expression in periapical lesions reveals multiple cytokine clusters accountable for lesions activity and inactivity status

    PubMed Central

    ARAUJO-PIRES, Ana Claudia; FRANCISCONI, Carolina Favaro; BIGUETTI, Claudia Cristina; CAVALLA, Franco; ARANHA, Andreza Maria Fabio; LETRA, Ariadne; TROMBONE, Ana Paula Favaro; FAVERI, Marcelo; SILVA, Renato Menezes; GARLET, Gustavo Pompermaier

    2014-01-01

    Previous studies demonstrate that the balance between pro- and anti-inflammatory mediators determines the stable or progressive nature of periapical granulomas by modulating the balance of the osteoclastogenic factor RANKL and its antagonist OPG. However, the cytokine networks operating in the development of periapical lesions are quite more complex than what the simple pro- versus anti-inflammatory mediators' paradigm suggests. Here we simultaneously investigated the patterns of Th1, Th2, Th9, Th17, Th22, Thf, Tr1 and Tregs cytokines/markers expression in human periapical granulomas. Methods The expression of TNF-α, IFN-γ, IL-17A, IL23, IL21, IL-33, IL-10, IL-4, IL-9, IL-22, FOXp3 markers (via RealTimePCR array) was accessed in active/progressive (N=40) versus inactive/stable (N=70) periapical granulomas (as determined by RANKL/OPG expression ratio), and also to compare these samples with a panel of control specimens (N=26). A cluster analysis of 13 cytokine levels was performed to examine possible clustering between the cytokines in a total of 110 granulomas. Results The expression of all target cytokines was higher in the granulomas than in control samples. TNF-α, IFN-γ, IL-17A and IL-21 mRNA levels were significantly higher in active granulomas, while in inactive lesions the expression levels of IL-4, IL-9, IL-10, IL-22 and FOXp3 were higher than in active granulomas. Five clusters were identified in inactive lesion groups, being the variance in the expression levels of IL-17, IL-10, FOXp3, IFN-γ, IL-9, IL-33 and IL-4 statistically significant (KW p<0.05). Three clusters were identified in active lesions, being the variance in the expression levels of IL-22, IL-10, IFN-γ, IL-17, IL-33, FOXp3, IL-21 and RANKL statistically significant (KW p<0.05). Conclusion There is a clear dichotomy in the profile of cytokine expression in inactive and active periapical lesions. While the widespread cytokine expression seems to be a feature of chronic lesions

  1. Combined CD4+ Th1 effect and lymphotactin transgene expression enhance CD8+ Tc1 tumor localization and therapy.

    PubMed

    Huang, H; Bi, X G; Yuan, J Y; Xu, S L; Guo, X L; Xiang, J

    2005-06-01

    Type 1 T cells are the major components in antitumor immunity. The lack of efficient CD8(+) cytotoxic T (Tc) cell infiltration of tumors is a major obstacle to adoptive Tc-cell therapy. We have previously demonstrated that adenovirus (AdV)-mediated transgene lymphotactin (Lptn) expression by intratumoral AdVLptn injection and intravenous CD4(+) helper T (Th) cell transfer can enhance Tc-cell tumor infiltration and eradication of early stage tumors (5 mm in diameter). In this study, we generated ovalbumin (OVA)-specific Tc1 and Th1 cells in vitro by incubation of OVA-pulsed dendritic cells with naive T cells from T-cell receptor (TCR) transgenic OT I and OT II mice. We then investigated the potential synergy of Th1 help effect and Lptn transgene expression in Tc1-cell therapy of well-established OVA-expressing EG7 solid tumors (7 mm in diameter). Our data showed that a combined adoptive T-cell therapy of Th1 (2.5 x 10(6) cells per mouse) and Tc1 (5 x 10(6) cells per mouse) resulted in regression of all eight (100%) transgene Lptn expressed EG7 tumors, which is significantly higher than four from eight (50%) in AdVLptn/Tc1 group and two from eight (25%) in Tc1/Th1 group (P < 0.05). The amount of transferred Tc1 cells detected in Lptn-expressed tumors with Th1 treatment is 0.72%, which is significantly higher than those of AdVLptn (0.22%), Th1 (0.41%) and the control AdVpLpA (0.09%) treatment groups (P < 0.05). Enhanced Tc1 tumor localization may be derived from the chemotactic effect of Lptn and the proliferative effect of Th1 and Lptn. This novel therapeutic strategy with enhancement of Tc1 tumor localization in the therapy of well-established tumors may become a tool of considerable conceptual interest in the implementation of future clinical objectives.

  2. Th2-Associated Alternative Kupffer Cell Activation Promotes Liver Fibrosis without Inducing Local Inflammation

    PubMed Central

    López-Navarrete, Giuliana; Ramos-Martínez, Espiridión; Suárez-Álvarez, Karina; Aguirre-García, Jesús; Ledezma-Soto, Yadira; León-Cabrera, Sonia; Gudiño-Zayas, Marco; Guzmán, Carolina; Gutiérrez-Reyes, Gabriela; Hernández-Ruíz, Joselín; Camacho-Arroyo, Ignacio; Robles-Díaz, Guillermo; Kershenobich, David; Terrazas, Luis I.; Escobedo, Galileo

    2011-01-01

    Cirrhosis is the final outcome of liver fibrosis. Kupffer cell-mediated hepatic inflammation is considered to aggravate liver injury and fibrosis. Alternatively-activated macrophages are able to control chronic inflammatory events and trigger wound healing processes. Nevertheless, the role of alternative Kupffer cell activation in liver harm is largely unclear. Thus, we evaluated the participation of alternatively-activated Kupffer cells during liver inflammation and fibrosis in the murine model of carbon tetrachloride-induced hepatic damage. To stimulate alternative activation in Kupffer cells, 20 Taenia crassiceps (Tc) larvae were inoculated into BALBc/AnN female mice. Six weeks post-inoculation, carbon tetrachloride or olive oil were orally administered to Tc-inoculated and non-inoculated mice twice per week during other six weeks. The initial exposure of animals to T. crassiceps resulted in high serum concentrations of IL-4 accompanied by a significant increase in the hepatic mRNA levels of Ym-1, with no alteration in iNOS expression. In response to carbon tetrachloride, recruitment of inflammatory cell populations into the hepatic parenchyma was 5-fold higher in non-inoculated animals than Tc-inoculated mice. In contrast, carbon tetrachloride-induced liver fibrosis was significantly less in non-inoculated animals than in the Tc-inoculated group. The latter showed elevated IL-4 serum levels and low IFN-γ concentrations during the whole experiment, associated with hepatic expression of IL-4, TGF-β, desmin and α-sma, as well as increased mRNA levels of Arg-1, Ym-1, FIZZ-1 and MMR in Kupffer cells. These results suggest that alternative Kupffer cell activation is favored in a Th2 microenvironment, whereby such liver resident macrophages could exhibit a dichotomic role during chronic hepatic damage, being involved in attenuation of the inflammatory response but at the same time exacerbation of liver fibrosis. PMID:22110380

  3. Differential regulation of Th1 and Th2 cells by p91–110 and p21–40 peptides of the 16-kD α-crystallin antigen of Mycobacterium tuberculosis

    PubMed Central

    AGREWALA, J N; WILKINSON, R J

    1998-01-01

    Permissively recognized peptides which can activate lymphocytes from subjects with a variety of class II HLA types are interesting diagnostic and vaccine candidates. In this study we generated T helper clones reactive to the permissively recognized p21–40 and p91–110 peptides of the 16-kD heat shock protein of Mycobacterium tuberculosis. All the clones specific for p91–110 secreted interferon-gamma (IFN-γ) and were of the Th1 phenotype. By contrast, the p21–40 peptide favoured the generation of IL-4-producing clones. Antibody blockade established that the peptide-specific Th clones could either be DR-, DP- or DQ-restricted. Thus, two permissively recognized sequences p21–40 and p91–110 from the same mycobacterial antigen can drive the differentiation of functionally distinct T helper subsets. Attempts to immunize against tuberculosis should bear in mind epitope specificity if a favourable Th subtype response is to be generated. PMID:9844048

  4. Crucial Contributions by T Lymphocytes (Effector, Regulatory, and Checkpoint Inhibitor) and Cytokines (TH1, TH2, and TH17) to a Pathological Complete Response Induced by Neoadjuvant Chemotherapy in Women with Breast Cancer

    PubMed Central

    Verma, Chandan; Eremin, Jennifer M.; Cowley, Gerard; Ilyas, Mohammed; Eremin, Oleg

    2016-01-01

    The tumour microenvironment consists of malignant cells, stroma, and immune cells. Prominent tumour-infiltrating lymphocytes (TILs) in breast cancer are associated with a good prognosis and are predictors of a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC). The contribution of different T effector/regulatory cells and cytokines to tumour cell death with NAC requires further characterisation and was investigated in this study. Breast tumours from 33 women with large and locally advanced breast cancers undergoing NAC were immunohistochemically (intratumoural, stromal) assessed for T cell subsets and cytokine expression using labelled antibodies, employing established semiquantitative methods. Prominent levels of TILs and CD4+, CD8+, and CTLA-4+ (stromal) T cells and CD8+ : FOXP3+ ratios were associated with a significant pCR; no association was seen with FOXP3+, CTLA-4+ (intratumoural), and PD-1+ T cells. NAC significantly reduced CD4+, FOXP3+, CTLA-4+ (stromal) (concurrently blood FOXP3+, CTLA-4+ Tregs), and PD-1+ T cells; no reduction was seen with CD8+ and CTLA-4+ (intratumoural) T cells. High post-NAC tumour levels of FOXP3+ T cells, IL-10, and IL-17 were associated with a failed pCR. Our study has characterised further the contribution of T effector/regulatory cells and cytokines to tumour cell death with NAC. PMID:27777963

  5. T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice.

    PubMed

    Pakala, S V; Kurrer, M O; Katz, J D

    1997-07-21

    Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

  6. Phosphatidylethanolamine-esterified eicosanoids in the mouse: tissue localization and inflammation-dependent formation in Th-2 disease.

    PubMed

    Morgan, Alwena H; Dioszeghy, Vincent; Maskrey, Benjamin H; Thomas, Christopher P; Clark, Stephen R; Mathie, Sara A; Lloyd, Clare M; Kühn, Hartmut; Topley, Nicholas; Coles, Barbara C; Taylor, Philip R; Jones, Simon A; O'Donnell, Valerie B

    2009-08-07

    In this study, murine peritoneal macrophages from naïve lavage were found to generate four phospholipids that contain 12-hydroxyeicosatetraenoic acid (12-HETE). They comprise three plasmalogen and one diacyl phosphatidylethanolamines (PEs) (16:0p, 18:1p, 18:0p, and 18:0a at sn-1) and are absent in macrophages from 12/15-lipoxygenase (12/15-LOX)-deficient mice. They are generated acutely in response to calcium mobilization, are primarily cell-associated, and are detected on the outside of the plasma membrane. Levels of 12-HETE-PEs in naïve lavage are in a similar range to those of free 12-HETE (5.5 +/- 0.2 ng or 18.5 +/- 1.03 ng/lavage for esterified versus free, respectively). In healthy mice, 12/15-LOX-derived 12-HETE-PEs are found in the peritoneal cavity, peritoneal membrane, lymph node, and intestine, with a similar distribution to 12/15-LOX-derived 12-HETE. In vivo generation of 12-HETE-PEs occurs in a Th2-dependent model of murine lung inflammation associated with interleukin-4/interleukin-13 expression. In contrast, in Toll receptor-dependent peritonitis mediated either by live bacteria or bacterial products, 12-HETE-PEs are rapidly cleared during the acute phase then reappear during resolution. The human homolog, 18:0a/15-HETE-PE inhibited human monocyte generation of cytokines in response to lipopolysaccharide. In summary, a new family of lipid mediators generated by murine macrophages during Th2 inflammation are identified and structurally characterized. The studies suggest a new paradigm for lipids generated by 12/15-LOX in inflammation involving formation of esterified eicosanoids.

  7. Intestinal Irradiation and Fibrosis in a Th1-Deficient Environment

    SciTech Connect

    Linard, Christine; Billiard, Fabienne; Benderitter, Marc

    2012-09-01

    Purpose: Changes in the Th1/Th2 immune balance may play a role in increasing the incidence of radiation-induced toxicity. This study evaluates the consequences of Th1 deficiency on intestinal response (fibrosis and T cell trafficking) to abdominal irradiation and examines in mucosa and mesenteric lymph nodes (MLN) the differential involvement of the two Th1 pathways, T-bet/STAT1 and IL-12/STAT4, in controlling this balance in mice. Methods and Materials: Using T-bet-deficient mice (T-bet{sup -/-}), we evaluated the mRNA and protein expression of the Th1 pathways (IFN-{gamma}, T-bet/STAT1, and IL-12/STAT4) and the CD4{sup +} and CD8{sup +} populations in ileal mucosa and MLN during the first 3 months after 10 Gy abdominal irradiation. Results: The T-bet-deficient mice showed an increased fibrotic response to radiation, characterized by higher TGF-{beta}1, col3a1 expression, and collagen deposition in mucosa compared with wild-type mice. This response was associated with drastically lower expression of IFN-{gamma}, the hallmark Th1 cytokine. Analysis of the Th1 expression pathways, T-bet/STAT1 and IL-12/STAT4, showed their equal involvement in the failure of Th1 polarization. A minimal IFN-{gamma} level depended on the IL-23-p19/STAT4 level. In addition, the radiation-induced deficiency in the priming of Th1 by IFN-{gamma} was related to the defective homing capacity of CD8{sup +} cells in the mucosa. Conclusion: Irradiation induces Th2 polarization, and the Th2 immune response may play a role in potentiating irradiation-induced intestinal collagen deposition.

  8. Food preservatives sodium benzoate and propionic acid and colorant curcumin suppress Th1-type immune response in vitro.

    PubMed

    Maier, Elisabeth; Kurz, Katharina; Jenny, Marcel; Schennach, Harald; Ueberall, Florian; Fuchs, Dietmar

    2010-07-01

    Food preservatives sodium benzoate and propionic acid and colorant curcumin are demonstrated to suppress in a dose-dependent manner Th1-type immune response in human peripheral blood mononuclear cells (PBMC) in vitro. Results show an anti-inflammatory property of compounds which however could shift the Th1-Th2-type immune balance towards Th2-type immunity.

  9. CD4+ Th1 cells promote CD8+ Tc1 cell survival, memory response, tumor localization and therapy by targeted delivery of interleukin 2 via acquired pMHC I complexes.

    PubMed

    Huang, Hui; Hao, Siguo; Li, Fang; Ye, Zhenmin; Yang, Junbao; Xiang, Jim

    2007-02-01

    The cooperative role of CD4+ helper T (Th) cells has been reported for CD8+ cytotoxic T (Tc) cells in tumor eradication. However, its molecular mechanisms have not been well elucidated. We have recently demonstrated that CD4+ Th cells can acquire major histocompatibility complex/peptide I (pMHC I) complexes and costimulatory molecules by dendritic cell (DC) activation, and further stimulate naïve CD8+ T cell proliferation and activation. In this study, we used CD4+ Th1 and CD8+ Tc1 cells derived from ovalbumin (OVA)-specific T cell receptor (TCR) transgenic OT II and OT I mice to study CD4+ Th1 cell's help effects on active CD8+ Tc1 cells and the molecular mechanisms involved in CD8+ Tc1-cell immunotherapy of OVA-expressing EG7 tumors. Our data showed that CD4+ Th1 cells with acquired pMHC I by OVA-pulsed DC (DCOVA) stimulation are capable of prolonging survival and reducing apoptosis formation of active CD8+ Tc1 cells in vitro, and promoting CD8+ Tc1 cell tumor localization and memory responses in vivo by 3-folds. A combined adoptive T-cell therapy of CD8+ Tc1 with CD4+ Th1 cells resulted in regression of well-established EG7 tumors (5 mm in diameter) in all 10/10 mice. The CD4+ Th1's help effect is mediated via the helper cytokine IL-2 specifically targeted to CD8+ Tc1 cells in vivo by acquired pMHC I complexes. Taken together, these results will have important implications for designing adoptive T-cell immunotherapy protocols in treatment of solid tumors.

  10. Epidermal expression of I-TAC (Cxcl11) instructs adaptive Th2-type immunity.

    PubMed

    Roebrock, Kirsten; Sunderkötter, Cord; Münck, Niels-Arne; Wolf, Marc; Nippe, Nadine; Barczyk, Katarzyna; Varga, Georg; Vogl, Thomas; Roth, Johannes; Ehrchen, Jan

    2014-04-01

    To decipher early promoters of the local microenvironment for Th2-type immunity, we wanted to identify gene patterns that were induced by Leishmania major in the infected skin of susceptible, Th2-prone BALB/c, but not of resistant, Th1-prone C57BL/6 mice. We found a marked up-regulation of the chemokine I-TAC (Cxcl11) during the first 2 d of infection in the epidermis of susceptible but not of resistant mice. Accordingly, local injection of I-TAC (2×1 μg) in resistant mice on the first day of infection resulted in a Th2-driven, sustained deterioration of disease and dramatically enhanced parasite levels. On the cellular level, I-TAC decreased IL-12 production by dendritic cells (DCs) in skin-draining lymph nodes and by DCs in vitro. Thus, we demonstrate for the first time that epidermis-derived I-TAC triggers a sustained Th2-response that determines the outcome of a complex immunological process.

  11. Selective Th2 Upregulation by Crocus sativus: A Neutraceutical Spice

    PubMed Central

    Bani, Sarang; Pandey, Anjali; Agnihotri, Vijai K.; Pathania, Vijaylata; Singh, Bikram

    2011-01-01

    The immunomodulatory activity of an Indian neutraceutical spice, saffron (Crocus sativus) was studied on Th1 and Th2 limbs of the immune system. Oral administration of alcoholic extract of Crocus sativus (ACS) at graded dose levels from 1.56–50 mg/kg p.o. potentiated the Th2 response of humoral immunity causing the significant increases in agglutinating antibody titre in mice at a dose of 6.25 mg/kg and an elevation of CD19+ B cells and IL-4 cytokine, a signature cytokine of Th2 pathway. Appreciable elevation in levels of IgG-1 and IgM antibodies of the primary and secondary immune response was observed. However, ACS showed no appreciable expression of the Th1 cytokines IL-2 (growth factor for CD4+ T cells) and IFN-γ (signature cytokine of Th1 response). A significant modulation of immune reactivity was observed in all the animal models used. This paper represents the selective upregulation of the Th2 response of the test material and suggests its use for subsequent selective Th2 immunomodulation. PMID:20953384

  12. Immunization with Low Doses of Recombinant Postfusion or Prefusion Respiratory Syncytial Virus F Primes for Vaccine-Enhanced Disease in the Cotton Rat Model Independently of the Presence of a Th1-Biasing (GLA-SE) or Th2-Biasing (Alum) Adjuvant.

    PubMed

    Schneider-Ohrum, Kirsten; Cayatte, Corinne; Bennett, Angie Snell; Rajani, Gaurav Manohar; McTamney, Patrick; Nacel, Krystal; Hostetler, Leigh; Cheng, Lily; Ren, Kuishu; O'Day, Terrence; Prince, Gregory A; McCarthy, Michael P

    2017-04-15

    Respiratory syncytial virus (RSV) infection of children previously immunized with a nonlive, formalin-inactivated (FI)-RSV vaccine has been associated with serious enhanced respiratory disease (ERD). Consequently, detailed studies of potential ERD are a critical step in the development of nonlive RSV vaccines targeting RSV-naive children and infants. The fusion glycoprotein (F) of RSV in either its postfusion (post-F) or prefusion (pre-F) conformation is a target for neutralizing antibodies and therefore an attractive antigen candidate for a pediatric RSV subunit vaccine. Here, we report the evaluation of RSV post-F and pre-F in combination with glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE) (GLA-SE) and alum adjuvants in the cotton rat model. Immunization with optimal doses of RSV F antigens in the presence of GLA-SE induced high titers of virus-neutralizing antibodies and conferred complete lung protection from virus challenge, with no ERD signs in the form of alveolitis. To mimic a waning immune response, and to assess priming for ERD under suboptimal conditions, an antigen dose de-escalation study was performed in the presence of either GLA-SE or alum. At low RSV F doses, alveolitis-associated histopathology was unexpectedly observed with either adjuvant at levels comparable to FI-RSV-immunized controls. This occurred despite neutralizing-antibody titers above the minimum levels required for protection and with no/low virus replication in the lungs. These results emphasize the need to investigate a pediatric RSV vaccine candidate carefully for priming of ERD over a wide dose range, even in the presence of strong neutralizing activity, Th1 bias-inducing adjuvant, and protection from virus replication in the lower respiratory tract.IMPORTANCE RSV disease is of great importance worldwide, with the highest burden of serious disease occurring upon primary infection in infants and children. FI-RSV-induced enhanced disease, observed in the 1960s

  13. So-Cheong-Ryong-Tang, tradititional Korean medicine, suppresses Th2 lineage development.

    PubMed

    Ko, Eunjung; Rho, Samwoong; Cho, Chongwoon; Choi, Hyun; Ko, Seonggyu; Lee, Youngwon; Hong, Moo-Chang; Shin, Min-Kyu; Jung, Seung-Gi; Bae, Hyunsu

    2004-05-01

    The present study was designed to evaluate the effect of So-Cheong-Ryong-Tang (SCRT, also called Sho-Seiryu-To or Xiao-Qing-Long-Tang) on helper T cell development by monitoring Th1/Th2-specific cytokine secretion patterns in artificially induced Th1 or Th2 polarized conditions. The results demonstrated that Th2 cells were dramatically underpopulated in the Th2-driven condition triggered by SCRT treatment, while the Th1 cells were not altered in the Th1-skewed condition. Furthermore, under Th2-skewed conditions the levels of interleukin-4 were considerably decreased with SCRT treatment. The expression of GATA-3, a transcription factor that plays a pivotal role in Th2 lineage programming, did not change with SCRT treatment, while the expression of another Th2 transcription factor, c-Maf, was dramatically suppressed. These data suggest that SCRT modulates Th2 development by suppressing c-Maf expression. This study implies that the SCRT effect on CD4(+) T cells is a key pharmacologic point of effect for treating IgE-mediated allergic asthma. These results also suggest that SCRT might be a useful agent for the correction of Th2-dominant pathologic disorders.

  14. Th1 epitope selection for clinically effective cancer vaccines.

    PubMed

    Disis, Mary L; Watt, William C; Cecil, Denise L

    2014-10-01

    New cancer immunotherapies mark progress in our understanding of tumor biology and harnessing the immune system's management of self. However, protein- and peptide-based vaccines are not yet consistently efficacious. Recent work uncovers principles governing the genesis of T helper type-restrictive immunity to self-antigens elicited by vaccine epitopes, enabling vaccines to skew the balance from tolerogenic Type II (Th2) to inflammatory Type I (Th1) T cells, and invigorating this cancer immunotherapeutic approach.

  15. Increased Calpain Correlates with Th1 Cytokine Profile in PBMCs from MS Patients

    PubMed Central

    Imam, Sarah A.; Guyton, Mary K.; Haque, Azizul; Vandenbark, Arthur; Tyor, William R.; Ray, Swapan K.; Banik, Naren L.

    2007-01-01

    Multiple sclerosis (MS) is a devastating autoimmune demyelinating disease of the CNS. This study investigated whether expression and activity of the calcium-activated protease calpain correlated with Th1/Th2 dysregulation in MS patients during states of relapse and remission. Calpain expression and activity were significantly increased in peripheral blood mononuclear cells (PBMCs) from MS patients, compared to controls, with the highest expression and activity noted during relapse. Th1 cytokines were highest and Th2 cytokines were lowest in MS patients during relapse. Treatment with calpain inhibitor, calpeptin, decreased Th1 cytokines in PBMCs from MS patients. Calpain inhibitor also reduced degradation of myelin basic protein (MBP) by inhibiting the calpain secreted from MBP-specific T cells. Taken together, these results suggested calpain involvement in Th1/Th2 dysregulation in MS patients. PMID:17765980

  16. Cell-mediated immunity to Toxoplasma gondii develops primarily by local Th-1 host immune responses in the absence of parasite replication1

    PubMed Central

    Gigley, Jason P.; Fox, Barbara A.; Bzik, David J.

    2008-01-01

    A single inoculation of mice with the live attenuated Toxoplasma gondii uracil auxotroph strain cps1-1 induces long-lasting immunity against lethal challenge with hyper-virulent strain RH. The mechanism for this robust immunity in the absence of parasite replication has not been addressed. The mechanism of long-lasting immunity, the importance of route of immunization, cellular recruitment to the site of infection, and local and systemic inflammation were evaluated. Our results show that infection with cps1-1 elicits long-lasting CD8+ T cell mediated immunity. We show that immunization with cps1-1 infected DCs elicits long-lasting immunity. Intraperitoneal infection with cps1-1 induced a rapid influx of GR1+ neutrophils and 2 stages of GR1+ CD68+ inflammatory monocyte infiltration into the site of inoculation. CD19+ B cells and CD3+ T cells steadily increase for 8 days after infection. CD8+ T cells were rapidly recruited to the site of infection and increased faster than CD4+ T cells. Surprisingly, cps1-1 infection induced high systemic levels of bioactive IL-12p70 and very low level and transient systemic Ifn-γ. Furthermore, we show significant levels of these inflammatory cytokines were locally produced at the site of cps1-1 inoculation. These findings offer new insight into immunological mechanisms and local host responses to a non-replicating Type I parasite infection associated with development of long-lasting immunity to Toxoplasma gondii. PMID:19124750

  17. Th1/Th2 Cytokines: An Easy Model to Study Gene Expression in Immune Cells

    PubMed Central

    González-Polo, Rosa A.; Soler, Germán; Fuentes, José M.

    2006-01-01

    This report describes a laboratory exercise that was incorporated into a Cell Biology and Molecular Biology advanced course. The exercise was made for a class size with eight students and was designed to reinforce the understanding of basic molecular biology techniques. Students used the techniques of reverse transcription and arginase activity measurement as well as nitric oxide determination to discover whether two specific genes were expressed by cytokine-stimulated dendritic cells. The experiment served as the basis for discussing the importance of differential gene expression inside the eukaryotic cell and the importance of cytokines in the immune system. PMID:17012221

  18. Th17 and treg cells innovate the TH1/TH2 concept and allergy research.

    PubMed

    Schmidt-Weber, C B

    2008-01-01

    Allergic reactions are caused by harmless allergens, which are recognized by the specific immune system. Allergen-specific T cells are assumed to play a key role in the sensitization phase and in immunological memory. Current immunological concepts suggest that asymptomatic T-cell memory cells also exist, tagging the allergen as harmless and preventing an inappropriate response and thus allergic symptoms. Proinflammatory T cells mediate allergic inflammation by exceeding the induction of IgE and competing with other T-cell subsets. Therefore, molecular mechanisms leading to pro- or anti-inflammatory T-cell memory cells appear as the key mechanism in allergy.

  19. Th1/Th2 Cytokines: An Easy Model to Study Gene Expression in Immune Cells

    ERIC Educational Resources Information Center

    Moran, Jose M.; Gonzalez-Polo, Rosa A.; Soler, German; Fuentes, Jose M.

    2006-01-01

    This report describes a laboratory exercise that was incorporated into a Cell Biology and Molecular Biology advanced course. The exercise was made for a class size with eight students and was designed to reinforce the understanding of basic molecular biology techniques. Students used the techniques of reverse transcription and arginase activity…

  20. Morphine Suppresses T helper Lymphocyte Differentiation to Th1 Type Through PI3K/AKT Pathway.

    PubMed

    Mao, Mao; Qian, Yanning; Sun, Jie

    2016-04-01

    To investigate the effect of morphine on T helper lymphocyte differentiation and PI3K/AKT pathway mechanism, CD4+ lymphocytes were treated by phorbol-myristate-acetate (25 ng/ml) (PMA) plus ionomycin (1 μg/ml) in the presence of various concentrations of morphine (25, 50, 100, 200 ng/ml) for 4 h. Th1 and Th2 subsets, supernatant cytokines, and PI3K, AKT, and protein kinase C-theta (PKC-θ) levels were detected. The Th1 cell percentage, Th1-derived cytokines, and ratio of Th1/Th2 decreased in the presence of morphine in a concentration-dependent manner. However, Th2 cell percentage kept stable after morphine treatment. The phosphorylation of PI3K and AKT decreased, but the phosphorylation of PKC-θ did not change in the presence of morphine. The decreased percentage of Th1 cells and ratio of Th1/Th2 was recovered by naloxone concentration-dependently. Morphine can inhibit the differentiation of Th1 lymphocytes and decrease the ratio of Th1/Th2 via the pathway of PI3K/AKT. The effect can be inhibited by naloxone.

  1. Selective suppression of Th2-mediated airway eosinophil infiltration by low-molecular weight CCR3 antagonists.

    PubMed

    Mori, Akio; Ogawa, Koji; Someya, Koichiro; Kunori, Yuichi; Nagakubo, Daisuke; Yoshie, Osamu; Kitamura, Fujiko; Hiroi, Takachika; Kaminuma, Osamu

    2007-08-01

    The effects of selective CC chemokine receptor (CCR)-3 antagonists on antigen-induced leukocyte accumulation in the lungs of mice adoptively transferred with in vitro-differentiated T(h)1 and T(h)2 were investigated. Inhalation of antigen by mice injected with T(h)1 and T(h)2 initiated the migration of T cells themselves into the lungs. Subsequently, neutrophils massively accumulated in T(h)1-transferred mice, whereas eosinophil infiltration was specifically induced by T(h)2. CCR3 antagonists, SB-297006 and/or SB-328437, suppressed antigen-induced accumulation of T(h)2 as well as eosinophils in the lungs, whereas they failed to affect T(h)1-mediated airway inflammation. Not only T(h)2 and eosinophil infiltration but also cellular mobilization in T(h)1-transferred mice was attenuated by an anti-CC chemokine ligand-11 antibody. CCR3 antagonists reduced chemokine production in the lungs of mice transferred with T(h)2 but not T(h)1, suggesting that down-regulation of chemokine synthesis is involved in the selective inhibition of T(h)2-mediated eosinophil infiltration by CCR3 antagonists.

  2. Th1-skewed tissue responses to a mycolyl glycolipid in mycobacteria-infected rhesus macaques

    SciTech Connect

    Morita, Daisuke; Miyamoto, Ayumi; Hattori, Yuki; Komori, Takaya; Nakamura, Takashi; Igarashi, Tatsuhiko; Harashima, Hideyoshi; Sugita, Masahiko

    2013-11-08

    Highlights: •Glucose monomycolate (GMM) is a marker glycolipid for active tuberculosis. •Tissue responses to GMM involved up-regulation of Th1-attracting chemokines. •Th1-skewed local responses were mounted at the GMM-injected tissue. -- Abstract: Trehalose 6,6′-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cell responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette–Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-γ, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection.

  3. Morphine withdrawal contributes to Th cell differentiation by biasing cells toward the Th2 lineage.

    PubMed

    Kelschenbach, Jennifer; Barke, Roderick A; Roy, Sabita

    2005-08-15

    The consequences that drug withdrawal has on immune functioning has only recently been appreciated; however, given the wide variety of use and abuse of opiate analgesics, understanding the decrements to immune function that withdrawal from these drugs causes is of crucial importance. In previous work, we have demonstrated that morphine treatment contributes to immunosuppression by polarizing Th cells toward the Th2 lineage. In the current study, it was hypothesized that morphine withdrawal would result in Th2 differentiation and subsequent immune dysfunction. To address this hypothesis, mice were chronically treated with morphine for 72 h followed by a 24-h withdrawal period. It was determined that 24-h morphine withdrawal resulted in a decrease in IFN-gamma, the Th1 signature cytokine, whereas the Th2 cytokine, IL-4, was increased. In addition, Western blot and EMSA experiments revealed that morphine withdrawal-induced Th2 differentiation was mediated through the classical Th2 transcription factors Stat-6 and GATA-3. In addition, the consequence of morphine withdrawal in the presence of an immune stimulation was also examined by treating mice in vivo with LPS before morphine withdrawal. Following withdrawal, it was found that the Th1-polarizing cytokine IL-12 was significantly decreased, providing further support for the observation that withdrawal results in Th2 differentiation by possibly impacting the generation of an appropriate innate immune response which directs subsequent adaptive Th1/Th2 responses.

  4. NK cells modulate the lung dendritic cell-mediated Th1/Th17 immunity during intracellular bacterial infection.

    PubMed

    Shekhar, Sudhanshu; Peng, Ying; Gao, Xiaoling; Joyee, Antony G; Wang, Shuhe; Bai, Hong; Zhao, Lei; Yang, Jie; Yang, Xi

    2015-10-01

    The impact of the interaction between NK cells and lung dendritic cells (LDCs) on the outcome of respiratory infections is poorly understood. In this study, we investigated the effect and mechanism of NK cells on the function of LDCs during intracellular bacterial lung infection of Chlamydia muridarum in mice. We found that the naive mice receiving LDCs from C. muridarum-infected NK-cell-depleted mice (NK-LDCs) showed more serious body weight loss, bacterial burden, and pathology upon chlamydial challenge when compared with the recipients of LDCs from infected sham-treated mice (NK+LDCs). Cytokine analysis of the local tissues of the former compared with the latter exhibited lower levels of Th1 (IFN-γ) and Th17 (IL-17), but higher levels of Th2 (IL-4), cytokines. Consistently, NK-LDCs were less efficient in directing C. muridarum-specific Th1 and Th17 responses than NK+LDCs when cocultured with CD4(+) T cells. In NK cell/LDC coculture experiments, the blockade of NKG2D receptor reduced the production of IL-12p70, IL-6, and IL-23 by LDCs. The neutralization of IFN-γ in the culture decreased the production of IL-12p70 by LDCs, whereas the blockade of TNF-α resulted in diminished IL-6 production. Our findings demonstrate that NK cells modulate LDC function to elicit Th1/Th17 immunity during intracellular bacterial infection.

  5. SerpinB2 is critical to Th2 immunity against enteric nematode infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    SerpinB2, a member of the serine protease inhibitor family, is expressed by macrophages and up-regulated significantly by inflammation. Recent studies implicated a role for SerpinB2 in the control of Th1 and Th2 immune responses, but the mechanisms of these effects are unknown. In the current study...

  6. TDI can induce respiratory allergy with Th2-dominated response in mice.

    PubMed

    Ban, Masarin; Morel, Georges; Langonné, Isabelle; Huguet, Nelly; Pépin, Elsa; Binet, Stéphane

    2006-01-20

    Toluene diisocyanate (TDI), a highly reactive industrial chemical is one of the leading causes of occupation-related asthma in industrialized countries. The pathophysiology of TDI-induced asthma, however, remains poorly understood, in part due to a lack of appropriate animal models. In this study, four models of TDI-sensitised mice were investigated. In model number 1, the mice were sensitised for 4 h/day on four consecutive days to 3 ppm inhaled TDI and challenged twice for 4 h each time with 0.3 ppm inhaled TDI. In model number 2, the sensitising condition was similar to that of model 1, but the challenge conditions involved an initial inhalation of 2 ppmTDI for 4h and then tracheal instillation with 50 microg/mouse albumin-TDI. In model number 3, the mice were sensitised first to 25% TDI (sc) and then three times for 4 h each time to 1 ppm inhaled TDI and challenged twice for 4h each time with 0.1 ppm inhalated TDI. In model number 4, the mice were first sensitised to 1% TDI by skin application and then with 0.2% TDI by tracheal instillation and challenged tree times by tracheal instillation of 0.1% TDI. In model number 4, skin application followed by tracheal instillations of TDI led to local and systemic Th2-dominated immune responses that were characterized: (1) in the lung-associated lymph nodes by a decrease in Th1 cytokine (IFN-gamma) production associated with an increase in Th2 cytokine (IL-4, IL-5, IL-3) production; (2) in the lungs by an allergic inflammation throughout the conducting airways: goblet cell proliferation and eosinophil influx and; (3) in the serums by increased total and specific IgE levels, 17.5- and 3.5-fold higher than that of the controls, respectively. The conditions used for sensitisation in the other models, i.e. inhalation or subcutaneous administration plus inhalation, failed to induce a strong Th2 response like that observed in model number 4. The findings indicate that TDI can induce a Th2-dominated response in mice when

  7. Caerulomycin A inhibits Th2 cell activity: a possible role in the management of asthma

    PubMed Central

    Kujur, Weshely; Gurram, Rama Krishna; Haleem, Nazia; Maurya, Sudeep K.; Agrewala, Javed N.

    2015-01-01

    We have recently demonstrated that Caerulomycin A induces regulatory T cells differentiation by suppressing Th1 cells activity. The role of regulatory T cells is well established in suppressing the function of Th2 cells. Th2 cells are known to inflict the induction of the activation of asthma. Consequently, in the present study, we monitored the influence of Caerulomycin A in inhibiting the activity of Th2 cells and its impact in recuperating asthma symptoms. Interestingly, we observed that Caerulomycin A significantly suppressed the differentiation of Th2 cells, as evidenced by downregulation in the GATA-3 expression. Further, decline in the levels of IL-4, IL-5 and IL-13 cytokines and IgE was noted in the animals suffering from asthma. Furthermore, we noticed substantial suppression in the inflammatory response and number of eosinophils in the lungs. In essence, this study signifies an important therapeutic role of Caerulomycin A in asthma. PMID:26481184

  8. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation

    NASA Astrophysics Data System (ADS)

    Williams, Jesse W.; Tjota, Melissa Y.; Clay, Bryan S.; Vander Lugt, Bryan; Bandukwala, Hozefa S.; Hrusch, Cara L.; Decker, Donna C.; Blaine, Kelly M.; Fixsen, Bethany R.; Singh, Harinder; Sciammas, Roger; Sperling, Anne I.

    2013-12-01

    Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation.

  9. Signals for the execution of Th2 effector function.

    PubMed

    Fowell, Deborah J

    2009-04-01

    Appropriate control of infection depends on the generation of lymphocytes armed with a particular array of cytokine and chemokine effector molecules. The differentiation of naïve T cells into functionally distinct effector subsets is regulated by signals from the T cell receptor (TCR) and cytokine receptors. Using gene knock-out approaches, the initiation of discrete effector programs appears differentially sensitive to the loss of individual TCR signaling components; likely due to differences in the transcription factors needed to activate individual cytokine genes. Less well understood however, are the signal requirements for the execution of effector function. With a focus on Th2 cells and the kinase ITK, we review recent observations that point to differences between the signals needed for the initiation and implementation of cytokine programs in CD4+ T cells. Indeed, Th2 effector cells signal differently from both their naïve counterparts and from Th1 effectors suggesting they may transduce activation signals differently or may be selectively receptive to different activation signals. Potential regulation points for effector function lie at the level of transcription and translation of cytokine genes. We also discuss how provision of these execution signals may be spatially segregated in vivo occurring at tissue sites of inflammation and subject to modulation by the pathogen itself.

  10. The contact allergen dinitrochlorobenzene (DNCB) and respiratory allergy in the Th2-prone Brown Norway rat.

    PubMed

    Kuper, C Frieke; Stierum, Rob H; Boorsma, Andre; Schijf, Marcel A; Prinsen, Menk; Bruijntjes, Joost P; Bloksma, Nanne; Arts, Josje H E

    2008-04-18

    All LMW respiratory allergens known to date can also induce skin allergy in test animals. The question here was if in turn skin allergens can induce allergy in the respiratory tract. Respiratory allergy was tested in Th2-prone Brown Norway (BN) rats by dermal sensitization with the contact allergen dinitrochlorobenzene (DNCB; 1%, day 0; 0.5%, day 7) and a head/nose-only inhalation challenge of 27mg/m3 of DNCB (15 min, day 21), using a protocol that successfully identified chemical respiratory allergens. Skin allergy to DNCB was examined in BN rats and Th1-prone Wistar rats in a local lymph node assay followed by a topical patch challenge of 0.1% DNCB. Sensitization of BN rats via the skin induced DNCB-specific IgG in serum, but not in all animals, and an increased number of CD4+ cells in the lung parenchyma. Subsequent inhalation challenge with DNCB did not provoke apneas or allergic inflammation (signs of respiratory allergy) in the BN rats. However, microarray analysis of mRNA isolated from the lung revealed upregulation of the genes for Ccl2 (MCP-1), Ccl4 (MIP-1beta), Ccl7 and Ccl17. Skin challenge induced considerably less skin irritation and allergic dermatitis in the BN rat than in the Wistar rat. In conclusion, the Th2-prone BN rat appeared less sensitive to DNCB than the Wistar rat; nevertheless, DNCB induced allergic inflammation in the skin of BN rats but even a relatively high challenge concentration did not induce allergy in the respiratory tract, although genes associated with allergy were upregulated in lung tissue.

  11. Myocardial Gene Expression of T-bet, GATA-3, Ror-γt, FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response

    PubMed Central

    Nogueira, Luciana Gabriel; Santos, Ronaldo Honorato Barros; Fiorelli, Alfredo Inácio; Mairena, Eliane Conti; Benvenuti, Luiz Alberto; Bocchi, Edimar Alcides; Stolf, Noedir Antonio; Kalil, Jorge; Cunha-Neto, Edecio

    2014-01-01

    Background. Chronic Chagas disease cardiomyopathy (CCC), a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg) in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-γ and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by TH2 cells (IL-4, IL-5, and IL-13) or associated with Treg (TGF-β and IL-10) were not upregulated in CCC myocardium. Expression of TH1-related genes such as T-bet, IFN-γ, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local TH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+ Treg cell population, which is unable to completely curb IFN-γ production in CCC myocardium, therefore fueling inflammation. PMID:25152568

  12. Alterations in the Th1/Th2 balance in breast cancer patients using reflexology and scalp massage.

    PubMed

    Green, Victoria L; Alexandropoulou, Afroditi; Walker, Mary B; Walker, Andrew A; Sharp, Donald M; Walker, Leslie G; Greenman, John

    2010-01-01

    The diagnosis and treatment of breast cancer can adversely affect quality of life. Here the aim was to determine the effects of reflexology on host defences and endocrine function in women with early breast cancer. Six weeks after surgery for early breast cancer, 183 women were randomly assigned to self-initiated support (SIS), SIS plus foot reflexology, or SIS plus scalp massage. Peripheral blood mononuclear cells and serum were isolated at T1 (6 weeks post surgery; baseline), T2 and T3 (4 and 10 weeks post completion of intervention, respectively). Lymphocyte phenotyping found that CD25(+) cells were significantly higher in the massage group compared with the SIS group at T3. The percentage of T cells, and more specifically the T helper subset expressing IL4, decreased significantly in the massage group compared with the SIS group at T3. This change was accompanied by an increase in the percentage of CD8(+) T cytotoxic cells expressing IFNγ in the massage group. Natural killer and lymphokine activated killer cell cytotoxicity measurements, serum levels of cortisol, prolactin and growth hormone, and flow cytometric assessment of their corresponding receptors all revealed no significant differences between the three groups of patients. This study provides evidence that the immunological balance of patients can be altered in a potentially beneficial manner by massage. The original trial was registered with the International Standard Randomised Controlled Trial Registry (ISRCTN87652313).

  13. Alterations in the Th1/Th2 balance in breast cancer patients using reflexology and scalp massage

    PubMed Central

    GREEN, VICTORIA L.; ALEXANDROPOULOU, AFRODITI; WALKER, MARY B.; WALKER, ANDREW A.; SHARP, DONALD M.; WALKER, LESLIE G.; GREENMAN, JOHN

    2010-01-01

    The diagnosis and treatment of breast cancer can adversely affect quality of life. Here the aim was to determine the effects of reflexology on host defences and endocrine function in women with early breast cancer. Six weeks after surgery for early breast cancer, 183 women were randomly assigned to self-initiated support (SIS), SIS plus foot reflexology, or SIS plus scalp massage. Peripheral blood mononuclear cells and serum were isolated at T1 (6 weeks post surgery; baseline), T2 and T3 (4 and 10 weeks post completion of intervention, respectively). Lymphocyte phenotyping found that CD25+ cells were significantly higher in the massage group compared with the SIS group at T3. The percentage of T cells, and more specifically the T helper subset expressing IL4, decreased significantly in the massage group compared with the SIS group at T3. This change was accompanied by an increase in the percentage of CD8+ T cytotoxic cells expressing IFNγ in the massage group. Natural killer and lymphokine activated killer cell cytotoxicity measurements, serum levels of cortisol, prolactin and growth hormone, and flow cytometric assessment of their corresponding receptors all revealed no significant differences between the three groups of patients. This study provides evidence that the immunological balance of patients can be altered in a potentially beneficial manner by massage. The original trial was registered with the International Standard Randomised Controlled Trial Registry (ISRCTN87652313). PMID:23136601

  14. Oral administration of an immunodominant T-cell epitope downregulates Th1/Th2 cytokines and prevents experimental myasthenia gravis

    PubMed Central

    Baggi, Fulvio; Andreetta, Francesca; Caspani, Elisabetta; Milani, Monica; Longhi, Renato; Mantegazza, Renato; Cornelio, Ferdinando; Antozzi, Carlo

    1999-01-01

    The mucosal administration of the native antigen or peptide fragments corresponding to immunodominant regions is effective in preventing or treating several T cell–dependent models of autoimmune disease. No data are yet available on oral tolerance with immunodominant T-cell peptides in experimental autoimmune myasthenia gravis (EAMG), an animal model of B cell–dependent disease. We report that oral administration of the T-cell epitope α146-162 of the Torpedo californica acetylcholine receptor (TAChR) α-subunit suppressed T-cell responses to AChR and ameliorated the disease in C57Bl/6 (B6) mice. Protection from EAMG was associated with reduced serum Ab’s to mouse AChR and reduced AChR loss in muscle. The effect of Tα146-162 feeding was specific; treatment with a control peptide did not affect EAMG manifestations. The protective effect induced by peptide Tα146-162 was mediated by reduced production of IFN-γ, IL-2, and IL-10 by TAChR-reactive cells, suggesting T-cell anergy. TGF-β–secreting Th3 cells did not seem to be involved in tolerance induction. We therefore demonstrate that feeding a single immunodominant epitope can prevent an Ab-mediated experimental model of autoimmune disease. PMID:10545527

  15. Modulation of mycobacterial-specific Th1 and Th17 cells in latent tuberculosis by coincident hookworm infection.

    PubMed

    George, Parakkal Jovvian; Anuradha, Rajamanickam; Kumaran, Paramasivam Paul; Chandrasekaran, Vedachalam; Nutman, Thomas B; Babu, Subash

    2013-05-15

    Hookworm infections and tuberculosis (TB) are coendemic in many parts of the world. It has been suggested that infection with helminth parasites could suppress the predominant Th1 (IFN-γ-mediated) response needed to control Mycobacterium tuberculosis infection and enhance susceptibility to infection and/or disease. To determine the role of coincident hookworm infection on responses at steady-state and on M. tuberculosis-specific immune responses in latent TB (LTB), we examined the cellular responses in individuals with LTB with or without concomitant hookworm infection. By analyzing the expression of Th1, Th2, and Th17 subsets of CD4(+) T cells, we were able to demonstrate that the presence of coincident hookworm infection significantly diminished both spontaneously expressed and M. tuberculosis-specific mono- and dual-functional Th1 and Th17 cells. Hookworm infection, in contrast, was associated with expanded frequencies of mono- and dual-functional Th2 cells at both steady-state and upon Ag stimulation. This differential induction of CD4(+) T cell subsets was abrogated upon mitogen stimulation. Additionally, coincident hookworm infection was associated with increased adaptive T regulatory cells but not natural regulatory T cells in LTB. Finally, the CD4(+) T cell cytokine expression pattern was also associated with alterations in the systemic levels of Th1 and Th2 cytokines. Thus, coincident hookworm infection exerts a profound inhibitory effect on protective Th1 and Th17 responses in LTB and may predispose toward the development of active tuberculosis in humans.

  16. Akt1-mediated Gata3 phosphorylation controls the repression of IFNγ in memory-type Th2 cells

    PubMed Central

    Hosokawa, Hiroyuki; Tanaka, Tomoaki; Endo, Yusuke; Kato, Miki; Shinoda, Kenta; Suzuki, Akane; Motohashi, Shinichiro; Matsumoto, Masaki; Nakayama, Keiichi I.; Nakayama, Toshinori

    2016-01-01

    Th2 cells produce Th2 cytokines such as IL-4, IL-5 and IL-13, but repress Th1 cytokine IFNγ. Recent studies have revealed various distinct memory-type Th2 cell subsets, one of which produces a substantial amount of IFNγ in addition to Th2 cytokines, however it remains unclear precisely how these Th2 cells produce IFNγ. We herein show that phosphorylation of Gata3 at Ser308, Thr315 and Ser316 induces dissociation of a histone deacetylase Hdac2 from the Gata3/Chd4 repressive complex in Th2 cells. We also identify Akt1 as a Gata3-phosphorylating kinase, and the activation of Akt1 induces derepression of Tbx21 and Ifng expression in Th2 cells. Moreover, T-bet-dependent IFNγ expression in IFNγ-producing memory Th2 cells appears to be controlled by the phosphorylation status of Gata3 in human and murine systems. Thus, this study highlights the molecular basis for posttranslational modifications of Gata3 that control the regulation of IFNγ expression in memory Th2 cells. PMID:27053161

  17. Interferon Regulatory Factor 4 controls TH1 cell effector function and metabolism

    PubMed Central

    Mahnke, Justus; Schumacher, Valéa; Ahrens, Stefanie; Käding, Nadja; Feldhoff, Lea Marie; Huber, Magdalena; Rupp, Jan; Raczkowski, Friederike; Mittrücker, Hans-Willi

    2016-01-01

    The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for TH2 and TH17 cell formation and controls peripheral CD8+ T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in TH1 responses. IRF4−/− mice generated only marginal numbers of listeria-specific TH1 cells. After transfer into infected mice, IRF4−/− CD4+ T cells failed to differentiate into TH1 cells as indicated by reduced T-bet and IFN-γ expression, and showed limited proliferation. Activated IRF4−/− CD4+ T cells exhibited diminished uptake of the glucose analog 2-NBDG, limited oxidative phosphorylation and strongly reduced aerobic glycolysis. Insufficient metabolic adaptation contributed to the limited proliferation and TH1 differentiation of IRF4−/− CD4+ T cells. Our study identifies IRF4 as central regulator of TH1 responses and cellular metabolism. We propose that this function of IRF4 is fundamental for the initiation and maintenance of all TH cell responses. PMID:27762344

  18. T-cell-intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy.

    PubMed

    Perez-Lloret, Jimena; Okoye, Isobel S; Guidi, Riccardo; Kannan, Yashaswini; Coomes, Stephanie M; Czieso, Stephanie; Mengus, Gabrielle; Davidson, Irwin; Wilson, Mark S

    2016-02-02

    There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ(+)CD4(+) T-helper 2 (TH2) cells orchestrate the type-2-driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081-E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4(gfp+)αβ(+)CD4(+) TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell-intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24(-/-) T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1-regulated signaling. Following this prediction, we found that Trim24(-/-) T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β-mediated activation in vitro and in vivo, and fail to respond to IL-1β-exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell-intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

  19. T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

    PubMed Central

    Perez-Lloret, Jimena; Okoye, Isobel S.; Guidi, Riccardo; Kannan, Yashaswini; Coomes, Stephanie M.; Czieso, Stephanie; Mengus, Gabrielle; Davidson, Irwin; Wilson, Mark S.

    2016-01-01

    There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity. PMID:26787865

  20. Thimerosal induces TH2 responses via influencing cytokine secretion by human dendritic cells.

    PubMed

    Agrawal, Anshu; Kaushal, Poonam; Agrawal, Sudhanshu; Gollapudi, Sastry; Gupta, Sudhir

    2007-02-01

    Thimerosal is an organic mercury compound that is used as a preservative in vaccines and pharmaceutical products. Recent studies have shown a TH2-skewing effect of mercury, although the underlying mechanisms have not been identified. In this study, we investigated whether thimerosal can exercise a TH2-promoting effect through modulation of functions of dendritic cells (DC). Thimerosal, in a concentration-dependent manner, inhibited the secretion of LPS-induced proinflammatory cytokines TNF-alpha, IL-6, and IL-12p70 from human monocyte-derived DC. However, the secretion of IL-10 from DC was not affected. These thimerosal-exposed DC induced increased TH2 (IL-5 and IL-13) and decreased TH1 (IFN-gamma) cytokine secretion from the T cells in the absence of additional thimerosal added to the coculture. Thimerosal exposure of DC led to the depletion of intracellular glutathione (GSH), and addition of exogenous GSH to DC abolished the TH2-promoting effect of thimerosal-treated DC, restoring secretion of TNF-alpha, IL-6, and IL-12p70 by DC and IFN-gamma secretion by T cells. These data suggest that modulation of TH2 responses by mercury and thimerosal, in particular, is through depletion of GSH in DC.

  1. Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway.

    PubMed Central

    Rincón, M; Enslen, H; Raingeaud, J; Recht, M; Zapton, T; Su, M S; Penix, L A; Davis, R J; Flavell, R A

    1998-01-01

    Signal transduction via MAP kinase pathways plays a key role in a variety of cellular responses, including growth factor-induced proliferation, differentiation and cell death. In mammalian cells, p38 MAP kinase can be activated by multiple stimuli, such as pro-inflammatory cytokines and environmental stress. Although p38 MAP kinase is implicated in the control of inflammatory responses, the molecular mechanisms remain unclear. Upon activation, CD4+ T cells differentiate into Th2 cells, which potentiate the humoral immune response or pro-inflammatory Th1 cells. Here, we show that pyridinyl imidazole compounds (specific inhibitors of p38 MAP kinase) block the production of interferon-gamma (IFNgamma) by Th1 cells without affecting IL-4 production by Th2 cells. These drugs also inhibit transcription driven by the IFNgamma promoter. In transgenic mice, inhibition of the p38 MAP kinase pathway by the expression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses. In contrast, activation of the p38 MAP kinase pathway by the expression of constitutivelyactivated MAP kinase kinase 6 in transgenic mice caused increased production of IFNgamma during the differentiation and activation of Th1 cells. Together, these data demonstrate that the p38 MAP kinase is relevant for Th1 cells, not Th2 cells, and that inhibition of p38 MAP kinase represents a possible site of therapeutic intervention in diseases where a predominant Th1 immune response leads to a pathological outcome. Moreover, our study provides an additional mechanism by which the p38 MAP kinase pathway controls inflammatory responses. PMID:9582275

  2. Th1 CD4+ lymphocytes delete activated macrophages through the Fas/APO-1 antigen pathway.

    PubMed Central

    Ashany, D; Song, X; Lacy, E; Nikolic-Zugic, J; Friedman, S M; Elkon, K B

    1995-01-01

    The Fas/APO-1 cytotoxic pathway plays an important role in the regulation of peripheral immunity. Recent evidence indicates that this regulatory function operates through deletion of activated T and B lymphocytes by CD4+ T cells expressing the Fas ligand. Because macrophages play a key role in peripheral immunity, we asked whether Fas was involved in T-cell-macrophage interactions. Two-color flow cytometry revealed that Fas receptor (FasR) was expressed on resting murine peritoneal macrophages. FasR expression was upregulated after activation of macrophages with cytokines or lipopolysaccharide, although only tumor necrosis factor-alpha rendered macrophages sensitive to anti-FasR antibody-mediated death. To determine the consequence of antigen presentation by macrophages to CD4+ T cells, macrophages were pulsed with antigen and then incubated with either Th1 or Th2 cell lines or clones. Th1, but not Th2, T cells induced lysis of 60-80% of normal macrophages, whereas macrophages obtained from mice with mutations in the FasR were totally resistant to Th1-mediated cytotoxicity. Macrophage cytotoxicity depended upon specific antigen recognition by T cells and was major histocompatibility complex restricted. These findings indicate that, in addition to deletion of activated lymphocytes, Fas plays an important role in deletion of activated macrophages after antigen presentation to Th1 CD4+ T cells. Failure to delete macrophages that constitutively present self-antigens may contribute to the expression of autoimmunity in mice deficient in FasR (lpr) or Fas ligand (gld). PMID:7479970

  3. Nuclear Role of WASp in the Pathogenesis of Dysregulated TH1 Immunity in Human Wiskott-Aldrich Syndrome

    PubMed Central

    Taylor, Matthew D.; Sadhukhan, Sanjoy; Kottangada, Ponnappa; Ramgopal, Archana; Sarkar, Koustav; D’Silva, Sheryl; Selvakumar, Annamalai; Candotti, Fabio; Vyas, Yatin M.

    2010-01-01

    The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (TH1) immunity alongside intact TH2 immunity. This suggests a role for WASp in patterning TH subtype immunity, yet the molecular basis for the TH1-TH2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the TH1 regulator gene TBX21 at the chromatin level. In primary TH1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a TH2 regulator gene) or RORc (a TH17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates TH1 cell fate choice in the human TH cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating TH1 cells. During TH1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASp-deficient TH cells, from natural mutation or RNA interference–mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under TH1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired TH1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a previously unappreciated role of WASp in the epigenetic control

  4. The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer

    PubMed Central

    Ling, Agnes; Lundberg, Ida V; Eklöf, Vincy; Wikberg, Maria L; Öberg, Åke; Palmqvist, Richard

    2015-01-01

    Abstract Giving strong prognostic information, T‐cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T‐bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype‐high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild‐type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1‐attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T‐bet may be a valuable marker in the clinical setting. Our results also indicate that T‐bet is of

  5. Behavior of  Visceral Leishmania donovani in an Experimentally Induced T Helper Cell 2 (Th2)-Associated Response Model

    PubMed Central

    Murray, Henry W.; Hariprashad, June; Coffman, Robert L.

    1997-01-01

    Although implicated in the clinical expression of human visceral leishmaniasis, a disease-exacerbating T helper cell 2 (Th2)-associated immune response involving interleukin-4 (IL-4) and/ or IL-10 is not readily detectable in experimental visceral infection. To overcome this obstacle to analyzing visceral Leishmania donovani in this relevant immunopathogenetic environment, we sought a model in which a Th2 response induces noncuring infection. Four initial approaches were tested primarily in BALB/c mice which control intracellular L. donovani via an IL-12– and interferon-γ (IFN-γ)–dependent Th1 mechanism: (a) modifying the cytokine milieu when the parasite is first encountered (treatment with exogenous IL-4 or anti–IL-12), (b) providing sustained endogenous exposure to a Th2 cytokine (infection of IL-4 transgenic mice), (c) increasing the parasite challenge inoculum, and (d) injecting heat-killed L. major promastigotes (HKLMP) to induce a cross-reactive Th2 response to live L. donovani. Only the last approach generated a functional Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly. In HKLMP-primed BALB/c mice, prophylaxis with anti–IL-4, anti–IL-10, or exogenous IL-12 (but not IFN-γ) readily restored resistance. In primed mice with established visceral infection, treatment with either IL-12 or IFN-γ also successfully induced antileishmanial activity. The results in this model (a) suggest that rather than acting alone, IL-4 and IL-10 may act in concert to prevent acquisition of resistance to L. donovani, (b) reemphasize the capacity of IL-12 to reverse early Th2-related effects, and (c) demonstrate that Th1 cytokines (IL-12, IFN-γ) have therapeutic action in an established systemic infection despite the presence of a disease-exacerbating Th2-type response. PMID:9120392

  6. Th1/Th17-Related Cytokines and Chemokines and Their Implications in the Pathogenesis of Pemphigus Vulgaris

    PubMed Central

    Timoteo, Rodolfo Pessato; Silva, Djalma Alexandre Alves; Catarino, Jonatas Da Silva; Rodrigues Junior, Virmondes

    2017-01-01

    Pemphigus vulgaris (PV) is an autoimmune disease characterized by the presence of IgG autoantibodies against desmoglein-3. Despite the variety of findings, the chemokine and cytokine profiles that characterize the immune response in the disease are still poorly explored. Thus, 20 PV patients and 20 controls were grouped according to gender, ethnicity, place of residence, and clinical parameters of the disease. Then, the levels of chemokines and of Th1/Th2/Th17/Treg/Th9/Th22-related cytokines were assessed in the serum. PV patients had higher levels of inflammatory Th1/Th17 cytokines (IFN-γ, IL-17, and IL-23), as well as higher levels of CXCL8 and reduced levels of Th1/Th2-related chemokines (IP-10 and CCL11). However, no differences in the levels of IL-2, IL-6, TNF-α, IL-1β, IL-4, IL-9, IL-12, TGF-β, IL-33, MCP-1, RANTES, and MIP-1α were found between PV patients and their control counterparts. Furthermore, PV patients with skin lesions had higher serum levels of IL-6 and CXCL8 when compared to PV patients without lesions. Taken together, our findings describe the role of cytokines and chemokines associated with Th1/Th17 immune response in PV patients. Finally, these data are important for better understanding of the immune aspects that control disease outcome, and they may also provide important information about why patients develop autoantibodies against desmogleins. PMID:28321152

  7. CD4+ T Cell Fate in Glomerulonephritis: A Tale of Th1, Th17, and Novel Treg Subtypes

    PubMed Central

    2016-01-01

    Multiple studies have identified CD4+ T cells as central players of glomerulonephritis (GN). Cells of the Th1 and Th17 responses cause renal tissue damage, while Tregs mediate protection. Recently, a high degree of plasticity among these T cell lineages was proposed. During inflammation, Th17 cells were shown to have the potential of transdifferentiation into Th1, Th2, or alternatively anti-inflammatory Tr1 cells. Currently available data from studies in GN, however, do not indicate relevant Th17 to Th1 or Th2 conversion, leaving the Th17 cell fate enigmatic. Tregs, on the other hand, were speculated to transdifferentiate into Th17 cells. Again, data from GN do not support this concept. Rather, it seems that previously unrecognized subspecialized effector Treg lineages exist. These include Th1 specific Treg1 as well as Th17 directed Treg17 cells. Furthermore, a bifunctional Treg subpopulation was recently identified in GN, which secrets IL-17 and coexpresses Foxp3 together with the Th17 characteristic transcription factor RORγt. Similarities between these different and highly specialized effector Treg subpopulations with the corresponding T helper effector cell lineages might have resulted in previous misinterpretation as Treg transdifferentiation. In summary, Th17 cells have a relatively stable phenotype during GN, while, in the case of Tregs, currently available data suggest lineage heterogeneity rather than plasticity. PMID:27974866

  8. Preventative Effect of an Herbal Preparation (HemoHIM) on Development of Airway Inflammation in Mice via Modulation of Th1/2 Cells Differentiation

    PubMed Central

    Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

    2013-01-01

    HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4+ T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA). In an in vitro experiment, naive CD4+ T cells displayed increased Th1 (IFN-γ+ cell) as well as decreased Th2 (IL-4+ cell) differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13) levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight) pretreatment (4 weeks). These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance. PMID:23844220

  9. Preventative effect of an herbal preparation (HemoHIM) on development of airway inflammation in mice via modulation of Th1/2 cells differentiation.

    PubMed

    Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

    2013-01-01

    HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4(+) T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA). In an in vitro experiment, naive CD4(+) T cells displayed increased Th1 (IFN-γ(+) cell) as well as decreased Th2 (IL-4(+) cell) differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13) levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight) pretreatment (4 weeks). These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance.

  10. Quantitative Proteomics Analysis of the Nuclear Fraction of Human CD4+ Cells in the Early Phases of IL-4-induced Th2 Differentiation*

    PubMed Central

    Moulder, Robert; Lönnberg, Tapio; Elo, Laura L.; Filén, Jan-Jonas; Rainio, Eeva; Corthals, Garry; Oresic, Matej; Nyman, Tuula A.; Aittokallio, Tero; Lahesmaa, Riitta

    2010-01-01

    We used stable isotope labeling with 4-plex iTRAQ (isobaric tags for relative and absolute quantification) reagents and LC-MS/MS to investigate proteomic changes in the nucleus of activated human CD4+ cells during the early stages of Th2 cell differentiation. The effects of IL-4 stimulation upon activated naïve CD4+ cells were measured in the nuclear fractions from 6 and 24 h in three biological replicates, each using pooled cord blood samples derived from seven or more individuals. In these analyses, in the order of 800 proteins were detected with two or more peptides and quantified in three biological replicates. In addition to consistent differences observed with the nuclear localization/expression of established human Th2 and Th1 markers, there were changes that suggested the involvement of several proteins either only recently reported or otherwise not known in this context. These included SATB1 and among the novel changes detected and validated an IL-4-induced increase in the level of YB1. This unique data set from human cord blood CD4+ T cells details an extensive list of protein determinations that compares with and complements previous data determined from the Jurkat cell nucleus. PMID:20467038

  11. Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering Th1 Lymphocyte Composition and Egress.

    PubMed

    Calik, Michael W; Shankarappa, Sahadev A; Langert, Kelly A; Stubbs, Evan B

    2015-01-01

    A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmune-mediated peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.2 km/day × 3 weeks) prior to P2-antigen induction of EAN. Sedentary rats developed a monophasic course of EAN beginning on postimmunization day 12.3 ± 0.2 and reaching peak severity on day 17.0 ± 0.3 (N = 12). By comparison, forced-exercise preconditioned rats exhibited a similar monophasic course but with significant (p < .05) reduction of disease severity. Analysis of popliteal lymph nodes revealed a protective effect of exercise preconditioning on leukocyte composition and egress. Compared with sedentary controls, forced exercise preconditioning promoted a sustained twofold retention of P2-antigen responsive leukocytes. The percentage distribution of pro-inflammatory (Th1) lymphocytes retained in the nodes from sedentary EAN rats (5.1 ± 0.9%) was significantly greater than that present in nodes from forced-exercise preconditioned EAN rats (2.9 ± 0.6%) or from adjuvant controls (2.0 ± 0.3%). In contrast, the percentage of anti-inflammatory (Th2) lymphocytes (7-10%) and that of cytotoxic T lymphocytes (∼20%) remained unaltered by forced exercise preconditioning. These data do not support an exercise-inducible shift in Th1:Th2 cell bias. Rather, preconditioning with forced exercise elicits a sustained attenuation of EAN severity, in part, by altering the composition and egress of autoreactive proinflammatory (Th1) lymphocytes from draining lymph nodes.

  12. Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

    PubMed Central

    Brundu, Serena; Palma, Linda; Picceri, Giusi Giada; Ligi, Daniela; Orlandi, Chiara; Galluzzi, Luca; Chiarantini, Laura; Casabianca, Anna; Schiavano, Giuditta Fiorella; Santi, Martina; Mannello, Ferdinando; Smietana, Michaël; Magnani, Mauro

    2016-01-01

    ABSTRACT Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine (I-152), an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice. IMPORTANCE The first report of an association between Th2 polarization and alteration of the redox state in LP-BM5

  13. Prevalence of atopy in children with type 1 diabetes mellitus, hepatitis B virus carriers, and healthy children: role of T helper 1 (Th1)-type immune response.

    PubMed

    Cakir, Murat; Akcay, Seker; Karakas, Taner; Gedik, Yusuf; Okten, Aysenur; Orhan, Fazil

    2008-01-01

    The prevalence of allergic diseases such as asthma, hay fever, and atopic dermatitis has increased over the past few decades, especially in developed countries. They are characterized by a chronic inflammatory reaction mediated by T helper 2 (Th2) cells. Two common chronic diseases of childhood-an autoimmune disease, type 1 diabetes mellitus (DM), and a chronic viral infection, hepatitis B virus (HBV) carriers-are associated with a Th1-dominant and Th1-insufficient cytokine profile, respectively. The purpose of this study was to analyze the frequency of allergic disease in patients with type 1 DM and, in HBV carriers, to evaluate the role of Th1-type immune response in atopy and allergic disease. The study included patients with type 1 DM (group I, n = 52), HBV carriers (group III, n = 47), and a healthy control group (group III, n = 209). Participants were screened for allergic disease and atopic sensitization. Symptoms of asthma, eczema, and atopy were found more commonly in HBV carrier children compared with those with DM and healthy controls. This study supports the Th1/Th2 model. The prevalence of allergic disease and atopy is decreased in Th1-mediated autoimmune disease, type 1 DM, and, conversely, is increased in insufficient Th1 response, chronic HBV carriers. Additional studies are needed to evaluate the effect of atopy and allergic diseases in glycemic control and long-term complications in patients with type 1 DM and the effect of atopy on progression of chronic HBV infection.

  14. Th1 cytokine-based immunotherapy for cancer.

    PubMed

    Xu, Hong-Mei

    2014-10-01

    Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited. Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment. In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings. Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice.

  15. Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity.

    PubMed

    Contreras, Francisco; Prado, Carolina; González, Hugo; Franz, Dafne; Osorio-Barrios, Francisco; Osorio, Fabiola; Ugalde, Valentina; Lopez, Ernesto; Elgueta, Daniela; Figueroa, Alicia; Lladser, Alvaro; Pacheco, Rodrigo

    2016-05-15

    Dopamine receptor D3 (DRD3) expressed on CD4(+) T cells is required to promote neuroinflammation in a murine model of Parkinson's disease. However, how DRD3 signaling affects T cell-mediated immunity remains unknown. In this study, we report that TCR stimulation on mouse CD4(+) T cells induces DRD3 expression, regardless of the lineage specification. Importantly, functional analyses performed in vivo using adoptive transfer of OVA-specific OT-II cells into wild-type recipients show that DRD3 deficiency in CD4(+) T cells results in attenuated differentiation of naive CD4(+) T cells toward the Th1 phenotype, exacerbated generation of Th2 cells, and unaltered Th17 differentiation. The reciprocal regulatory effect of DRD3 signaling in CD4(+) T cells favoring Th1 generation and impairing the acquisition of Th2 phenotype was also reproduced using in vitro approaches. Mechanistic analysis indicates that DRD3 signaling evokes suppressor of cytokine signaling 5 expression, a negative regulator of Th2 development, which indirectly favors acquisition of Th1 phenotype. Accordingly, DRD3 deficiency results in exacerbated eosinophil infiltration into the airways of mice undergoing house dust mite-induced allergic response. Interestingly, our results show that, upon chronic inflammatory colitis induced by transfer of naive CD4(+) T cells into lymphopenic recipients, DRD3 deficiency not only affects Th1 response, but also the frequency of Th17 cells, suggesting that DRD3 signaling also contributes to Th17 expansion under chronic inflammatory conditions. In conclusion, our findings indicate that DRD3-mediated signaling in CD4(+) T cells plays a crucial role in the balance of effector lineages, favoring the inflammatory potential of CD4(+) T cells.

  16. The increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Th1 skewing in ovalbumin immunized mice.

    PubMed

    Fraternale, Alessandra; Paoletti, Maria Filomena; Dominici, Sabrina; Caputo, Antonella; Castaldello, Arianna; Millo, Enrico; Brocca-Cofano, Egidio; Smietana, Michaël; Clayette, Pascal; Oiry, Joël; Benatti, Umberto; Magnani, Mauro

    2010-11-10

    In the present work, the capacity of new pro-GSH molecules to increase the intra-macrophage thiol content in vitro and in vivo as well as to shift the immune response to Th1 in ovalbumin (Ova)-sensitized mice were examined. The molecules were the N-butanoyl GSH derivative, GSH-C4, and a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (MEA), I-152. In vitro, 2h-incubation with both molecules was found to increase intra-macrophage thiol content; in vivo, Ova-sensitized mice pre-treated by intraperitoneal administration of the pro-GSH molecules showed an increase in plasma anti-Ova IgG2a and IgG2b, characterizing Th1 immune response, and a decrease in IgG1, typical of the Th2 response. Such findings were connected to a shift to a Th1 response also involving splenocyte IFN-γ production as revealed by ELISPOT assay and higher levels of IL-12 in circulation. Although immune responses are in vivo mediated both by dendritic cells and macrophages, the data reported in this paper corroborate the suggestion that the pro-GSH molecules, increasing the intra-cellular thiol pool, modulate the Th1/Th2 balance favouring Th1-type responses and may be employed as Th1-directing adjuvants in new vaccination protocols and as immunomodulators in those diseases where Th1 response patterns are compromised in favour of Th2.

  17. SB-273005, an antagonist of αvβ3 integrin, reduces the production of Th2 cells and cytokine IL-10 in pregnant mice.

    PubMed

    Wang, Shaojuan; Yang, Jing; Wang, Chongyang; Yang, Qing; Zhou, Xiaoli

    2014-06-01

    Pregnancy is associated with complex immunoreactions. In the present study, the effect of SB-273005, an antagonist of αvβ3 integrin, on the alterations of T helper (Th) cells and their derived cytokines that occur during pregnancy was investigated in mice. Five non-pregnant mice were used as a negative control. Mice were impregnated by co-housing females and males at a ratio of 2:1 overnight and pregnancy was confirmed by the appearance of vaginal plugs the following morning. Day 1 (D1) pregnant mice were randomly divided into two groups (n=20) and were administered either dimethylsulfoxide (mock treatment) or SB-273005 (3 mg/kg) by gavage at D3, D4 and D5. At D8, the levels of Th1 and Th2 cells and interleukin (IL)-2 and IL-10 in the spleen and peripheral blood were determined using flow cytometry and enzyme-linked immunosorbent assay. Pregnancy significantly increased the ratio of Th2:Th1 cells in the spleen compared with that in non-pregnant mice (P<0.01). However, this increase was significantly reduced by SB-273005 (P<0.001). Furthermore, whilst pregnancy decreased Th1 cell-produced IL-2 levels and increased Th2 cell-derived IL-10 levels, SB-273005 reversed both processes (P<0.05 for IL-2; P<0.01 for IL-10). The results from the present study demonstrated that pregnancy induces changes in the spleen, including a reduction of IL-2 and an increase in IL-10 production by Th1 and Th2 cells, respectively, as well as an upregulation of the Th2:Th1 ratio in the spleen. These immunological changes are reversed by SB-273005, indicating an important role for αvβ3 integrin in mediating these immunological alterations.

  18. FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy

    PubMed Central

    Lexmond, Willem S.; Goettel, Jeremy A.; Lyons, Jonathan J.; Jacobse, Justin; Deken, Marion M.; Lawrence, Monica G.; DiMaggio, Thomas H.; Kotlarz, Daniel; Garabedian, Elizabeth; Sackstein, Paul; Nelson, Celeste C.; Jones, Nina; Stone, Kelly D.; Rings, Edmond H.H.M.; Thrasher, Adrian J.; Milner, Joshua D.; Snapper, Scott B.; Fiebiger, Edda

    2016-01-01

    In addition to the infectious consequences of immunodeficiency, patients with Wiskott-Aldrich syndrome (WAS) often suffer from poorly understood exaggerated immune responses that result in autoimmunity and elevated levels of serum IgE. Here, we have shown that WAS patients and mice deficient in WAS protein (WASP) frequently develop IgE-mediated reactions to common food allergens. WASP-deficient animals displayed an adjuvant-free IgE-sensitization to chow antigens that was most pronounced for wheat and soy and occurred under specific pathogen–free as well as germ-free housing conditions. Conditional deletion of Was in FOXP3+ Tregs resulted in more severe Th2-type intestinal inflammation than that observed in mice with global WASP deficiency, indicating that allergic responses to food allergens are dependent upon loss of WASP expression in this immune compartment. While WASP-deficient Tregs efficiently contained Th1- and Th17-type effector differentiation in vivo, they failed to restrain Th2 effector responses that drive allergic intestinal inflammation. Loss of WASP was phenotypically associated with increased GATA3 expression in effector memory FOXP3+ Tregs, but not in naive-like FOXP3+ Tregs, an effect that occurred independently of increased IL-4 signaling. Our results reveal a Treg-specific role for WASP that is required for prevention of Th2 effector cell differentiation and allergic sensitization to dietary antigens. PMID:27643438

  19. Cathepsin B in Antigen-Presenting Cells Controls Mediators of the Th1 Immune Response during Leishmania major Infection

    PubMed Central

    Gonzalez-Leal, Iris J.; Röger, Bianca; Schwarz, Angela; Schirmeister, Tanja; Reinheckel, Thomas; Lutz, Manfred B.; Moll, Heidrun

    2014-01-01

    Resistance and susceptibility to Leishmania major infection in the murine model is determined by the capacity of the host to mount either a protective Th1 response or a Th2 response associated with disease progression. Previous reports involving the use of cysteine cathepsin inhibitors indicated that cathepsins B (Ctsb) and L (Ctsl) play important roles in Th1/Th2 polarization during L. major infection in both susceptible and resistant mouse strains. Although it was hypothesized that these effects are a consequence of differential patterns of antigen processing, the mechanisms underlying these differences were not further investigated. Given the pivotal roles that dendritic cells and macrophages play during Leishmania infection, we generated bone-marrow derived dendritic cells (BMDC) and macrophages (BMM) from Ctsb−/− and Ctsl−/− mice, and studied the effects of Ctsb and Ctsl deficiency on the survival of L. major in infected cells. Furthermore, the signals used by dendritic cells to instruct Th cell polarization were addressed: the expression of MHC class II and co-stimulatory molecules, and cytokine production. We found that Ctsb−/− BMDC express higher levels of MHC class II molecules than wild-type (WT) and Ctsl−/− BMDC, while there were no significant differences in the expression of co-stimulatory molecules between cathepsin-deficient and WT cells. Moreover, both BMDC and BMM from Ctsb−/− mice significantly up-regulated the levels of interleukin 12 (IL-12) expression, a key Th1-inducing cytokine. These findings indicate that Ctsb−/− BMDC display more pro-Th1 properties than their WT and Ctsl−/− counterparts, and therefore suggest that Ctsb down-regulates the Th1 response to L. major. Moreover, they propose a novel role for Ctsb as a regulator of cytokine expression. PMID:25255101

  20. Phthalate-Induced Liver Protection against Deleterious Effects of the Th1 Response: A Potentially Serious Health Hazard

    PubMed Central

    Badr, Mostafa Z.; Shnyra, Alexander; Zoubine, Mikhail; Norkin, Maxim; Herndon, Betty; Quinn, Tim; Miranda, Roberto N.; Cunningham, Michael L.; Molteni, Agostino

    2007-01-01

    Infection with Mycobacterium tuberculosis (TB) induces pulmonary immunopathology mediated by classical Th1 type of acquired immunity with hepatic involvement in up to 80% of disseminated cases. Since PPAR agonists cause immune responses characterized by a decrease in the secretion of Th1 cytokines, we investigated the impact of activating these receptors on hepatic pathology associated with a well-characterized model of Th1-type pulmonary response. Male Fischer 344 rats were either maintained on a drug-free diet (groups I and II), or a diet containing diethylhexylphthalate (DEHP), a compound transformed in vivo to metabolites known to activate PPARs, for 21 days (groups III and IV). Subsequently, animals were primed with Mycobacterium bovis purified protein derivative (PPD) in a Complete Freund's Adjuvant. Fifteen days later, animals in groups II and IV were challenged with Sepharose 4B beads covalently coupled with PPD, while animals in groups I and III received blank Sepharose beads. Animals with Th1 response (group II) showed a marked structural disruption in the hepatic lobule. Remarkably, these alterations were conspicuously absent in animals which received DEHP (group IV), despite noticeable accumulation of T cells in the periportal triads. Immunostaining and confocal microscopy revealed hepatic accumulation of IFNγ+ Th1 and IL-4+ Th2 cells in animals from groups II and IV, respectively. Our data suggest a PPARα-mediated suppression of the development of a Th1 immune response in the liver, resulting in hepatoprotective effect. However, potentially negative consequences of PPAR activation, such as decreased ability of the immune system to fight infection and interference with the efficacy of vaccines designed to evoke Th1 immune responses, remain to be investigated. PMID:18566640

  1. Phthalate-Induced Liver Protection against Deleterious Effects of the Th1 Response: A Potentially Serious Health Hazard.

    PubMed

    Badr, Mostafa Z; Shnyra, Alexander; Zoubine, Mikhail; Norkin, Maxim; Herndon, Betty; Quinn, Tim; Miranda, Roberto N; Cunningham, Michael L; Molteni, Agostino

    2007-01-01

    Infection with Mycobacterium tuberculosis (TB) induces pulmonary immunopathology mediated by classical Th1 type of acquired immunity with hepatic involvement in up to 80% of disseminated cases. Since PPAR agonists cause immune responses characterized by a decrease in the secretion of Th1 cytokines, we investigated the impact of activating these receptors on hepatic pathology associated with a well-characterized model of Th1-type pulmonary response. Male Fischer 344 rats were either maintained on a drug-free diet (groups I and II), or a diet containing diethylhexylphthalate (DEHP), a compound transformed in vivo to metabolites known to activate PPARs, for 21 days (groups III and IV). Subsequently, animals were primed with Mycobacterium bovis purified protein derivative (PPD) in a Complete Freund's Adjuvant. Fifteen days later, animals in groups II and IV were challenged with Sepharose 4B beads covalently coupled with PPD, while animals in groups I and III received blank Sepharose beads. Animals with Th1 response (group II) showed a marked structural disruption in the hepatic lobule. Remarkably, these alterations were conspicuously absent in animals which received DEHP (group IV), despite noticeable accumulation of T cells in the periportal triads. Immunostaining and confocal microscopy revealed hepatic accumulation of IFNgamma+ Th1 and IL-4+ Th2 cells in animals from groups II and IV, respectively. Our data suggest a PPARalpha-mediated suppression of the development of a Th1 immune response in the liver, resulting in hepatoprotective effect. However, potentially negative consequences of PPAR activation, such as decreased ability of the immune system to fight infection and interference with the efficacy of vaccines designed to evoke Th1 immune responses, remain to be investigated.

  2. Chemokines fail to up-regulate beta 1 integrin-dependent adhesion in human Th2 T lymphocytes.

    PubMed

    Clissi, B; D'Ambrosio, D; Geginat, J; Colantonio, L; Morrot, A; Freshney, N W; Downward, J; Sinigaglia, F; Pardi, R

    2000-03-15

    Th1 and Th2 cells are functionally distinct subsets of CD4+ T lymphocytes whose tissue-specific homing to sites of inflammation is regulated in part by the differential expression of P- and E-selectin ligands and selected chemokine receptors. Here we investigated the expression and function of beta 1 integrins in Th1 and Th2 cells polarized in vitro. Th1 lymphocytes adhere transiently to the extracellular matrix ligands laminin 1 and fibronectin in response to chemokines such as RANTES and stromal cell-derived factor-1, and this process is paralleled by the activation of the Rac1 GTPase and by a rapid burst of actin polymerization. Selective inhibitors of phosphoinositide-3 kinase prevent efficiently all of the above processes, whereas the protein kinase C inhibitor bisindolylmaleimide prevents chemokine-induced adhesion without affecting Rac1 activation and actin polymerization. Notably, chemokine-induced adhesion to beta 1 integrin ligands is markedly reduced in Th2 cells. Such a defect cannot be explained by a reduced sensitivity to chemokine stimulation in this T cell subset, nor by a defective activation of the signaling cascade involving phosphoinositide-3 kinase, Rac1, and actin turnover, as all these processes are activated at comparable levels by chemokines in the two subsets. We propose that reduced beta 1 integrin-mediated adhesion in Th2 cells may restrain their ability to invade and/or reside in sites of chronic inflammation, which are characterized by thickening of basement membranes and extensive fibrosis, requiring efficient interaction with organized extracellular matrices.

  3. Renovation activities during pregnancy induce a Th2 shift in fetal but not in maternal immune system.

    PubMed

    Herberth, Gunda; Herzog, Thomas; Hinz, Denise; Röder, Stefan; Schilde, Maik; Sack, Ulrich; Diez, Ulrike; Borte, Michael; Lehmann, Irina

    2013-06-01

    The aim of the present study was to investigate to which extent environmental influences like indoor renovation activities affect the immune system of mother and child during the gestation period. Within the LINA (Lifestyle and Environmental Factors and their Influence on Newborn Allergy risk) birth cohort study blood samples of mothers during pregnancy and cord blood samples were analyzed for concentrations of the Th1/Th2 cytokines IL-4, IL-5, IL-13, IFN-γ and IgE. Data on indoor renovation activities (painting, flooring and new furniture) were assessed with questionnaires. Data on cytokine blood concentrations and exposure variables were available for 422 mother/child pairs. Neonates, who were strongly affected by renovation activities (especially floor covering and new furniture) during pregnancy, had significantly higher concentrations of IL-4 and IL-5 in cord blood. Among the single activities, new furniture, particularly flake board, were associated with increased IL-4 levels. Elevated IL-4 levels were also observed in the cord blood of children whose mothers reported wall-to-wall carpeting. Among flooring, polyvinylchloride (PVC) showed the strongest effect with increased IL-5 concentrations. The Th1/Th2 imbalance towards Th2 at birth was related to allergic sensitization in children at the age of one. There were only few and negative associations between renovation activities and Th1/Th2 cytokine concentration in maternal blood. Our study shows that under similar exposure situations the fetal immune system is more susceptible to the influence of environmental factors, in particular renovation products (flake board, wall-to-wall carpets and PVC) compared to the maternal.

  4. Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally Administered Bacterial Extract

    PubMed Central

    Bowman, L. M.; Holt, P. G.

    2001-01-01

    Infant rats primed during the first week of life with soluble antigen displayed adult-equivalent levels of T-helper 2 (Th2)-dependent immunological memory development as revealed by production of secondary immunoglobulin G1 (IgG1) antibody responses to subsequent challenge, but in contrast to adults failed to prime for Th1-dependent IgG2b responses. We demonstrate that this Th2 bias in immune function can be redressed by oral administration to neonates of a bacterial extract (Broncho-Vaxom OM-85) comprising lyophilized fractions of several common respiratory tract bacterial pathogens. Animals given OM-85 displayed a selective upregulation in primary and secondary IgG2b responses, accompanied by increased gamma interferon and decreased interleukin-4 production (both antigen specific and polyclonal), and increased capacity for development of Th1-dependent delayed hypersensitivity to the challenge antigen. We hypothesize that the bacterial extract functions via enhancement of the process of postnatal maturation of Th1 function, which is normally driven by stimuli from the gastrointestinal commensal microflora. PMID:11349036

  5. Enhanced Th1 and Th17 responses in peripheral blood in active non-segmental vitiligo.

    PubMed

    Zhen, Yu; Yao, Lei; Zhong, Shuxia; Song, Yang; Cui, Yan; Li, Shanshan

    2016-12-01

    Accumulating studies have indicated that vitiligo, especially non-segmental vitiligo (NSV), is one kind of autoimmune diseases and CD4(+) T cells play important roles in the pathogenesis. However, there have been very limited data on the detailed changes of each of the CD4(+) T cell subsets in periphery in active NSV. To clarify this issue, we collected the peripheral blood mononuclear cells (PBMCs) from 30 patients with active NSV and 30 age- and sex-matched healthy controls. The percentages of circulating Th1, Th2, Th17 and Tregs were evaluated using flow cytometry and the expressions of their specific transcription factors T-bet, GATA3, RORγt and FOXP3 at mRNA level and protein levels were qualified by qPCR and flow cytometry, respectively. Meanwhile, the expression levels of IFN-γ, IL-4, TGF-β, and IL-17A in serum were measured. We found that in patients with NSV, the percentages and absolute numbers of circulating Th1 and Th17 were both significantly higher than those of healthy controls, while the percentages of Th2 and Tregs and absolute numbers showed no significant difference compared to healthy controls. Moreover, the ratios of Th1/Tregs and Th17/Tregs in circulation were both statistically elevated in active NSV. Similar results were got in qualification of their corresponding transcription factors at mRNA level and protein levels. Compared with healthy controls, the expression level of IL-17A was significantly increased in serum of patients with NSV, while the productions of IFN-γ, IL-4, TGF-β had no significant change. These data suggested that in circulating CD4(+) T cell subsets, Th1 and Th17 played the major role in cellular immunity in the progression of vitiligo. The immune lever in circulation was inclined to effector CD4(+) T cells not suppressor CD4(+) T cells that may result in the loss of self-tolerance to melanocytes.

  6. Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals

    PubMed Central

    Ly, Judy; Lagman, Minette; Saing, Tommy; Singh, Manpreet Kaur; Tudela, Enrique Vera; Morris, Devin; Anderson, Jessica; Daliva, John; Ochoa, Cesar; Patel, Nishita; Pearce, Daniel

    2015-01-01

    Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4+ T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response

  7. Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis Infection in HIV-Infected Individuals.

    PubMed

    Ly, Judy; Lagman, Minette; Saing, Tommy; Singh, Manpreet Kaur; Tudela, Enrique Vera; Morris, Devin; Anderson, Jessica; Daliva, John; Ochoa, Cesar; Patel, Nishita; Pearce, Daniel; Venketaraman, Vishwanath

    2015-11-01

    Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response

  8. TET1 and TET3 are essential in induction of Th2-type immunity partly through regulation of IL-4/13A expression in zebrafish model.

    PubMed

    Yang, Chao; Li, Zhuo; Kang, Wei; Tian, Yu; Yan, Yuzhu; Chen, Wei

    2016-10-10

    It has been considered that epigenetic modulation can affect a diverse array of cellular activities, in which ten eleven translocation (TET) methylcytosine dioxygenase family members refer to a group of fundamental components involved in catalyzation of 5-hydroxymethylcytosine and modification of gene expression. Even though the function of TET proteins has been gradually revealed, their roles in immune regulation are still largely unknown. Recent studies provided clues that TET2 could regulate several innate immune-related inflammatory mediators in mammals. This study sought to explore the function of TET family members in potential T-helper (Th) cell differentiation involved in adaptive immunity by utilizing a zebrafish model. As shown by results, soluble antigens could induce expression of zebrafish IL-4/13A (i.e. a pivotal Th2-type cytokine essential in Th2 cell differentiation and functions), and further trigger the expression of Th1- and Th2-related genes. It is noteworthy that this response was accompanied by the up-regulation of two TET family members (TET1 and TET3) both in immune organs (spleen and kidney) and cells (peripheral lymphocytes). Knocking-down of TET1 and TET3 will give rise to the decreased responses of IL-4/13A induction against exogenous soluble antigen stimulation, and further restrain the expression of Th2-related genes, which indicates a restrained Th2 cell differentiation. Nonetheless, TET2 did not exhibit effect on the modification of Th1/Th2 related gene expression. Hence, these data showed that TET1 and TET3 might be two significant epigenetic regulators involved in Th2 differentiation through regulation of IL-4/13A expression. This is the first report to show that TET family members play indispensable roles in Th2-type immunity, indicating an epigenetic modulation manner involved in adaptive immune regulations and responses.

  9. A nematode immunomodulator suppresses grass pollen-specific allergic responses by controlling excessive Th2 inflammation.

    PubMed

    Daniłowicz-Luebert, Emilia; Steinfelder, Svenja; Kühl, Anja A; Drozdenko, Gennadiy; Lucius, Richard; Worm, Margitta; Hamelmann, Eckard; Hartmann, Susanne

    2013-03-01

    Helminth parasites modulate the immune system by complex mechanisms to ensure persistence in the host. Released immunomodulatory parasite components lead to a beneficial environment for the parasite by targeting different host cells and in parallel to a modulation of unrelated inflammatory responses in the host, such as allergy. The aim of this study was to investigate the effect of the potent helminth immunomodulator, filarial cystatin, in a murine model of airway inflammation and hyperreactivity induced by a clinically relevant aeroallergen (timothy grass (Phleum pratense) pollen) and on the function of peripheral blood mononuclear cells (PBMCs) from timothy grass pollen allergic patients. BALB/c mice were systemically sensitised with a recombinant major allergen of timothy grass pollen (rPhl p 5b) and then challenged with timothy grass pollen extract (GPE) via the airways. Filarial cystatin was applied i.p. during the sensitisation phase. Airway hyperresponsiveness to methacholine challenges, inflammation of airways, inflammatory cell recruitment, cytokine production and lung histopathology were investigated. In a translational approach, PBMCs from allergic subjects and healthy controls were treated in vitro with cystatin prior to stimulation with GPE. Administration of filarial cystatin suppressed rPhl p 5b-induced allergen-specific Th2-responses and airway inflammation, inhibited local recruitment of eosinophils, reduced levels of allergen-specific IgE and down-regulated IL-5 and IL-13 in the bronchoalveolar lavage (BAL). Ex vivo restimulation with cystatin of spleen cells from cystatin-treated mice induced the production of IL-10, while cystatin inhibited allergen-specific IL-5 and IL-13 levels. Human PBMCs from timothy grass pollen allergic patients displayed a shift towards a Th1 response after treatment with cystatin. These results show that filarial cystatin ameliorates allergic inflammation and disease in a clinically relevant model of allergy. This data

  10. Th2 cells are essential for modulation of vascular repair by allogeneic endothelial cells

    PubMed Central

    Methe, Heiko; Nanasato, Mamoru; Spognardi, Anna-Maria; Groothuis, Adam; Edelman, Elazer R.

    2009-01-01

    Background Endothelial cells (EC) embedded within three-dimensional matrices (MEEC) when placed in the vascular adventitia control lumenal inflammation and intimal hyperplasia. Matrix-embedding alters endothelial immunogenicity in vitro. T helper (Th) driven host immunity is a major impediment for of allogeneic grafts. We therefore aimed to identify if modulation of T helper balance would affect immune compatibility and endothelial regulation of vascular repair in vivo. Methods Pigs (n=4/group) underwent balloon injury of both carotid arteries and were left alone (group 1) or received perivascular implants of porcine MEEC (group 2), a 12 days course of cyclosporine A (CsA) (group 3), or a combination of MEEC and CsA (group 4). Host immune reactivity (EC-specific antibodies, activation of splenocytes) was analyzed after 28 and 90 days in 2 pigs/group respectively. Results MEEC treatment alone induced formation of EC-specific IgG1-antibodies (41±6 mean fluorescence intensity (MFI)) and differentiation of host splenocytes into Th2, but not Th1, cytokine-producing cells (IL-4: 242±102, IL-10: 273±114 number of spots). Concomitant CsA-therapy reduced the frequency of IgG1-antibodies (25±2 MFI; p<0.02) and Th2-cytokine producing splenocytes upon MEEC treatment (IL-4: 157±19, IL-10: 124±26 number of spots; p< 0.05). MEEC significantly inhibited luminal occlusion 28 and 90 days after balloon injury compared to untreated controls (12±7 vs. 68±14%; p<0.001) but to a lesser extent in the face of immunomodulation with concomitant CsA-treatment (34±13%; p<0.02 vs. group 2). Conclusions MEEC do not induce a significant Th1-driven immune response expected from alloimplants, but do enhance differentiation of splenocytes into Th2-cytokine producing cells. Reduction in this Th2 response reduces the vasoregulatory effects of allogeneic EC after injury. PMID:20036161

  11. Induction of interferon-gamma (IFN-gamma) and T helper 1 (Th1) immune response by bitter gourd extract.

    PubMed

    Ike, Kazunori; Uchida, Yuko; Nakamura, Tomohiko; Imai, Soichi

    2005-05-01

    Mice were inoculated intraperitoneally wih 34 different types of vegetable juices, and interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured as markers for the induction of Th1 and Th2 cells, respectively. Serum IFN-gamma level was markedly increased in mice inoculated with bitter gourd (Momordica charantia) juice, but IL-4 levels were not increased with any of the 34 vegetable juices. Testing of the various components of bitter gourd, including peel, pulp, and seed, showed that the pulp induced the highest levels of IFN-gamma. Trial immunogen including the heat extract of the pulp induced specific IgG(2a) antibody of the mice serum inoculated with this immunogen. These results demonstrate that bitter gourd pulp induced IFN-gamma production and show its promise as a means of effective immunostimulatory therapy specific for Th1 cells and IFN-gamma production.

  12. A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

    PubMed Central

    Cho, Hyoung-Soo; Shin, Hyun Mu; Haberstock-Debic, Helena; Xing, Yan; Owens, Timothy D.; Funk, Jens Oliver; Hill, Ronald J.; Bradshaw, J. Michael

    2015-01-01

    In T cells, the Tec kinases IL-2–inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk−/− and Itk−/−Rlk−/− mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4+ T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases. PMID:26466958

  13. Tolerance to staphylococcal enterotoxin B initiated Th1 cell differentiation in mice infected with Candida albicans.

    PubMed Central

    Romani, L; Puccetti, P; Mencacci, A; Spaccapelo, R; Cenci, E; Tonnetti, L; Bistoni, F

    1994-01-01

    Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that specifically activates T cells bearing V beta 8 T-cell receptor domains, which eventually leads to a long-lasting state of clonal anergy accompanied by selective cell death in the targeted CD4+ subset. Because the superantigen is known to promote Th1 cell differentiation in vitro, we have investigated the effect of SEB treatment on the course of Th2-associated progressive disease in mice infected systemically with Candida albicans. On the basis of the kinetics of SEB-induced changes in CD4+ cells and production in sera of interleukin 4 (IL-4), IL-10, and gamma interferon, we obtained evidence that V beta 8+ cell anergy concomitant with infection abolished the early IL-4/IL-10 response of the host to the yeast, ultimately leading to a state of resistance characterized by gamma interferon secretion in vitro by antigen-specific CD4+ cells. In contrast, SEB administered near the time of challenge resulted in accelerated mortality. Significant resistance to infection was also afforded by exposure of mice to a retrovirally encoded endogenous superantigen. These data suggest that CD4+ V beta 8+ T cells play an important role in vivo in the initiation of a Th2 response to C. albicans and that suppression of their activity may alter the qualitative development of the T-cell response and the outcome of infection. PMID:7914883

  14. Sublingual immunotherapy mechanisms of action: the role of Th1 response.

    PubMed

    Ciprandi, G; Tosca, M A; Marseglia, G L

    2009-01-01

    Specific immunotherapy (SIT) is the only treatment able to modify the natural history of allergic subjects. Several aspects of the immunopathological response modified by sublingual immunotherapy (SLIT), which is an alternative route of administration for SIT, have been investigated. A shift from Th2-polarized immune response toward Th1-oriented pattern has been reported after SLIT. More recently, a crucial role for a subpopulation of T cells has been evidenced: T regulatory cells (Treg). Allergic patients have a defect of Tregs, and SLIT should be able to induce a specific Treg response. This issue is very relevant as the Treg-dependent cytokines, namely IL-10 and TGF-beta, are involved in the regulation of IgG and IgA antibodies production. Recent evidence shows that SLIT is also able of inducing a Treg response as detected by IL-10 production. IFNgamma is a typical Th1-dependent cytokine. SLIT may induce a significantly increased production of this cytokine and it may be considered as an early marker of SLIT response. Therefore, also SLIT is able of exerting the effects on immune response as well as the subcutaneous route.

  15. IFNbeta-1a treatment and reestablishment of Th1 regulation in MS patients: dose effects.

    PubMed

    Pellegrini, Patrizia; Totaro, Rocco; Contasta, Ida; Berghella, Anna Maria; Russo, Tomassina; Carolei, Antonio; Adorno, Domenico

    2004-01-01

    The authors evaluated the relationships between clinical and pharmacologic parameters and the Th1/Th2/Th3 cytokine network in patients with relapsing-remitting multiple sclerosis treated with differing doses of interferon-beta1a (IFN-beta1a). Their results show that low doses are ineffective but that high doses restore Th1 regulation of the maturation and activation of monocytes, T cells, immature dendritic cells, dendritic cells, and T regulatory cells for central and peripheral self-tolerance. Interaction between interleukin (IL)-10, IL-12 p70, and IL-6 production appears to play an important role in the control of the maturation and activation states of dendritic cells and T regulatory cells, and is at the basis of the benefit of high doses. The results also indicate that the physiologic mechanisms involved in aging help immunologic reestablishment in IFNbeta-1a-treated patients. Finally, it would appear that the failure of IFNbeta-1a therapy to resolve multiple sclerosis completely is due to the suppression of IL-12 p70 mechanisms (responsible for the physiologic deletion of self-reactive cells) in activation conditions, probably by IFNbeta-1a itself.

  16. Identification of a variant-specific phosphorylation of TH2A during spermiogenesis

    PubMed Central

    Hada, Masashi; Masuda, Koji; Yamaguchi, Kosuke; Shirahige, Katsuhiko; Okada, Yuki

    2017-01-01

    Tissue-specific histone variant incorporation into chromatin plays dynamic and important roles in tissue development. Testis is one such tissue, and a number of testis-specific histone variants are expressed that have unique roles. While it is expected that such variants acquire post-transcriptional modifications to be functional, identification of variant-specific histone modifications is challenging because of the high similarity of amino acid sequences between canonical and variant versions. Here we identified a novel phosphorylation on TH2A, a germ cell-specific histone H2A variant. TH2A-Thr127 is unique to the variant and phosphorylated concomitant with chromatin condensation including spermiogenesis and early embryonic mitosis. In sperm chromatin, phosphorylated TH2A-Thr127 (=pTH2A) is co-localized with H3.3 at transcriptional starting sites of the genome, and subsequently becomes absent from the paternal genome upon fertilization. Notably, pTH2A is recurrent and accumulated in the pericentromeric heterochromatin of both paternal and maternal chromosomes in the first mitosis of embryos, suggesting its unique regulation during spermiogenesis and early embryogenesis. PMID:28387373

  17. PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

    PubMed Central

    Stempin, Cinthia C.; Motrán, Claudia C.; Aoki, María P.; Falcón, Cristian R.

    2016-01-01

    Macrophage plasticity is critical for controlling inflammation including those produced by helminth infections, where alternatively activated macrophages (AAM) are accumulated in tissues. AAM expressing the co-inhibitory molecule programmed death ligand 2 (PD-L2), which is capable of binding programmed death 1 (PD-1) expressed on activated T cells, have been demonstrated in different parasitic infections. However, the role of PD-L2 during F. hepatica infection has not yet been explored. We observed that F. hepatica infection or a F. hepatica total extract (TE) injection increased the expression of PD-L2 on peritoneal macrophages. In addition, the absence of PD-L2 expression correlated with an increase in susceptibility to F. hepatica infection, as evidenced by the shorter survival and increased liver damage observed in PD-L2 deficient (KO) mice. We assessed the contribution of the PD-L2 pathway to Th2 polarization during this infection, and found that the absence of PD-L2 caused a diminished Th2 type cytokine production by TE stimulated splenocytes from PD-L2 KO infected compared with WT mice. Besides, splenocytes and intrahepatic leukocytes from infected PD-L2 KO mice showed higher levels of IFN-γ than those from WT mice. Arginase expression and activity and IL-10 production were reduced in macrophages from PD-L2 KO mice compared to those from WT mice, revealing a strong correlation between PD-L2 expression and AAM polarization. Taken together, our data indicate that PD-L2 expression in macrophages is critical for AAM induction and the maintenance of an optimal balance between the Th1- and Th2-type immune responses to assure host survival during F. hepatica infection. PMID:27783986

  18. An aza-anthrapyrazole negatively regulates Th1 activity and suppresses experimental autoimmune encephalomyelitis.

    PubMed

    Clark, Matthew P; Leaman, Douglas W; Hazelhurst, Lori A; Hwang, Eun S; Quinn, Anthony

    2016-02-01

    Previously we showed that BBR3378, a novel analog of the anticancer drug mitoxantrone, had the ability to ameliorate ascending paralysis in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis, without the drug-induced cardiotoxicity or lymphopenia associated with mitoxantrone therapy. Chemotherapeutic drugs like mitoxantrone, a topoisomerase inhibitor, are thought to provide protection in inflammatory autoimmune diseases like EAE by inducing apoptosis in rapidly proliferating autoreactive lymphocytes. Here, we show that while BR3378 blocked cell division, T cells were still able to respond to antigenic stimulation and upregulate surface molecules indicative of activation. However, in contrast to mitoxantrone, BBR3378 inhibited the production of the proinflammatory cytokine IFN-γ both in recently activated T cell blasts and established Th1 effectors, while sparing the activities of IL-13-producing Th2 cells. IFN-γ is known to be regulated by the transcription factor T-bet. In addition to IFN-γ, in vitro and in vivo exposure to BBR3378 suppressed the expression of other T-bet regulated proteins, including CXCR3 and IL-2Rβ. Microarray analysis revealed BBR3378-induced suppression of additional T-bet regulated genes, suggesting that the drug might disrupt global Th1 programming. Importantly, BBR3378 antagonized ongoing Th1 autoimmune responses in vivo, modulated clinical disease and CNS inflammation in acute and relapsing forms of EAE. Therefore, BBR3378 may be a unique inhibitor of T-bet regulated genes and may have potential as a therapeutic intervention in human autoimmune disease.

  19. MyD88 deficiency leads to decreased NK cell gamma interferon production and T cell recruitment during Chlamydia muridarum genital tract infection, but a predominant Th1 response and enhanced monocytic inflammation are associated with infection resolution.

    PubMed

    Nagarajan, Uma M; Sikes, James; Prantner, Daniel; Andrews, Charles W; Frazer, Lauren; Goodwin, Anna; Snowden, Jessica N; Darville, Toni

    2011-01-01

    We have previously shown that MyD88 knockout (KO) mice exhibit delayed clearance of Chlamydia muridarum genital infection compared to wild-type (WT) mice. A blunted Th1 response and ineffective suppression of the Th2 response were also observed in MyD88 KO mice. The goal of the present study was to investigate specific mechanisms whereby absence of MyD88 leads to these effects and address the compensatory mechanisms in the genital tract that ultimately clear infection in the absence of MyD88. It was observed that NK cells recruited to the genital tract in MyD88 KO mice failed to produce gamma interferon (IFN-γ) mRNA and protein. This defect was associated with decreased local production of interleukin-17 (IL-17), IL-18, and tumor necrosis factor alpha (TNF-α) but normal levels of IL-12p70. Additionally, recruitment of CD4 T cells to the genital tract was reduced in MyD88 KO mice compared to that in WT mice. Although chronic infection in MyD88 KO mice resulted in oviduct pathology comparable to that of WT mice, increased histiocytic inflammation was observed in the uterine horns. This was associated with increased CCL2 levels and recruitment of macrophages as a potential compensatory mechanism. Further deletion of TLR4-TRIF signaling in MyD88 KO mice, using TLR4/MyD88 double-KO mice, did not further compromise host defense against chlamydiae, suggesting that compensatory mechanisms are Toll-like receptor (TLR) independent. Despite some polarization toward a Th2 response, a Th1 response remained predominant in the absence of MyD88, and it provided equivalent protection against a secondary infection as observed in WT mice.

  20. IL-4 suppresses Very Late Antigen-4 expression which is required for therapeutic Th1 T cell trafficking into tumors12

    PubMed Central

    Sasaki, Kotaro; Pardee, Angela D.; Qu, Yanyan; Zhao, Xi; Ueda, Ryo; Kohanbash, Gary; Bailey, Lisa M.; Okada, Hideho; Muthuswamy, Ravikumar; Kalinski, Pawel; Basse, Per H.; Falo, Louis D.; Storkus, Walter J.

    2009-01-01

    Murine CD4+ T cells cultured under Type-1 polarizing conditions selectively express significantly higher levels of the VLA-4 and VLA-6 integrins when compared to T cells cultured under Type-2 or non-polarizing (Type-0) conditions. This difference appears due to the action of IL-4, since loss of VLA-4/-6 expression on Th cells was prevented by inclusion of neutralizing anti-IL-4 mAb during the initial culture period. We also observed that CD4+ T cells deficient in Stat6, a critical component of the IL-4R signaling cascade, retained high levels of VLA-4 and VLA-6 expression, regardless IL-4 status in culture conditions. When applied to committed Th1 cells, rIL-4 readily inhibited VLA-4 and VLA-6 expression to levels observed for Th2 cells, without altering the Type-1 functional status of these cells. Conversely, low levels of VLA-4/-6 expressed by committed Th2 cells could not be resurrected by culture in the presence of the Th1-kines IL-12p70 and IFN-γ. Predictably, among the Th populations evaluated, Th1 cells alone adhered efficiently to, and were co-stimulated by, plate-bound VCAM-1 and laminin in a VLA-4- or VLA-6-dependent manner, respectively. Finally, adoptive-transferred Th1 (but not Th2) cells developed from OT-II mice were uniquely competent to traffick into OVA+ M05 melanoma lesions in vivo, thereby enhancing the therapeutic benefits associated with co-transferred OVA-specific Tc1 (OT-I) cells. These data suggest that treatment strategies capable of sustaining/enhancing VLA-4/-6 expression on Th1 effector cells may yield improved clinical efficacy in the cancer setting. PMID:19752754

  1. IL-4 suppresses very late antigen-4 expression which is required for therapeutic Th1 T-cell trafficking into tumors.

    PubMed

    Sasaki, Kotaro; Pardee, Angela D; Qu, Yanyan; Zhao, Xi; Ueda, Ryo; Kohanbash, Gary; Bailey, Lisa M; Okada, Hideho; Muthuswamy, Ravikumar; Kalinski, Pawel; Basse, Per H; Falo, Louis D; Storkus, Walter J

    2009-10-01

    Murine CD4 T cells cultured under type 1 polarizing conditions selectively express significantly higher levels of the very late antigen (VLA)-4 and VLA-6 integrins when compared with T cells cultured under type 2 or nonpolarizing (type 0) conditions. This difference appears due to the action of interleukin (IL)-4, as loss of VLA-4/-6 expression on Th cells was prevented by inclusion of neutralizing anti-IL-4 mAb during the initial culture period. We also observed that CD4 T cells deficient in Stat6, a critical component of the IL-4R signaling cascade, retained high levels of VLA-4 and VLA-6 expression, regardless of IL-4 status in the culture conditions. When applied to committed Th1 cells, rIL-4 readily inhibited VLA-4 and VLA-6 expression to levels observed for Th2 cells, without altering the type 1 functional status of these cells. Conversely, low levels of VLA-4/VLA-6 expressed by committed Th2 cells could not be resurrected by culture in the presence of the Th1-kines IL-12p70 and interferon-gamma. Predictably, among the Th populations evaluated, Th1 cells alone adhered efficiently to, and were costimulated by, plate-bound VCAM-1 and laminin in a VLA-4-dependent or VLA-6-dependent manner, respectively. Finally, adoptive-transferred Th1 (but not Th2) cells developed from OT-II mice were uniquely competent to traffick into OVA M05 melanoma lesions in vivo, thereby enhancing the therapeutic benefits associated with cotransferred OVA-specific type 1 CD8 (OT-I) cells. These data suggest that treatment strategies capable of sustaining/enhancing VLA-4/VLA-6 expression on Th1 effector cells may yield improved clinical efficacy in the cancer setting.

  2. Prenatal secondhand cigarette smoke promotes Th2 polarization and impairs goblet cell differentiation and airway mucus formation.

    PubMed

    Singh, Shashi P; Gundavarapu, Sravanthi; Peña-Philippides, Juan C; Rir-Sima-ah, Jules; Mishra, Neerad C; Wilder, Julie A; Langley, Raymond J; Smith, Kevin R; Sopori, Mohan L

    2011-11-01

    Parental, particularly maternal, smoking increases the risk for childhood allergic asthma and infection. Similarly, in a murine allergic asthma model, prenatal plus early postnatal exposure to secondhand cigarette smoke (SS) exacerbates airways hyperreactivity and Th2 responses in the lung. However, the mechanism and contribution of prenatal versus early postnatal SS exposure on allergic asthma remain unresolved. To identify the effects of prenatal and/or early postnatal SS on allergic asthma, BALB/c dams and their offspring were exposed gestationally and/or 8-10 wk postbirth to filtered air or SS. Prenatal, but not postnatal, SS strongly increased methacholine and allergen (Aspergillus)-induced airway resistance, Th2 cytokine levels, and atopy and activated the Th2-polarizing pathway GATA3/Lck/ERK1/2/STAT6. Either prenatal and/or early postnatal SS downregulated the Th1-specific transcription factor T-bet and, surprisingly, despite high levels of IL-4/IL-13, dramatically blocked the allergen-induced mucous cell metaplasia, airway mucus formation, and the expression of mucus-related genes/proteins: Muc5ac, γ-aminobutyric acid A receptors, and SAM pointed domain-containing Ets-like factor. Given that SS/nicotine exposure of normal adult mice promotes mucus formation, the results suggested that fetal and neonatal lung are highly sensitive to cigarette smoke. Thus, although the gestational SS promotes Th2 polarization/allergic asthma, it may also impair and/or delay the development of fetal and neonatal lung, affecting mucociliary clearance and Th1 responses. Together, this may explain the increased susceptibility of children from smoking parents to allergic asthma and childhood respiratory infections.

  3. CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN.

    PubMed

    Paust, Hans-Joachim; Riedel, Jan-Hendrik; Krebs, Christian F; Turner, Jan-Eric; Brix, Silke R; Krohn, Sonja; Velden, Joachim; Wiech, Thorsten; Kaffke, Anna; Peters, Anett; Bennstein, Sabrina B; Kapffer, Sonja; Meyer-Schwesinger, Catherine; Wegscheid, Claudia; Tiegs, Gisa; Thaiss, Friedrich; Mittrücker, Hans-Willi; Steinmetz, Oliver M; Stahl, Rolf A K; Panzer, Ulf

    2016-07-01

    Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the TH1-associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA-associated crescentic GN and colocalize with CXCR3(+) effector T cells. To investigate the functional role of CXCR3(+) Tregs, we generated mice that lack CXCR3 in Tregs specifically (Foxp3(eGFP-Cre) × Cxcr3(fl/fl)) and induced experimental crescentic GN. Treg-specific deletion of CXCR3 resulted in reduced Treg recruitment to the kidney and an overwhelming TH1 immune response, with an aggravated course of the nephritis that was reversible on anti-IFNγ treatment. Together, these findings show that a subset of Tregs expresses CXCR3 and thereby, acquires trafficking properties of pathogenic CXCR3(+) TH1 cells, allowing Treg localization and control of excessive TH1 responses at sites of inflammation.

  4. Th2 and eosinophil responses suppress inflammatory arthritis

    PubMed Central

    Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Voehringer, David; Schett, Georg; Bozec, Aline

    2016-01-01

    Th2–eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2–eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis. PMID:27273006

  5. Innate immunological function of TH2 cells in vivo.

    PubMed

    Guo, Liying; Huang, Yuefeng; Chen, Xi; Hu-Li, Jane; Urban, Joseph F; Paul, William E

    2015-10-01

    Type 2 helper T cells (TH2 cells) produce interleukin 13 (IL-13) when stimulated by papain or house dust mite extract (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2 cells) are the dominant innate producers of IL-13 in naive mice, we found here that helminth-infected mice had more TH2 cells compared to uninfected mice, and thes e cells became major mediators of innate type 2 responses. TH2 cells made important contributions to HDM-induced antigen-nonspecific eosinophilic inflammation and protected mice recovering from infection with Ascaris suum against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role for effector TH2 cells during TCR-independent innate-like immune responses.

  6. Dendritic Cells Promoted by Ginseng Saponins Drive a Potent Th1 Polarization

    PubMed Central

    Takei, Masao; Tachikawa, Eiichi; Umeyama, Akemi

    2008-01-01

    Dendritic cells (DC) play a pivotal role in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. The interaction of T cells with DC is crucial for directing T cell differentiation towards the Th1, Th2 or Th17 type, and several factors determining the direction of the T cell polarization. IL-12 plays a central role in the immune system, not only by augmenting the cytotoxic activity of T cells and NK cells and regulating IFN-γ production, but also by the capacity of IL-12 to promote the development of Th1 cells. Therefore, it is important to identify factors that might affect the differentiation, maturation and function of DC. Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Moreover, T-cadinol and calamenene are sesquterpenes isolated from the heartwood of Cryptomeria japonica being pharmacologically active substances. We investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, as well as T-cadinol and calamenene can drive DC maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days in the presence of M1, M4, T-cadinol or calamenene. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on M1-primed DC, M4-primed DC, T-cadinol-primed DC and calamenene-primed DC were enhanced with a concomitant decrease in endocytic activity. M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC enhanced the T cell stimulatory capacity in an allo MLR (allogeneic mixed lymphocyte reaction). Naïve T cells co-cultured with allogeneic M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC turned into typical Th1 cells, which produced large quantities of IFN-γ and released small amounts of IL-4 depending on IL-12 secretion. In the CTL assay

  7. Transcriptome signature for dampened Th2 dominance in acellular pertussis vaccine-induced CD4+ T cell responses through TLR4 ligation

    PubMed Central

    Brummelman, Jolanda; Raeven, René H. M.; Helm, Kina; Pennings, Jeroen L. A.; Metz, Bernard; van Eden, Willem; van Els, Cécile A. C. M.; Han, Wanda G. H.

    2016-01-01

    Current acellular pertussis (aP) vaccines promote a T helper 2 (Th2)-dominated response, while Th1/Th17 cells are protective. As our previous study showed, after adding a non-toxic TLR4 ligand, LpxL1, to the aP vaccine in mice, the Bordetella pertussis-specific Th2 response is decreased and Th1/Th17 responses are increased as measured at the cytokine protein level. However, how this shift in Th response by LpxL1 addition is regulated at the gene expression level remains unclear. Transcriptomics analysis was performed on purified CD4+ T cells of control and vaccinated mice after in vitro restimulation with aP vaccine antigens. Multiple key factors in Th differentiation, including transcription factors, cytokines, and receptors, were identified within the differentially expressed genes. Upregulation of Th2- and downregulation of follicular helper T cell-associated genes were found in the CD4+ T cells of both aP- and aP+LpxL1-vaccinated mice. Genes exclusively upregulated in CD4+ T cells of aP+LpxL1-vaccinated mice included Th1 and Th17 signature cytokine genes Ifng and Il17a respectively. Overall, our study indicates that after addition of LpxL1 to the aP vaccine the Th2 component is not downregulated at the gene expression level. Rather an increase in expression of Th1- and Th17-associated genes caused the shift in Th subset outcome. PMID:27118638

  8. Submicroscopic infection of placenta by Plasmodium produces Th1/Th2 cytokine imbalance, inflammation and hypoxia in women from north-west Colombia

    PubMed Central

    2014-01-01

    Background A large-scale study was set up in order to study the epidemiology, clinical aspects, and immunopathology of gestational and placental malaria in north-west Colombia. In this region, recent reports using a qPCR technique, confirmed frequencies of infection, by Plasmodium falciparum or Plasmodium vivax, up to 45%. Given the high rates of infection observed both in mother and placenta, a first exploratory study was proposed in order to characterize the effect on the inflammation status, tissue damage and hypoxia in Plasmodium spp. infected placentas. Methods A descriptive, prospective, cross-sectional design was applied to pregnant women with (PM+) and without (PM-) placental malaria. Messenger RNA expression of Fas, FasL; COX-1, COX-2, HIF, VEGF, and the cytokines IL-2, IL-4, IL-10, IFN-γ and TNF, were measured in peripheral and placental blood using a quantitative PCR. The percentage of apoptotic cells was determined with a TUNEL assay. Results In total 50 placentas were studied: 25 were positive for submicroscopic infection and 25 were negative for Plasmodium infection. Expression of IL-4 and IL-10 was observed high in placental tissue of PM+, while IL-2 was high in peripheral blood of the same group. Expression of TNF and IFNγ in peripheral blood of the PM + group was high. Similarly, the apoptotic index and Fas expression were significantly high in PM+. However, FasL expression was observed low in PM + compared to PM-. Inflammation markers (HIF, VEGF) and hypoxia markers (COX-1, COX-2) were high in the PM + group. Conclusion During placental malaria expression of some pro-inflammatory cytokines is up-regulated and markers of hypoxia and tissue damage are increased in cases of submicroscopic infection. PMID:24673747

  9. Effect of nutrient deficiencies on in vitro Th1 and Th2 cytokine response of peripheral blood mononuclear cells to Plasmodium falciparum infection

    PubMed Central

    2010-01-01

    Background An appropriate balance between pro-inflammatory and anti-inflammatory cytokines that mediate innate and adaptive immune responses is required for effective protection against human malaria and to avoid immunopathology. In malaria endemic countries, this immunological balance may be influenced by micronutrient deficiencies. Methods Peripheral blood mononuclear cells from Tanzanian preschool children were stimulated in vitro with Plasmodium falciparum-parasitized red blood cells to determine T-cell responses to malaria under different conditions of nutrient deficiencies and malaria status. Results The data obtained indicate that zinc deficiency is associated with an increase in TNF response by 37%; 95% CI: 14% to 118% and IFN-γ response by 74%; 95% CI: 24% to 297%. Magnesium deficiency, on the other hand, was associated with an increase in production of IL-13 by 80%; 95% CI: 31% to 371% and a reduction in IFN-γ production. These results reflect a shift in cytokine profile to a more type I cytokine profile and cell-cell mediated responses in zinc deficiency and a type II response in magnesium deficiency. The data also reveal a non-specific decrease in cytokine production in children due to iron deficiency anaemia that is largely associated with malaria infection status. Conclusions The pathological sequels of malaria potentially depend more on the balance between type I and type II cytokine responses than on absolute suppression of these cytokines and this balance may be influenced by a combination of micronutrient deficiencies and malaria status. PMID:20546583

  10. Topical azithromycin and clarithromycin inhibit acute and chronic skin inflammation in sensitized mice, with apparent selectivity for Th2-mediated processes in delayed-type hypersensitivity.

    PubMed

    Ivetić Tkalčević, Vanesa; Cužić, Snježana; Kramarić, Miroslava Dominis; Parnham, Michael J; Eraković Haber, Vesna

    2012-02-01

    Macrolide antibiotics inhibit the secretion of Th1 cytokines while their effects on the release of Th2 cytokines are variable. We investigated molecular and cellular markers of Th1- and Th2-mediated inflammatory mechanisms and the anti-inflammatory activity of azithromycin and clarithromycin in phorbol 12-myristate 13-acetate (PMA) and oxazolone (OXA)-induced skin inflammation. Dexamethasone (50 μg/ear), azithromycin, and clarithromycin (500 μg/ear) reduced TNF-α and interleukin (IL)-1β concentration in ear tissue by inhibiting inflammatory cell accumulation in PMA-induced inflammation. In OXA-induced early delayed-type hypersensitivity (DTH), the macrolides (2 mg/ear) and dexamethasone (25 μg/ear) reduced ear tissue inflammatory cell infiltration and secretion of IL-4 while clarithromycin also decreased IFN-γ concentration. Macrolides showed better activity when administered after the challenge. In OXA-induced chronic DTH, azithromycin (1 mg/ear) reduced the number of ear tissue mast cells and decreased the concentration of IL-4 in ear tissue and of immunoglobulin (Ig)E in serum. Clarithromycin (1 mg/ear) reduced serum IgE concentration, possibly by a mechanism independent of IL-4, while both macrolides attenuated mast cell degranulation. In conclusion, azithromycin and clarithromycin attenuate pro-inflammatory cytokine production and leukocyte infiltration during innate immune reactions, while selectively affecting Th2 rather than Th1 immunity in DTH reactions.

  11. Th17 and Th1 Lymphocytes Are Correlated with Chronic Periodontitis.

    PubMed

    Chen, Xiao-Tao; Chen, Li-Li; Tan, Jing-Yi; Shi, Dan-Hui; Ke, Ting; Lei, Li-Hong

    2016-01-01

    T cells are involved in the homeostasis of periodontal tissues and mediate bone loss in periodontitis, but the involvement of T-helper cells in chronic periodontitis (CP) in a Chinese population is still unclear. This study aimed to assess the distribution of peripheral and local T helper (Th17) and Th1 in CP. Sixty-eight patients with CP and 43 healthy controls were recruited from April 2012 to July 2014 at the Department of Stomatology, People's Hospital of Xinjiang Uygur Autonomous Region (China). The proportions of Th17 (CD3(+)CD4(+)IL-17(+)) and Th1 (CD3(+)CD4(+)IFN-γ(+)) T-cells in peripheral blood samples were assessed by flow cytometry. Immunohistochemistry was used to quantify interleukin-17 (IL-17) and interferon-gamma (IFN-γ) protein levels in gingival biopsy samples. mRNA levels of IL-17, IFN-γ RORγt, and T-bet in gingival biopsy samples were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proportions of circulating Th17 cells and Th1 cells were both more abundant in CP patients than in controls (Th17: 1.05% ± 0.87% vs. 0.62% ± 0.49%, P < 0.01; Th1: 13.93% ± 7.94% vs. 8.22% ± 4.50%, P < 0.001). Positive correlations were obtained between the proportion of circulating Th17 cells and probing depth (PD) (r = 0.320, P = 0.001) and between the proportion of circulating Th1 cells and PD (r = 0.372, P < 0.001). IL-17 and IFN-γ protein levels in gingival biopsy samples were markedly increased in CP compared to controls (both P < 0.05). Relative IFN-γ, IL-17A, and T-bet mRNA levels in CP biopsies were higher compared to controls (all P < 0.05). These results suggest that elevated peripheral and local Th17 and Th1 cells might be involved in the pathogenesis of CP.

  12. Th1 type lymphocyte reactivity to metals in patients with total hip arthroplasty

    PubMed Central

    Hallab, Nadim James; Caicedo, Marco; Finnegan, Alison; Jacobs, Joshua J

    2008-01-01

    , Cobalt and/or Titanium (as defined by a statistically significant >2 fold stimulation index response, p < 0.05) and were designated as metal-reactive. Metals such as Cobalt, Copper, Manganese, and Vanadium were toxic at concentrations as low as 0.5 mM while other metals, such as Aluminum, Chromium, Iron, Molybdenum, and Nickel, became toxic at much higher concentrations (>10 mM). The differential secretion of signature T-cell subsets' cytokines (Th1 and Th2 lymphocytes releasing IFN-gamma and IL-4, respectively) between those total hip arthroplasty subjects which demonstrated metal-reactivity and those that did not, indicated a Th1 type (IFN-gamma) pro-inflammatory response. Conclusion Elevated proliferation and production of IFN-gamma to metals in hip arthroplasty subjects' lymphocytes indicates that a Th1 (vs. Th2) type response is likely associated with any metal induced reactivity. The involvement of an elevated and specific lymphocyte response suggests an adaptive (macrophage recruiting) immunity response to metallic implant debris rather than an innate (nonspecific) immune response. PMID:18271968

  13. Sitagliptin inhibit human lymphocytes proliferation and Th1/Th17 differentiation in vitro.

    PubMed

    Pinheiro, Marcelo Maia; Stoppa, Caroline Lais; Valduga, Claudete Justina; Okuyama, Cristina Eunice; Gorjão, Renata; Pereira, Regina Mara Silva; Diniz, Susana Nogueira

    2017-03-30

    Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents that are widely used in clinical practice to improve glycemic control in patients with type 2 diabetes. DPP-4 is also known as lymphocyte cell surface protein, CD26, and plays an important role in T-cell immunity. Recent studies suggest that DPP-4 inhibitors improve beta-cell function and attenuate autoimmunity in type 1 diabetic mouse models. To investigate the direct effect of DPP4 in immune response, human peripheral blood mononuclear cells (PBMC) from healthy volunteers were obtained by Ficoll gradient and cultivated in the absence (control) or presence of phytohemagglutinin (PHA), or stimulated with PHA and treated with sitagliptin. The immune modulation mechanisms analyzed were: cell proliferation, by MTT assay; cytokine quantification by ELISA or cytometric bead array (CBA), Th1/Th2/Th17 phenotyping by flow cytometric analysis and CD26 gene expression by real time PCR. The results showed that sitagliptin treatment inhibited the proliferation of PBMC-PHA stimulated cells in a dose dependent manner and decreased CD26 expression by these cells, suggesting that sitagliptin may interfere in CD26 expression, dimerization and cell signaling. Sitagliptin treatment not only inhibited IL-10 (p<0.05) and IFN-gamma (p=0.07) cytokines, but also completely abolish IL-6 expression by PBMCs (p<0.001). On the other hand, IL-4 were secreted in culture supernatants from sitagliptin treated cells. A statistically significant increase (p<0.05) in the ratio of TGF-beta/proliferation index after sitagliptin treatment (2627.97±1351.65), when comparing to untreated cells (646.28±376.94), was also demonstrated, indicating higher TGF-beta1 production by viable cells in cultures. Sitagliptin treatment induced a significantly (p<0.05) decrease in IL-17 and IFN-gamma intracellular expression compared with PHA alone. Also, the percentage of T CD4(+)IL-17(+), T CD4(+)IFNgamma(+) and T CD4(+)IL-4(+) cells

  14. Editor’s Highlight: Subvisible Aggregates of Immunogenic Proteins Promote a Th1-Type Response

    PubMed Central

    Ratanji, Kirsty D.; Dearman, Rebecca J.; Kimber, Ian; Thorpe, Robin; Wadhwa, Meenu; Derrick, Jeremy P.

    2016-01-01

    Protein aggregation is associated with enhanced immunogenicity of biotherapeutics. As a result, regulatory guidelines recommend screening for aggregation during bioprocessing. However, the mechanisms underlying the enhanced immunogenicity of aggregates are poorly understood. In the investigations described herein, the immunogenicity in mice of a humanized single chain variable antibody fragment (scFv) purified after expression in Escherichia coli has been examined. Reproducible scFv aggregates were obtained within the subvisible particle size range (mean diameter 2 µm) using thermal and mechanical stresses. Intraperitoneal immunization of BALB/c strain mice with 1 mg/ml of aggregated or monomeric scFv induced similar IgG and IgG1 antibody responses. In contrast, aggregate preparations stimulated significantly higher levels of anti-scFv IgG2a antibody than did the monomer. In comparative studies, aggregates of ovalbumin (OVA) within the subvisible particle size range were prepared by stir stress, and their immunogenicity compared with that of monomeric OVA in mice. Aggregated and monomeric OVA induced similar anti-OVA IgG and IgG1 antibody responses, whereas IgG2a antibody levels were significantly higher in aggregate-immunized mice. Furthermore, cytokine profiles in supernatants taken from splenocyte-dendritic cell co-cultures were consistent with aggregated preparations inducing a T helper (Th) 1-type response. Aggregated proteins within the subvisible range were therefore shown to induce a preferential Th1 type response, whereas monomeric proteins elicited a selective Th2 response. These data indicate that protein aggregation can impact on both the vigor and quality of immune responses. PMID:27370416

  15. Flow cytometric analysis of gut mucosal lymphocytes supports an impaired Th1 cytokine profile in spondyloarthropathy

    PubMed Central

    Van Damme, N; De Vos, M; Baeten, D; Demetter, P; Mielants, H; Verbruggen, G; Cuvelier, C; Veys, E; De Keyser, F

    2001-01-01

    OBJECTIVE—To quantify the fraction of gut mucosal lymphocytes expressing the T helper type 1 (Th1) cytokines, interferon γ (IFNγ) and interleukin (IL)2, and the Th2 cytokines, IL4 and IL10, at the single cell level in patients with spondyloarthropathy (SpA) in comparison with healthy controls.
METHODS—An improved extraction protocol was used for the enrichment of intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) from colonic and ileal biopsy specimens obtained from patients with SpA (n=20) and healthy controls (n=13). After stimulation with phorbol ester/ionomycin, expression of the intracellular cytokines IFNγ, IL2, IL4, and IL10 was determined in CD3+, CD3+CD8+ and CD3+CD8− T cells by flow cytometry.
RESULTS—In colonic LPLs, a significant decrease in IFNγ-producing CD3+ cells was observed (p=0.02) in patients with SpA. In the CD3+CD8− subset, the proportion of cells producing IFNγ and IL2 was decreased in patients with SpA (p=0.021 and p=0.027 respectively). In ileal LPLs, the percentage of IL10-producing CD3+CD8− cells was significantly increased (p=0.046).
CONCLUSION—An impaired Th1 cytokine profile is observed in gut mucosal lymphocytes from patients with SpA. This adds to the existing evidence that the gut mucosal immune apparatus is involved in the pathogenesis of SpA.

 PMID:11302872

  16. Innate Immune Function of TH2 Cells in vivo

    PubMed Central

    Guo, Liying; Huang, Yuefeng; Chen, Xi; Hu-Li, Jane; Urban, Joseph F.; Paul, William E.

    2015-01-01

    Type 2 helper T (TH) cells produce interleukin 13 (IL-13) when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2s) are the dominant innate producers of IL-13 in naïve animals, we show here that in helminth-infected mice, TH2 cell numbers increased and became major mediators of innate type II responses. TH2 cells made important contributions to HDM-induced antigen–non-specific eosinophilic inflammation and protected mice recovering from Ascaris suum infection against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role of effector TH2 cells during TCR-independent innate-like immune responses. PMID:26322482

  17. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice

    PubMed Central

    1995-01-01

    Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen- induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel

  18. Immunization with a recombinant bacillus Calmette-Guerin strain confers protective Th1 immunity against the human metapneumovirus.

    PubMed

    Palavecino, Christian E; Céspedes, Pablo F; Gómez, Roberto S; Kalergis, Alexis M; Bueno, Susan M

    2014-01-01

    Along with the human respiratory syncytial virus (hRSV), the human metapneumovirus (hMPV) is one of the leading causes of childhood hospitalization and a major health burden worldwide. Unfortunately, owing to an inefficient immunological memory, hMPV infection provides limited immune protection against reinfection. Furthermore, hMPV can induce an inadequate Th2 type immune response that causes severe lung inflammation, leading to airway obstruction. Similar to hRSV, it is likely that an effective clearance of hMPV would require a balanced Th1 type immunity by the host, involving the activation of IFN-γ-secreting T cells. A recognized inducer of Th1 immunity is Mycobacterium bovis bacillus Calmette-Guérin (BCG), which has been used in newborns for many decades and in several countries as a tuberculosis vaccine. We have previously shown that immunization with BCG strains expressing hRSV Ags can induce an efficient immune response that protects against this virus. In this study, we show that immunization with rBCG strains expressing the phosphoprotein from hMPV also can induce protective Th1 immunity. Mice immunized with rBCG were protected against weight loss, airway inflammation, and viral replication in the lungs after hMPV infection. Our rBCG vaccine also induced the activation of hMPV-specific T cells producing IFN-γ and IL-2, which could protect from hMPV infection when transferred to recipient mice. These data strongly support the notion that rBCG induces protective Th1 immunity and could be considered as an efficient vaccine against hMPV.

  19. Innate immunological function of TH2 cells in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Th2 cells produce IL-13 when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response of cells of the adaptive immune system is dependent on IL-33-, not T cell receptor-, based stimulation. While type 2 innate lymphoid cells (ILC2s) are the dominant ...

  20. Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: a large retrospective study

    PubMed Central

    2011-01-01

    Background Previous studies indicate that successful resolution of Lyme neuroborreliosis (NB) is associated with a strong T helper (Th) 1-type cytokine response in the cerebrospinal fluid (CSF) followed by a down-regulating Th2 response, whereas the role of the recently discovered Th17 cytokine response is unknown. Methods To investigate the relative contribution of different Th associated cytokine/chemokine responses, we used a multiple bead array to measure the levels of CXCL10 (Th1 marker), CCL22 (Th2 marker), IL-17 (Th17 marker) and CXCL8 (general inflammation marker), in serum and in CSF from untreated patients with confirmed NB (n = 133), and non-NB patients (n = 96), and related the findings to clinical data. Samples from patients with possible early NB (n = 15) and possible late NB (n = 19) were also analysed, as well as samples from an additional control group with orthopaedic patients (n = 17), where CSF was obtained at spinal anaesthesia. Results The most prominent differences across groups were found in the CSF. IL-17 was elevated in CSF in 49% of the patients with confirmed NB, but was not detectable in the other groups. Patients with confirmed NB and possible early NB had significantly higher CSF levels of CXCL10, CCL22 and CXCL8 compared to both the non-NB group and the control group (p < 0.0001 for all comparisons). Patients in the early NB group, showing a short duration of symptoms, had lower CCL22 levels in CSF than did the confirmed NB group (p < 0.0001). Furthermore, patients within the confirmed NB group showing a duration of symptoms <2 weeks, tended to have lower CCL22 levels in CSF than did those with longer symptom duration (p = 0.023). Cytokine/chemokine levels were not correlated with clinical parameters or to levels of anti-Borrelia-antibodies. Conclusion Our results support the notion that early NB is dominated by a Th1-type response, eventually accompanied by a Th2 response. Interestingly, IL-17 was increased exclusively in CSF from

  1. Looking beyond the induction of Th2 responses to explain immunomodulation by helminths.

    PubMed

    Nutman, T B

    2015-06-01

    Although helminth infections are characteristically associated with Th2-mediated responses that include the production of the prototypical cytokines IL-4, IL-5 and IL-13 by CD4(+) cells, the production of IgE, peripheral blood eosinophilia and mucus production in localized sites, these responses are largely attenuated when helminth infections become less acute. This modulation of the immune response that occurs with chronic helminth infection is often induced by molecules secreted by helminth parasites, by non-Th2 regulatory CD4(+) cells, and by nonclassical B cells, macrophages and dendritic cells. This review will focus on those parasite- and host-mediated mechanisms underlying the modulated T-cell response that occurs as the default in chronic helminth infections.

  2. Depletion of interleukin-4 in BALB/c mice with established Leishmania major infections increases the efficacy of antimony therapy and promotes Th1-like responses.

    PubMed Central

    Nabors, G S; Farrell, J P

    1994-01-01

    Whereas most inbred mouse strains mount a protective Th1 helper T-cell response following infection with Leishmania major, an ineffective Th2 response develops in BALB/c mice, leading to the development of disseminated, ultimately fatal disease. Interleukin-4 (IL-4) production is required for the initiation of the Th2 response, though little is known about the requirements for the long-term maintenance of this response. In order to investigate the role of the expanding parasite population on the Th2 response, mice infected for 2 weeks with L. major, which exhibited a Th2-like cytokine profile, were treated with a leishmanicidal agent (Pentostam) and/or various doses of anti-IL-4 antibody. Untreated mice, mice treated with Pentostam alone, or mice treated with 2.5 mg of anti-IL-4 antibody given at days 13 and 21 of infection developed progressive disease. However, in 8 of 10 mice treated with this dose of anti-IL-4 antibody plus Pentostam lesion development was arrested and lesions were either controlled or eventually healed. Healing was associated with the production of high levels of gamma interferon by spleen cells, and low levels of immunoglobulin E in serum compared with levels for control animals, indicating that a Th1-like response had developed in mice receiving both treatments. Thus, depletion of IL-4 only in combination with a reduction in the parasite burden allowed the expression of a Th1 response. When the dose of anti-IL-4 antibody was increased to 5 mg per injection, all mice treated with this dose of antibody, with or without Pentostam therapy, healed. However, combined therapy with Pentostam in mice treated with this dose of antibody had an additional protective effect. As expected, a Th1 response developed in mice treated with this dose of anti-IL-4 antibody with or without combined therapy with Pentostam, whereas a Th2 response developed in control mice. Thus, a significant effect on the course of disease is noted when mice with established L

  3. Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization

    PubMed Central

    Kuipers, Hedwich F.; Rieck, Mary; Gurevich, Irina; Nagy, Nadine; Negrin, Robert S.; Wight, Thomas N.; Steinman, Lawrence; Bollyky, Paul L.

    2016-01-01

    The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3+ regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS. PMID:26787861

  4. Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization.

    PubMed

    Kuipers, Hedwich F; Rieck, Mary; Gurevich, Irina; Nagy, Nadine; Butte, Manish J; Negrin, Robert S; Wight, Thomas N; Steinman, Lawrence; Bollyky, Paul L

    2016-02-02

    The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3(+) regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS.

  5. Neutrophils Exert a Suppressive Effect on Th1 Responses to Intracellular Pathogen Brucella abortus

    PubMed Central

    Ordoñez-Rueda, Diana; Arce-Gorvel, Vilma; Alfaro-Alarcón, Alejandro; Lepidi, Hubert; Malissen, Bernard; Malissen, Marie; Gorvel, Jean-Pierre; Moreno, Edgardo

    2013-01-01

    Polymorphonuclear neutrophils (PMNs) are the first line of defense against microbial pathogens. In addition to their role in innate immunity, PMNs may also regulate events related to adaptive immunity. To investigate the influence of PMNs in the immune response during chronic bacterial infections, we explored the course of brucellosis in antibody PMN-depleted C57BL/6 mice and in neutropenic mutant Genista mouse model. We demonstrate that at later times of infection, Brucella abortus is killed more efficiently in the absence of PMNs than in their presence. The higher bacterial removal was concomitant to the: i) comparatively reduced spleen swelling; ii) augmented infiltration of epithelioid histiocytes corresponding to macrophages/dendritic cells (DCs); iii) higher recruitment of monocytes and monocyte/DCs phenotype; iv) significant activation of B and T lymphocytes, and v) increased levels of INF-γ and negligible levels of IL4 indicating a balance of Th1 over Th2 response. These results reveal that PMNs have an unexpected influence in dampening the immune response against intracellular Brucella infection and strengthen the notion that PMNs actively participate in regulatory circuits shaping both innate and adaptive immunity. PMID:23458832

  6. Neutrophils exert a suppressive effect on Th1 responses to intracellular pathogen Brucella abortus.

    PubMed

    Barquero-Calvo, Elías; Martirosyan, Anna; Ordoñez-Rueda, Diana; Arce-Gorvel, Vilma; Alfaro-Alarcón, Alejandro; Lepidi, Hubert; Malissen, Bernard; Malissen, Marie; Gorvel, Jean-Pierre; Moreno, Edgardo

    2013-02-01

    Polymorphonuclear neutrophils (PMNs) are the first line of defense against microbial pathogens. In addition to their role in innate immunity, PMNs may also regulate events related to adaptive immunity. To investigate the influence of PMNs in the immune response during chronic bacterial infections, we explored the course of brucellosis in antibody PMN-depleted C57BL/6 mice and in neutropenic mutant Genista mouse model. We demonstrate that at later times of infection, Brucella abortus is killed more efficiently in the absence of PMNs than in their presence. The higher bacterial removal was concomitant to the: i) comparatively reduced spleen swelling; ii) augmented infiltration of epithelioid histiocytes corresponding to macrophages/dendritic cells (DCs); iii) higher recruitment of monocytes and monocyte/DCs phenotype; iv) significant activation of B and T lymphocytes, and v) increased levels of INF-γ and negligible levels of IL4 indicating a balance of Th1 over Th2 response. These results reveal that PMNs have an unexpected influence in dampening the immune response against intracellular Brucella infection and strengthen the notion that PMNs actively participate in regulatory circuits shaping both innate and adaptive immunity.

  7. Picroside II Attenuates Airway Inflammation by Downregulating the Transcription Factor GATA3 and Th2-Related Cytokines in a Mouse Model of HDM-Induced Allergic Asthma

    PubMed Central

    Kim, Jin seok; Lee, Jae-Won; Park, Hyun Ah; Ryu, Hyung Won; Lee, Su Ui; Hwang, Kwang Woo; Yun, Won-Kee; Kim, Hyoung-Chin; Ahn, Kyung-Seop; Oh, Sei-Ryang

    2016-01-01

    Picroside II isolated from Pseudolysimachion rotundum var. subintegrum has been used as traditional medicine to treat inflammatory diseases. In this study, we assessed whether picroside II has inhibitory effects on airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. In the HDM-induced asthmatic model, picroside II significantly reduced inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), the levels of total immunoglobulin (Ig) E and HDM-specific IgE and IgG1 in serum, airway inflammation, and mucus hypersecretion in the lung tissues. ELISA analysis showed that picroside II down-regulated the levels of Th2-related cytokines (including IL-4, IL-5, and IL-13) and asthma-related mediators, but it up-regulated Th1-related cytokine, IFNγ in BALF. Picroside II also inhibited the expression of Th2 type cytokine genes and the transcription factor GATA3 in the lung tissues of HDM-induced mice. Finally, we demonstrated that picroside II significantly decreased the expression of GATA3 and Th2 cytokines in developing Th2 cells, consistent with in vivo results. Taken together, these results indicate that picroside II has protective effects on allergic asthma by reducing GATA3 expression and Th2 cytokine bias. PMID:27870920

  8. Hierarchical IL-5 expression defines a subpopulation of highly differentiated human Th2 cells.

    PubMed

    Upadhyaya, Bhaskar; Yin, Yuzhi; Hill, Brenna J; Douek, Daniel C; Prussin, Calman

    2011-09-15

    Each of the three Th2 cytokine genes, IL-4, IL-5, and IL-13, has different functions. We hypothesized that Th2 heterogeneity could yield Th2 subpopulations with different cytokine expression and effector functions. Using multiple approaches, we demonstrate that human Th2 cells are composed of two major subpopulations: a minority IL-5(+) (IL-5(+), IL-4(+), IL-13(+)) and majority IL-5(-) Th2 (IL-5(-), IL-4(+), IL-13(+)) population. IL-5(+) Th2 cells comprised only 20% of all Th2 cells. Serial rounds of in vitro differentiation initially yielded IL-5(-) Th2, but required multiple rounds of differentiation to generate IL-5(+) Th2 cells. IL-5(+) Th2 cells expressed less CD27 and greater programmed cell death-1 than IL-5(-) Th2 cells, consistent with their being more highly differentiated, Ag-exposed memory cells. IL-5(+) Th2 cells expressed greater IL-4, IL-13, and GATA-3 relative to IL-5(-) Th2 cells. GATA-3 and H3K4me(3) binding to the IL5 promoter (IL5p) was greater in IL-5(+) relative to IL-5(-) Th2 cells, whereas there was no difference in their binding to the IL4p and IL13p. Conversely, H3K27me(3) binding to the IL5p was greater in IL-5(-) Th2 cells. These findings demonstrate Th2 lineage heterogeneity, in which the IL5 gene is regulated in a hierarchical manner relative to other Th2 genes. IL-5(+) Th2 cells are phenotypically distinct and have epigenetic changes consistent with greater IL5p accessibility. Recurrent antigenic exposure preferentially drives the differentiation of IL-5(+) Th2 cells. These results demonstrate that IL-5(+) and IL-5(-) Th2 cells, respectively, represent more and less highly differentiated Th2 cell subpopulations. Such Th2 subpopulations may differentially contribute to Th2-driven pathology.

  9. Quantitative Proteomics of Gut-Derived Th1 and Th1/Th17 Clones Reveal the Presence of CD28+ NKG2D- Th1 Cytotoxic CD4+ T cells*

    PubMed Central

    Riaz, Tahira; Sollid, Ludvig Magne; Olsen, Ingrid; de Souza, Gustavo Antonio

    2016-01-01

    T-helper cells are differentiated from CD4+ T cells and are traditionally characterized by inflammatory or immunosuppressive responses in contrast to cytotoxic CD8+ T cells. Mass-spectrometry studies on T-helper cells are rare. In this study, we aimed to identify the proteomes of human Th1 and Th1/Th17 clones derived from intestinal biopsies of Crohn's disease patients and to identify differentially expressed proteins between the two phenotypes. Crohn's disease is an inflammatory bowel disease, with predominantly Th1- and Th17-mediated response where cells of the “mixed” phenotype Th1/Th17 have also been commonly found. High-resolution mass spectrometry was used for protein identification and quantitation. In total, we identified 7401 proteins from Th1 and Th1/Th17 clones, where 334 proteins were differentially expressed. Major differences were observed in cytotoxic proteins that were overrepresented in the Th1 clones. The findings were validated by flow cytometry analyses using staining with anti-granzyme B and anti-perforin and by a degranulation assay, confirming higher cytotoxic features of Th1 compared with Th1/Th17 clones. By testing a larger panel of T-helper cell clones from seven different Crohn's disease patients, we concluded that only a subgroup of the Th1 cell clones had cytotoxic features, and these expressed the surface markers T-cell-specific surface glycoprotein CD28 and were negative for expression of natural killer group 2 member D. PMID:26637539

  10. Protection against Naegleria fowleri infection in mice immunized with Cry1Ac plus amoebic lysates is dependent on the STAT6 Th2 response.

    PubMed

    Carrasco-Yepez, M; Rojas-Hernandez, S; Rodriguez-Monroy, M A; Terrazas, L I; Moreno-Fierros, L

    2010-01-01

    We previously reported that intranasal administration of Cry1Ac protoxin alone or in combination with amoebic lysates increases protection against Naegleria fowleri meningoencephalitis in mice. Those results suggested that both antibody responses and innate immune mechanisms may be participating in the protective effects observed. The present study was aimed to investigate whether the STAT6-induced Th2 immune response is essential for the resistance to N. fowleri infection, conferred by immunization with amoebic lysates plus Cry1Ac. STAT6-deficient (STAT6-/-) and wild-type (STAT6+/+) BALB/c mice were immunized by the intranasal route with a combination of N. fowleri lysates plus Cry1Ac, and subsequently challenged with lethal doses of N. fowleri trophozoites. STAT6+/+ mice displayed 100% protection, while no protection was observed in STAT6-/- mice. Significantly higher titres of Th2-associated IgG1 as well as interleukin-4 (IL-4) were found in STAT6+/+ mice, whereas in STAT6-/- mice significantly more IL-12 and IFN-gamma as well as significantly higher titres of Th1-associated IgG2a were detected. Thus, whereas protected STAT6+/+-immunized mice elicited a Th-2 type inclined immune response that produced predominantly humoral immunity, unprotected STAT6-/- mice exhibited a polarized Th1 type cellular response. These findings suggest that the STAT6-signalling pathway is critical for defence against N. fowleri infection.

  11. Non-invasive, epicutaneous immunisation with toxoid in deformable vesicles protects mice against tetanus, chiefly owing to a Th2 response.

    PubMed

    Chopra, Amla; Cevc, Gregor

    2014-06-02

    A non-invasive, intra/transcutaneous immunisation of mice with a suitable combination of tetanus toxoid, ultradeformable vesicle (Transfersome®) carrier, and monophosphoryl lipid A adjuvant targets immuno-competent cells in a body and can protect 100% of the tested mice against an otherwise lethal (50×LD50) parenteral tetanus toxin challenge. The late immune response to the epicutaneously applied tetanus toxoid in such vesicles consists chiefly of circulating IgG1 and IgG2b antibody isotypes, indicative of a specific Th2 cellular response bias. Immunisations by subcutaneous injections moreover protect 100% of mice against a similar, otherwise lethal, dose of tetanus toxin. However, the immune response to transcutaneous and invasive immunisation differs. The latter elicits mainly IgG1 and IgG2b as well as IgG2a antibody isotypes, indicative of a mixed Th1/Th2 response. The cytokine response of the intra/transcutaneously and subcutaneously immunised mice reflects the difference in the organ-specific manner. IFN-γ concentration is appreciably increased in the draining lymph nodes and IL-10 in spleen. Since tetanus is a neutral antigen, both the Th1-specific IFN-γ and the Th-2 specific-IL-10 are observable.

  12. 27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes

    SciTech Connect

    Kim, Sun-Mi; Kim, Bo-Young; Lee, Sae-A; Eo, Seong-Kug; Yun, Yungdae; Kim, Chi-Dae; Kim, Koanhoi

    2014-02-01

    Th1 lymphocyte recruitment in a cholesterol-rich milieu. We propose a model via which 27OHChol and 7αOHChol contribute to the predominance of Th1 cells in atherosclerotic lesions on the basis of our results and previous findings. Cholesterol deposited in the artery undergoes oxidative modification to oxysterols. Exposure of monocytic cells to 27OHChol or 7αOHChol results in increased transcription and secretion of CCR5 ligands, like CCL3 and CCL4, which leads to a concentration gradient of the chemokines. Among the lymphocytes attached to cell adhesion molecules expressed on endothelial cells, Th1 cells that express CCR5 recognize the gradient and follow the signal of increasing chemokine concentration towards the source of the chemokines, whereas other subtypes of T cells that do not express CCR5 (Tregs and Th2 cells) do not respond. The preferential infiltration of Th1 cells leads to predominance of Th1 cells. Since oxidized LDL (oxLDL) enhances the expression of cell adhesion molecules on endothelial cells, existence of oxLDL will accelerate the recruitment of Th1 lymphocytes into atherosclerotic lesions in response to the oxysterols. - Highlights: • High-cholesterol diet induces CCR5L expression, like CCL3 and CCL4, in ApoE{sup −/−} mice. • 27OHChol and 7αOHChol enhance secretion of CCL3 and CCL4 by monocytic cells. • The secreted CCR5 ligands promote migration of CCR5-expressing Th1 cells. • We report a mechanism underlying Th1 cell recruitment into atherosclerotic lesions.

  13. Th1-mediated experimental autoimmune encephalomyelitis is CXCR3 independent.

    PubMed

    Lalor, Stephen J; Segal, Benjamin M

    2013-11-01

    Drugs that block leukocyte trafficking ameliorate multiple sclerosis (MS). Occurrences of opportunistic infection, however, highlight the need for novel drugs that modulate more restricted subsets of T cells. In this context, chemokines and their receptors are attractive therapeutic targets. CXCR3, a Th1-associated chemokine receptor, is preferentially expressed on T cells that accumulate in MS lesions and central nervous system (CNS) infiltrates of mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice genetically deficient in either CXCR3 or CXCL10 succumb to EAE following active immunization with myelin antigens. EAE is mediated by a heterogeneous population of T cells in myelin-immunized mice. Hence, disease might develop in the absence of CXCR3 secondary to the compensatory action of encephalitogenic CCR6(+) Th17 cells. However, in the current study, we show for the first time that blockade or genetic deficiency of either CXCR3 or of its primary ligand has no impact on clinical EAE induced by the adoptive transfer of highly polarized Th1 effector cells. Our data illustrate the fact that, although highly targeted immunotherapies might have more favorable side effect profiles, they are also more likely to be rendered ineffective by inherent redundancies in chemokine and cytokine networks that arise at sites of neuroinflammation.

  14. Selective development of T helper (Th)2 cells induced by continuous administration of low dose soluble proteins to normal and beta(2)- microglobulin-deficient BALB/c mice

    PubMed Central

    1996-01-01

    Continuous administration of soluble proteins, delivered over a 10-d period by a mini-osmotic pump implanted subcutaneously, induces a long- lasting inhibition of antigen-specific T cell proliferation in lymph node cells from BALB/c mice subsequently primed with antigen in adjuvant. The decreased T cell proliferative response is associated with a down-regulation of the T helper cell (Th)1 cytokines interleukin (IL)-2 and interferon (IFN)-gamma and with a strong increase in the secretion of the Th2 cytokines IL-4 and IL-5 by antigen specific CD4+ T cells. This is accompanied by predominant inhibition of antigen- specific antibody production of IgG2a and IgG2b, rather than IgG1 isotype. Interestingly, inhibition of Th1 and priming of Th2 cells is also induced in beta(2) microglobulin-deficient BALB/c mice, indicating that neither CD8+ nor CD4+ NK1.1+ T cells, respectively, are required. The polarization in Th2 cells is stably maintained by T cell lines, all composed of CD4+/CD8- cells expressing T cell receptor for antigen (TCR) alpha/beta chains, derived from BALB/c mice treated with continuous antigen administration, indicating that they originate from Th2 cells fully differentiated in vivo. This polarization is induced in BALB/c mice by continuous administration of any protein antigen tested, including soluble extracts from pathogenic microorganisms. Priming of Th2 cells is dose dependent and it is optimal for low rather than high doses of protein. Blocking endogenous IL-4 in vivo inhibits expansion of antigen-specific Th2 cells, but does not restore IFN-gamma production by T cells from mice treated with soluble antigen-specific Th2 cells, but does not restore IFN-gamma production by T cells from mice treated with soluble antigen, indicating the involvement of two independent mechanisms. Consistent with this, Th2 cell development, but not inhibition of Th1 cells, depends on non-major histocompatibility complex genetic predisposition, since the Th2 response is

  15. Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus

    PubMed Central

    Hayashida, Jun-Nosuke; Maehara, Takashi; Ishiguro, Noriko; Kubota, Keigo; Furukawa, Sachiko; Ohta, Miho; Sakamoto, Mizuki; Tanaka, Akihiko; Nakamura, Seiji

    2017-01-01

    Oral lichen planus (OLP) is a chronic inflammatory disease characterized by subepithelial T-cell infiltration. Recent studies reported that specific T helper (Th) subsets, especially Th2 cells, are involved in the pathogenesis of OLP. Thymic stromal lymphopoietin (TSLP) is mainly secreted by epithelial cells and potently activates myeloid dendritic cells (mDCs) to induce Th2-mediated inflammation. Here, we investigated the expression of TSLP and related molecules in OLP. Buccal mucosa specimens from patients with OLP, hyperkeratosis, and ulcer were analyzed by immunohistochemistry for expression of TSLP, its receptor (TSLPR), and inflammatory cells. TSLP was detected in/around the epithelium of patients with OLP and hyperkeratosis, whereas TSLPR, CD11c (mDC), and GATA3 (Th2) were strongly expressed in the subepithelial layer only in OLP patients. Double immunofluorescence staining showed that TSLPR expression mainly co-localized with CD11c. Moreover, the number of CD11c- and GATA-3 positive cells was correlated in OLP patients. In lesions selectively extracted by laser microdissection, the mRNA expression of Th2 (IL-4, MDC, TARC, GATA3)- and Th17 (IL-17, RORγt)-related molecules in OLP patients was significantly higher than in other groups. These results suggest that CD11c+ mDCs expressing TSLPR contribute to aberrant Th2 immune responses and the pathogenesis of OLP via TSLP stimulation. PMID:28278185

  16. CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model

    PubMed Central

    Connolly, Michael; Marketon, Anthony

    2016-01-01

    Allergies caused by Japanese Red Cedar (JRC) pollen affect up to a third of Japanese people, necessitating development of an effective therapeutic. We utilized the lysosomal targeting property of lysosomal-associated membrane protein-1 (LAMP-1) to make DNA vaccines that encode LAMP-1 and the sequences of immunodominant allergen CryJ1 or CryJ2 from the JRC pollen. This novel strategy is designed to skew the CD4 T cell responses to the target allergens towards a nonallergenic Th1 response. CryJ1-LAMP and CryJ2-LAMP were administrated to BALB/c mice and antigen-specific Th1-type IgG2a and Th2-type IgG1 antibodies, as well as IgE antibodies, were assayed longitudinally. We also isolated different T cell populations from immunized mice and adoptively transferred them into naïve mice followed by CryJ1/CryJ2 protein boosts. We demonstrated that CryJ-LAMP immunized mice produce high levels of IFN-γ and anti-CryJ1 or anti-CryJ2 IgG2a antibodies and low levels of IgE antibodies, suggesting that a Th1 response was induced. In addition, we found that CD4+ T cells are the immunological effectors of DNA vaccination in this allergy model. Together, our results suggest the CryJ-LAMP Vaccine has a potential as an effective therapeutic for JRC induced allergy by skewing Th1/Th2 responses. PMID:27239481

  17. Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response.

    PubMed

    Jayawardena, Uthpala A; Ratnasooriya, Wanigasekara D; Wickramasinghe, Deepthi D; Udagama, Preethi V

    2016-10-01

    Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~5ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~9360pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P<0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P<0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P<0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco-challenges.

  18. Valsartan Attenuates Atherosclerosis via Upregulating the Th2 Immune Response in Prolonged Angiotensin II-Treated ApoE(-/-) Mice.

    PubMed

    Meng, Kai; Zeng, Qiutang; Lu, Qinghua; Lin, Yingzhong; Wu, Bangwei; Yu, Kunwu; Dong, Zhaoqiang; Zhang, Jianwei; Chai, Meng; Liu, Yuyang; Ji, Qingwei; Zhou, Yujie

    2015-02-09

    Valsartan has a protective effect against hypertension and atherosclerosis in humans and experimental animal models. This study aimed to determine the effect of prolonged treatment with angiotensin II (Ang II) on atherosclerosis and the effect of valsartan on the activity of CD4(+) T lymphocyte subsets. The results showed that prolonged treatment (8 wks) with exogenous Ang II resulted in an increased atherosclerotic plaque size and a switch of stable-to-unstable plaque via modulating on CD4(+) T lymphocyte activity, including an increase in the T helper cell type 1 (Th1) and Th17 cells and a decrease in Th2 and regulatory T (Treg) cells. In contrast, valsartan treatment efficiently reversed the imbalance in CD4(+) T lymphocyte activity, ameliorated atherosclerosis and elicited a stable plaque phenotype in addition to controlling blood pressure. In addition, treatment with anti-interleukin (IL)-5 monoclonal antibodies weakened the antiatherosclerotic effects of valsartan without affecting blood pressure.

  19. Th1-Biased Immunomodulation and Therapeutic Potential of Artemisia annua in Murine Visceral Leishmaniasis

    PubMed Central

    Islamuddin, Mohammad; Chouhan, Garima; Farooque, Abdullah; Dwarakanath, Bilikere S.; Sahal, Dinkar; Afrin, Farhat

    2015-01-01

    Background In the absence of vaccines and limitations of currently available chemotherapy, development of safe and efficacious drugs is urgently needed for visceral leishmaniasis (VL) that is fatal, if left untreated. Earlier we reported in vitro apoptotic antileishmanial activity of n-hexane fractions of Artemisia annua leaves (AAL) and seeds (AAS) against Leishmania donovani. In the present study, we investigated the immunostimulatory and therapeutic efficacy of AAL and AAS. Methodology/Principal Findings Ten-weeks post infection, BALB/c mice were orally administered AAL and AAS for ten consecutive days. Significant reduction in hepatic (86.67% and 89.12%) and splenic (95.45% and 95.84%) parasite burden with decrease in spleen weight was observed. AAL and AAS treated mice induced the strongest DTH response, as well as three-fold decrease in IgG1 and two-fold increase in IgG2a levels, as compared to infected controls. Cytometric bead array further affirmed the elicitation of Th1 immune response as indicated by increased levels of IFN-γ, and low levels of Th2 cytokines (IL-4 and IL-10) in serum as well as in culture supernatant of lymphocytes from treated mice. Lymphoproliferative response, IFN-γ producing CD4+ and CD8+ T lymphocytes and nitrite levels were significantly enhanced upon antigen recall in vitro. The co-expression of CD80 and CD86 on macrophages was significantly augmented. CD8+ T cells exhibited CD62Llow and CD44hi phenotype, signifying induction of immunological memory in AAL and AAS treated groups. Serum enzyme markers were in the normal range indicating inertness against nephro- and hepato-toxicity. Conclusions/Significance Our results establish the two-prong antileishmanial efficacy of AAL and AAS for cure against L. donovani that is dependent on both the direct leishmanicidal action as well as switching-on of Th1-biased protective cell-mediated immunity with generation of memory. AAL and AAS could represent adjunct therapies for the treatment

  20. Mycobacterium vaccae induces a strong Th1 response that subsequently declines in C57BL/6 mice

    PubMed Central

    Zhang, Lijiao; Jiang, Yanlong; Cui, Ziyin; Yang, Wentao; Yue, Limin; Ma, Yingcong; Shi, Shaohua; Wang, Chunfang

    2016-01-01

    Mycobacterium (M.) vaccae is a fast-growing species of saprophytic bacteria that is widely distributed. To understand the host immune responses induced by M. vaccae isolated from bovine submaxillary lymph nodes, C57BL/6 mice were infected with reference strain M. vaccae Bacillus Calmette-Guérin (BCG) and isolated M. vaccae using intraperitoneal injections. Comparison of the bacterial replication and organ pathology between M. vaccae and M. vaccae BCG revealed that M. vaccae was more malignant than M. vaccae in mice. We also demonstrated that serum from the M. vaccae-infected mice contained a higher expression level of gamma-interferon (IFN-γ), tumor necrosis factor alpha, monocyte chemoattractant protein-1, interleukin (IL)-4, IL-12, IL-10 and transforming growth factor beta than did the other groups, especially after week 4. Furthermore, when the numbers of CD3+CD4+IFN-γ+ and CD3+CD4+IL4+ cells in the infected mice were observed by flow cytometry, we found that a powerful T helper 1 (Th1) response was induced by M. vaccae infection, which was associated with the emergence of CD3+CD4+IFN-γ+ cells. However, the Th1 response declined over time, which was associated with appearance of the CD4+CD25+FoxP3+ and CD4+CD25+CD152+Treg cell reaction. In addition, a strong Th2 response was found. Finally, we found that M. vaccae infection increased the production of type I IFNs, which was associated with a reduced Th1 response. PMID:27994210

  1. Association of CD30 transcripts with Th1 responses and proinflammatory cytokines in patients with end-stage renal disease.

    PubMed

    Velásquez, Sonia Y; Opelz, Gerhard; Rojas, Mauricio; Süsal, Caner; Alvarez, Cristiam M

    2016-05-01

    High serum sCD30 levels are associated with inflammatory disorders and poor outcome in renal transplantation. The contribution to these phenomena of transcripts and proteins related to CD30-activation and -cleavage is unknown. We assessed in peripheral blood of end-stage renal disease patients (ESRDP) transcripts of CD30-activation proteins CD30 and CD30L, CD30-cleavage proteins ADAM10 and ADAM17, and Th1- and Th2-type immunity-related factors t-bet and GATA3. Additionally, we evaluated the same transcripts and release of sCD30 and 32 cytokines after allogeneic and polyclonal T-cell activation. In peripheral blood, ESRDP showed increased levels of t-bet and GATA3 transcripts compared to healthy controls (HC) (both P<0.01) whereas levels of CD30, CD30L, ADAM10 and ADAM17 transcripts were similar. Polyclonal and allogeneic stimulation induced higher levels of CD30 transcripts in ESRDP than in HC (both P<0.001). Principal component analysis (PCA) in allogeneic cultures of ESRDP identified two correlation clusters, one consisting of sCD30, the Th-1 cytokine IFN-γ, MIP-1α, RANTES, sIL-2Rα, MIP-1β, TNF-β, MDC, GM-CSF and IL-5, and another one consisting of CD30 and t-bet transcripts, IL-13 and proinflammatory proteins IP-10, IL-8, IL-1Rα and MCP-1. Reflecting an activated immune state, ESRDP exhibited after allostimulation upregulation of CD30 transcripts in T cells, which was associated with Th1 and proinflammatory responses.

  2. Dectin-2 Deficiency Promotes Th2 Response and Mucin Production in the Lungs after Pulmonary Infection with Cryptococcus neoformans

    PubMed Central

    Nakamura, Yuri; Sato, Ko; Yamamoto, Hideki; Matsumura, Kana; Matsumoto, Ikumi; Nomura, Toshiki; Miyasaka, Tomomitsu; Ishii, Keiko; Kanno, Emi; Tachi, Masahiro; Yamasaki, Sho; Saijo, Shinobu; Iwakura, Yoichiro

    2014-01-01

    Dectin-2 is a C-type lectin receptor that recognizes high mannose polysaccharides. Cryptococcus neoformans, a yeast-form fungal pathogen, is rich in polysaccharides in its cell wall and capsule. In the present study, we analyzed the role of Dectin-2 in the host defense against C. neoformans infection. In Dectin-2 gene-disrupted (knockout) (Dectin-2KO) mice, the clearance of this fungus and the inflammatory response, as shown by histological analysis and accumulation of leukocytes in infected lungs, were comparable to those in wild-type (WT) mice. The production of type 2 helper T (Th2) cytokines in lungs was higher in Dectin-2KO mice than in WT mice after infection, whereas there was no difference in the levels of production of Th1, Th17, and proinflammatory cytokines between these mice. Mucin production was significantly increased in Dectin-2KO mice, and this increase was reversed by administration of anti-interleukin 4 (IL-4) monoclonal antibody (MAb). The levels of expression of β1-defensin, cathelicidin, surfactant protein A (Sp-A), and Sp-D in infected lungs were comparable between these mice. In in vitro experiments, IL-12p40 and tumor necrosis factor alpha (TNF-α) production and expression of CD86 and major histocompatibility complex (MHC) class II by bone marrow-derived dendritic cells and alveolar macrophages were completely abrogated in Dectin-2KO mice. Finally, the disrupted lysates of C. neoformans, but not of whole yeast cells, activated Dectin-2-triggered signaling in an assay with nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Dectin-2 may oppose the Th2 response and IL-4-dependent mucin production in the lungs after infection with C. neoformans, and it may not be required for the production of Th1, Th17, and proinflammatory cytokines or for clearance of this fungal pathogen. PMID:25422263

  3. Suppression of Th2 immune responses by the sulfated polysaccharide from Porphyra haitanensis in tropomyosin-sensitized mice.

    PubMed

    Shi, Chaolan; Pan, Tzuming; Cao, Minjie; Liu, Qingmei; Zhang, Lingjing; Liu, Guangming

    2015-02-01

    The sulfated polysaccharide from Porphyra was hypothesized to exhibit immunoregulatory, anti-tumor and anti-inflammatory activity, but its anti-allergic activity is not fully understood. Therefore, the aim of this study was to isolate sulfated polysaccharide from Porphyra haitanensis (PHPS) and investigate its anti-allergic potential using a tropomyosin (TM)-induced mouse allergy model. Intraperitoneal injection of PHPS suppressed the allergic reaction by modulating serum IgE, IgG1 and IgG2a levels in mice. In particular, when PHPS was injected prior to the first immunization with TM, the IgE level decreased by 34.2% compared with the control (PBS) group. Oral therapeutic administration of PHPS to TM-sensitized mice decreased histamine release and repaired the pathology in the jejunum of the small intestine. In vitro, the mRNA expressions of the TM-induced Th2 cytokines (interleukin-4 (IL-4), IL-5 and IL-13) in splenic lymphocytes were reduced by PHPS; however, the expression of Th1 and regulatory cytokines (interferon gamma (IFN-γ) and IL-10) were up-regulated in PHPS-treated splenic lymphocytes. In the splenic lymphocyte supernatant, the IL-4, IL-13 and IFN-γ levels were also regulated by PHPS. Moreover, PHPS induced IFN-γ secretion via the Jun N-terminal kinase (JNK) and Janus kinase 2 (JAK2) signaling pathways. Therefore, these results suggest that PHPS suppresses the TM-induced allergic reaction, possibly by modulating the imbalance of the Th1/Th2 immune response.

  4. Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines.

    PubMed

    Mordue, D G; Monroy, F; La Regina, M; Dinarello, C A; Sibley, L D

    2001-10-15

    Virulence in Toxoplasma gondii is strongly influenced by the genotype of the parasite. Type I strains uniformly cause rapid death in mice regardless of the host genotype or the challenge dose. In contrast, the outcome of infections with type II strains is highly dependent on the challenge dose and the genotype of the host. To understand the basis of acute virulence in toxoplasmosis, we compared low and high doses of the RH strain (type I) and the ME49/PTG strain (type II) of T. gondii in outbred mice. Differences in virulence were reflected in only modestly different growth rates in vivo, and both strains disseminated widely to different tissues. The key difference in the virulent RH strain was the ability to reach high tissue burdens rapidly following a low dose challenge. Lethal infections caused by type I (RH) or type II (PTG) strain infections were accompanied by extremely elevated levels of Th1 cytokines in the serum, including IFN-gamma, TNF-alpha, IL-12, and IL-18. Extensive liver damage and lymphoid degeneration accompanied the elevated levels of cytokines produced during lethal infection. Increased time of survival following lethal infection with the RH strain was provided by neutralization of IL-18, but not TNF-alpha or IFN-gamma. Nonlethal infections with a low dose of type II PTG strain parasites were characterized by a modest induction of Th1 cytokines that led to control of infection and minimal damage to host tissues. Our findings establish that overstimulation of immune responses that are normally necessary for protection is an important feature of acute toxoplasmosis.

  5. New drugs targeting Th2 lymphocytes in asthma

    PubMed Central

    Caramori, Gaetano; Groneberg, David; Ito, Kazuhiro; Casolari, Paolo; Adcock, Ian M; Papi, Alberto

    2008-01-01

    Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled β2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic

  6. Increased hepatic Th2 and Treg subsets are associated with biliary fibrosis in different strains of mice caused by Clonorchis sinensis

    PubMed Central

    Fang, Fan; Du, Ying; Ma, Rui; Li, Xiang-Yang; Yu, Qian; Meng, Di; Tang, Ren-Xian; Zheng, Kui-Yang

    2017-01-01

    Previous studies showed that CD4+T cells responses might be involved in the process of biliary fibrosis. However, the underlying mechanism resulting in biliary fibrosis caused by Clonorchis sinensis remains not yet fully elucidated. The objectives of the present study were to investigate the different profiles of hepatic CD4+T cell subsets (Th1, Th2, Th17 and Treg cells) and their possible roles in the biliary fibrosis of different strains of mice (C57BL/6, BALB/c and FVB mice) induced by C. sinensis infection. C57BL/6, BALB/c and FVB mice were orally gavaged with 45 metacercariae. All mice were sacrificed on 28 days post infection in deep anesthesia conditions. The leukocytes in the liver were separated to examine CD4+T cell subsets by flow cytometry and the left lobe of liver was used to observe pathological changes, collagen depositions and the concentrations of hydroxyproline. The most serious cystic and fibrotic changes appeared in FVB infected mice indicated by gross observation, Masson’s trichrome staining and hydroxyproline content detection. In contrast to C57BL/6 infected mice, diffuse nodules and more intensive fibrosis were observed in the BALB/c infected mice. No differences of the hepatic Th1 subset and Th17 subset were found among the three strains, but the hepatic Th2 and Treg cells and their relative cytokines were dramatically increased in the BALB/c and FVB infected groups compared with the C57BL/6 infected group (P<0.01). Importantly, increased Th2 subset and Treg subset all positively correlated with hydroxyproline contents (P<0.01). This result for the first time implied that the increased hepatic Th2 and Treg cell subsets were likely to play potential roles in the formation of biliary fibrosis in C. sinensis-infected mice. PMID:28151995

  7. Th2 Allergic Immune Response to Inhaled Fungal Antigens is Modulated By TLR-4-Independent Bacterial Products

    PubMed Central

    Allard, Jenna B.; Rinaldi, Lisa; Wargo, Matt; Allen, Gilman; Akira, Shizuo; Uematsu, Satoshi; Poynter, Matthew E.; Hogan, Deborah A.; Rincon, Mercedes; Whittaker, Laurie A.

    2009-01-01

    SUMMARY Allergic airway disease is characterized by eosinophilic inflammation, mucus hypersecretion and increased airway resistance. Fungal antigens are ubiquitous within the environment and are well know triggers of allergic disease. Bacterial products are also frequently encountered within the environment and may alter the immune response to certain antigens. The consequence of simultaneous exposure to bacterial and fungal products on the lung adaptive immune response has not been explored. Here we show that oropharyngeal aspiration of fungal lysates (Candida albicans, Aspergillus fumigatus) promotes airway eosinophilia, secretion of Th2 cytokines and mucus cell metaplasia. In contrast, oropharyngeal exposure to bacterial lysates (Pseudomonas aeruginosa) promotes airway inflammation characterized by neutrophils, Th1 cytokine secretion and no mucus production. More importantly, administration of bacterial lysates together with fungal lysates deviates the adaptive immune response to a Th1 type associated with neutrophilia and diminished mucus production. The immunomodulatory effect that bacterial lysates have on the response to fungi is TLR4-independent but MyD88 dependent. Thus, different types of microbial products within the airway can alter the host's adaptive immune response, and potentially impact the development of allergic airway disease to environmental fungal antigens. PMID:19224641

  8. Early Exposure of Infants to GI Nematodes Induces Th2 Dominant Immune Responses Which Are Unaffected by Periodic Anthelminthic Treatment

    PubMed Central

    Wright, Victoria J.; Ame, Shaali Makame; Haji, Haji Said; Weir, Rosemary E.; Goodman, David; Pritchard, David I.; Ramsan Mohamed, Mahdi; Haji, Hamad Juma; Tielsch, James M.; Stoltzfus, Rebecca J.; Bickle, Quentin D.

    2009-01-01

    We have previously shown a reduction in anaemia and wasting malnutrition in infants <3 years old in Pemba Island, Zanzibar, following repeated anthelminthic treatment for the endemic gastrointestinal (GI) nematodes Ascaris lumbricoides, hookworm and Trichuris trichiura. In view of the low intensity of worm infections in this age group, this was unexpected, and it was proposed that immune responses to the worms rather than their direct effects may play a significant role in morbidity in infants and that anthelminthic treatment may alleviate such effects. Therefore, the primary aims of this study were to characterise the immune response to initial/early GI nematode infections in infants and the effects of anthelminthic treatment on such immune responses. The frequency and levels of Th1/Th2 cytokines (IL-5, IL-13, IFN-γ and IL-10) induced by the worms were evaluated in 666 infants aged 6–24 months using the Whole Blood Assay. Ascaris and hookworm antigens induced predominantly Th2 cytokine responses, and levels of IL-5 and IL-13 were significantly correlated. The frequencies and levels of responses were higher for both Ascaris positive and hookworm positive infants compared with worm negative individuals, but very few infants made Trichuris-specific cytokine responses. Infants treated every 3 months with mebendazole showed a significantly lower prevalence of infection compared with placebo-treated controls at one year following baseline. At follow-up, cytokine responses to Ascaris and hookworm antigens, which remained Th2 biased, were increased compared with baseline but were not significantly affected by treatment. However, blood eosinophil levels, which were elevated in worm-infected children, were significantly lower in treated children. Thus the effect of deworming in this age group on anaemia and wasting malnutrition, which were replicated in this study, could not be explained by modification of cytokine responses but may be related to eosinophil function

  9. CD4(+) Th2 cells are directly regulated by IL-10 during allergic airway inflammation.

    PubMed

    Coomes, S M; Kannan, Y; Pelly, V S; Entwistle, L J; Guidi, R; Perez-Lloret, J; Nikolov, N; Müller, W; Wilson, M S

    2017-01-01

    Interleukin-10 (IL-10) is an important regulatory cytokine required to control allergy and asthma. IL-10-mediated regulation of T cell-mediated responses was previously thought to occur indirectly via antigen-presenting cells. However, IL-10 can act directly on regulatory T cells and T helper type 17 (Th17) cells. In the context of allergy, it is therefore unclear whether IL-10 can directly regulate T helper type 2 (Th2) cells and whether this is an important regulatory axis during allergic responses. We sought to determine whether IL-10 signaling in CD4(+) Th2 cells was an important mechanism of immune regulation during airway allergy. We demonstrate that IL-10 directly limits Th2 cell differentiation and survival in vitro and in vivo. Ablation of IL-10 signaling in Th2 cells led to enhanced Th2 cell survival and exacerbated pulmonary inflammation in a murine model of house dust mite allergy. Mechanistically, IL-10R signaling regulated the expression of several genes in Th2 cells, including granzyme B. Indeed, IL-10 increased granzyme B expression in Th2 cells and led to increased Th2 cell death, identifying an IL-10-regulated granzyme B axis in Th2 cells controlling Th2 cell survival. This study provides clear evidence that IL-10 exerts direct effects on Th2 cells, regulating the survival of Th2 cells and severity of Th2-mediated allergic airway inflammation.

  10. Gene expression profiles of hair and wool sheep reveal importance of Th2 immune mechanisms for increased resistance to.

    PubMed

    MacKinnon, K M; Bowdridge, S A; Kanevsky-Mullarky, I; Zajac, A M; Notter, D R

    2015-05-01

    Management of gastrointestinal parasites is a critical issue for sheep producers worldwide. Increases in the prevalence of drug-resistant worms have complicated parasite control and increased economic losses. Therefore, other methods of parasite control need to be assessed, including the use of genetically resistant animals in breeding programs. Hair sheep breeds such as the St. Croix have greater parasite resistance than conventional wool breeds. However, the immune mechanisms that control parasite resistance in hair or wool breeds have not yet been fully determined, and information on cytokine expression profiles for both wool sheep selected for increased resistance and hair sheep is limited. Our objective was to investigate gene expression differences in 24 parasite-resistant hair and 24 susceptible wool sheep to identify immune effectors associated with resistance to . One-half of the lambs were infected and sacrificed at 3 or 27 d after infection. Remaining lambs were not infected. Breed differences in expression of genes associated with Th1 and Th2 immune responses in lymph nodes and abomasal tissue were determined. Th2-associated genes included IL-4, IL-13, IL-5, IgE, the α chain of the IL-4 receptor, and the α chain of the high-affinity IgE receptor (FcεRI). Th1-associated genes included interferon gamma (IFN-γ), the p35 subunit of IL-12 (IL-12 p35), and the β1 and β2 chains of the IL-12 receptor (IL-12 Rβ1 and IL-12 Rβ2, respectively). In both hair and wool sheep, infection with resulted in greater expression of IgE, IL-13, IL-5, and IL-12 p35 and somewhat reduced expression of IFNγ in lymph nodes. In abomasal tissue, parasite infection resulted in greater IgE, IL-13, FcεRI, and IL-12 p35 expression in infected lambs compared with control lambs. Between breeds, hair sheep had a stronger Th2 response after infection than wool sheep, with increased expression of IgE and IL-13 and decreased expression of IFNγ in lymph nodes and increased expression

  11. Lead effects on development and function of bone marrow-derived dendritic cells promote Th2 immune responses

    SciTech Connect

    Gao Donghong; Mondal, Tapan K.; Lawrence, David A. . E-mail: lawrencd@wadsworth.org

    2007-07-01

    Although lead (Pb) has significant effects on the development and function of macrophages, B cells, and T cells and has been suggested to promote allergic asthma in mice and humans, Pb modulation of bone marrow (BM)-derived dendritic cells (DCs) and the resultant DC effects on Th1 and Th2 development have not been examined. Accordingly, we cultured BM cells with murine granulocyte macrophage-colony stimulating factor (mGM-CSF) {+-} PbCl{sub 2}. At day 10, culture supernatant (SN) and non-adherent cells were harvested for analysis. Additionally, day 10 non-adherent BM-DCs were harvested and recultured with mGM-CSF + LPS {+-} Pb for 2 days. The day 10 Pb exposure significantly inhibited BM-DC generation, based on CD11c expression. Although fewer DCs were generated with Pb, the existing Pb-exposed DCs had significantly greater MHC-II expression than did the non-Pb-exposed DCs. However, these differences diminished upon LPS stimulation. After LPS stimulation, CD80, CD86, CD40, CD54, and MHC-II were all up-regulated on both Pb-DCs and DCs, but Pb-DCs expressed significantly less CD80 than did DCs. The CD86:CD80 ratio suggests a Pb-DC potential for Th2 cell development. After LPS stimulation, IL-6, IL-10, IL-12 (p70), and TNF-{alpha} levels significantly increased with both Pb-DCs and DCs, but Pb-DCs produced significantly less cytokines than did DCs, except for IL-10, which further supports Pb-DC preferential skewing toward type-2 immunity. In vitro studies confirm that Pb-DCs have the ability to polarize antigen-specific T cells to Th2 cells. Pb-DCs also enhanced allogeneic and autologous T cell proliferation in vitro, and in vivo studies suggested that Pb-DCs inhibited Th1 effects on humoral and cell-mediated immunity. The Pb effect was mainly on DCs, rather than on T cells, and Pb's modification of DC function appears to be the main cause of Pb's promotion of type-2-related immunity, which may relate to Pb's enhanced activation of the Erk/MAP kinase pathway.

  12. Herbal medicine Gamgungtang down-regulates autoimmunity through induction of TH2 cytokine production by lymphocytes in experimental thyroiditis model.

    PubMed

    Sa, Eun-Ho; Jin, Un-Ho; Kim, Dong-Soo; Kang, Bong-Seok; Ha, Ki-Tae; Kim, June-Ki; Park, Won-Hwan; Kim, Cheorl-Ho

    2007-02-12

    The crude herbal formulation, Gamgungtang (GGT), has been shown to protect animals against a wide range of spontaneously developing or induced autoimmune diseases. We have previously reported that GGT shows marked down-regulation of several experimental autoimmune diseases. Although very effective at preventing thyroid infiltrates in mice immunized with mouse deglycosylated thyroglobulin and complete Freund's adjuvant and in spontaneous models of thyroiditis, it completely failed to modify experimental autoimmune thyroiditis (EAT) induced in mice immunized with mouse thyroglobulin and lipopolysaccharide. In this study, in an effort to elucidate the mechanisms by which GGT suppresses EAT, and autoimmunity in general, we investigated the in vivo effects of this drug on the Th1/Th2 lymphocyte balance, which is important for the induction or inhibition of autoreactivity. Naive SJL/J mice were treated orally for 5 days with GGT (80 mg/(kg day)). Spleen cells were obtained at various time points during the treatment period and were stimulated in vitro with concanavalin A. Interleukins IL-4, IL-10 and IL-12, transforming growth factor-beta (TGF-beta) and interferon-gamma (IFN-gamma) cytokine production was evaluated at the protein levels of the cytokines in the medium and mRNA expressions. A significant upregulation of IL-4, IL-10 and TGF-beta was observed following treatment with GGT, which peaked at day 5 (IL-10) or day 10 (IL-4). On the other hand, IL-12 and IFN-gamma production were either unchanged or decreased. It seems therefore that GGT induces in vivo a shift towards Th2 lymphocytes which may be one of the mechanisms of down-regulation of the autoimmune reactivity in EAT. Our observations indicate that down-regulation of TH1 cytokines (especially IL-12) and enhancement of Th2 cytokine production may play an important role in the control of T-cell-mediated autoimmunity. These data may contribute to the design of new immunomodulating treatments for a group of

  13. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

    PubMed

    Wu, Xin; Dou, Yannong; Yang, Yan; Bian, Difei; Luo, Jinque; Tong, Bei; Xia, Yufeng; Dai, Yue

    2015-08-15

    Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway.

  14. Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity.

    PubMed

    Plank, Maximilian W; Kaiko, Gerard E; Maltby, Steven; Weaver, Jessica; Tay, Hock L; Shen, Wei; Wilson, Mark S; Durum, Scott K; Foster, Paul S

    2017-03-01

    Th22 cells are a major source of IL-22 and have been found at sites of infection and in a range of inflammatory diseases. However, their molecular characteristics and functional roles remain largely unknown because of our inability to generate and isolate pure populations. We developed a novel Th22 differentiation assay and generated dual IL-22/IL-17A reporter mice to isolate and compare pure populations of cultured Th22 and Th17 cells. Il17a fate-mapping and transcriptional profiling provide evidence that these Th22 cells have never expressed IL-17A, suggesting that they are potentially a distinct cell lineage from Th17 cells under in vitro culture conditions. Interestingly, Th22 cells also expressed granzymes, IL-13, and increased levels of Tbet. Using transcription factor-deficient cells, we demonstrate that RORγt and Tbet act as positive and negative regulators of Th22 differentiation, respectively. Furthermore, under Th1 culture conditions in vitro, as well as in an IFN-γ-rich inflammatory environment in vivo, Th22 cells displayed marked plasticity toward IFN-γ production. Th22 cells also displayed plasticity under Th2 conditions in vitro by upregulating IL-13 expression. Our work has identified conditions to generate and characterize Th22 cells in vitro. Further, it provides evidence that Th22 cells develop independently of the Th17 lineage, while demonstrating plasticity toward both Th1- and Th2-type cells.

  15. Tilapia hepcidin (TH)2-3 as a transgene in transgenic fish enhances resistance to Vibrio vulnificus infection and causes variations in immune-related genes after infection by different bacterial species.

    PubMed

    Hsieh, Jung-Chen; Pan, Chieh-Yu; Chen, Jyh-Yih

    2010-09-01

    Hepcidin is an antimicrobial peptide (AMP) secreted by the liver during inflammation that plays a central role in mammalian iron homeostasis. But the function of hepcidin in fish is still not completely understood. We recently described three different hepcidins (named tilapia hepcidin (TH)1-5, TH2-2, and TH2-3) from tilapia Oreochromis mossambicus, the cDNA sequences were determined, the predicted peptides were synthesized, and the TH2-3 peptide showed antimicrobial activity against several bacteria. We hypothesized that TH2-3 may have a biological function like an AMP in fishes and can be used as a transgene to boost resistance against bacterial infection. To examine the antimicrobial effects of TH2-3, we produced and engineered the overexpression of TH2-3 in zebrafish (Danio rerio) and the convict cichlid (Archocentrus nigrofasciatus). The microinjected plasmid also contained a green fluorescent protein (GFP) which was used as an indicator to trace germline transmission. In vivo, transgenic TH2-3 fish (of the F3 generation) were challenged with Vibrio vulnificus (204) and Streptococcus agalactiae (SA). Results showed significant clearance of bacterial numbers of V. vulnificus (204) but not of S. agalactiae in transgenic TH2-3 fish. A gene expression study using a real-time RT-PCR revealed that transgenic TH2-3 zebrafish showed increased endogenous expressions of Myd88, tumor necrosis factor-alpha, and TRAM1 in vivo. After transgenic TH2-3 zebrafish were infected with V. vulnificus (204), interleukin (IL)-10, IL-26, lysozyme, toll-like receptor (TLR)-4a, and Myd88 were upregulated, but IL-1beta (at 12-24 h) and IL-15 (at 1-12 h) were downregulated post-infection. After transgenic TH2-3 zebrafish were infected with S. agalactiae, IL-1beta (at 1-24 h), IL-15 (at 6 h), IL-22 (at 1-6 h), and TLR3 (at 1-24 h) were downregulated, but TLR4a (at 6-12 h) and c3b (at 12 h) were upregulated post-infection. Our findings identify the TH2-3 transgene in transgenic fish as an

  16. Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation

    PubMed Central

    Dai, Min; Wei, Huafeng; Yip, Yuen Yee; Feng, Qinghua; He, Kecheng; Popov, Viorica; Hellstrom, Ingegerd; Hellstrom, Karl Erik

    2013-01-01

    Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137+PD-1+CTLA4 7-15 days following tumor initiation. Survival of mice with ID8 tumors tripled and >40% of mice with SW1 tumors remain healthy >150 days after later treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity and required CD4+ cells and involved CD8+ cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19+ cells at tumor sites, increased IFNγ and TNFα producing CD4+ and CD8+ T cells and mature CD86+ DC, and it increased the ratios of effector CD4+ and CD8+ T cells to CD4+Foxp3+ regulatory T cells and to CD11b+Gr-1+ myeloid suppressor cells. This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137+PD-1+CLA4+CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity. PMID:23603859

  17. Efficient lung recruitment of respiratory syncytial virus-specific Th1 cells induced by recombinant bacillus Calmette-Guérin promotes virus clearance and protects from infection.

    PubMed

    Cautivo, Kelly M; Bueno, Susan M; Cortes, Claudia M; Wozniak, Aniela; Riedel, Claudia A; Kalergis, Alexis M

    2010-12-15

    Infection by the respiratory syncytial virus (RSV) can cause extensive inflammation and lung damage in susceptible hosts due to a Th2-biased immune response. Such a deleterious inflammatory response can be enhanced by immunization with formalin- or UV-inactivated RSV, as well as with vaccinia virus expressing the RSV-G protein. Recently, we have shown that vaccination with rBCG-expressing RSV Ags can prevent the disease in the mouse. To further understand the immunological mechanisms responsible for protection against RSV, we have characterized the T cell populations contributing to virus clearance in mice immunized with this BCG-based vaccine. We found that both CD4(+) and CD8(+) T cells were recruited significantly earlier to the lungs of infected mice that were previously vaccinated. Furthermore, we observed that simultaneous adoptive transfer of CD8(+) and CD4(+) RSV-specific T cells from vaccinated mice was required to confer protection against virus infection in naive recipients. In addition, CD4(+) T cells induced by vaccination released IFN-γ after RSV challenge, indicating that protection is mediated by a Th1 immune response. These data suggest that vaccination with rBCG-expressing RSV Ags can induce a specific effector/memory Th1 immune response consisting on CD4(+) and CD8(+) T cells, both necessary for a fully protective response against RSV. These results support the notion that an effective induction of Th1 T cell immunity against RSV during childhood could counteract the unbalanced Th2-like immune response triggered by the natural RSV infection.

  18. Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4.

    PubMed

    Im, S H; Barchan, D; Maiti, P K; Fuchs, S; Souroujon, M C

    2001-06-01

    Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent Ab-mediated autoimmune disorders, in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1-type cells and costimulatory factors such as CD40 ligand (CD40L) contribute to disease pathogenesis by producing proinflammatory cytokines and by activating autoreactive B cells. In this study we demonstrate the capacity of CD40L blockade to modulate EAMG, and analyze the mechanism underlying this disease suppression. Anti-CD40L Abs given to rats at the chronic stage of EAMG suppress the clinical progression of the autoimmune process and lead to a decrease in the AChR-specific humoral response and delayed-type hypersensitivity. The cytokine profile of treated rats suggests that the underlying mechanism involves down-regulation of AChR-specific Th1-regulated responses with no significant effect on Th2- and Th3-regulated AChR-specific responses. EAMG suppression is also accompanied by a significant up-regulation of CTLA-4, whereas a series of costimulatory factors remain unchanged. Adoptive transfer of splenocytes from anti-CD40L-treated rats does not protect recipient rats against subsequently induced EAMG. Thus it seems that the suppressed progression of chronic EAMG by anti-CD40L treatment does not induce a switch from Th1 to Th2/Th3 regulation of the AChR-specific immune response and does not induce generation of regulatory cells. The ability of anti-CD40L treatment to suppress ongoing chronic EAMG suggests that blockade of CD40L may serve as a potential approach for the immunotherapy of MG and other Ab-mediated autoimmune diseases.

  19. Rat acute GvHD is Th1-driven and characterized by predominant donor CD4(+) T cell infiltration of skin and gut.

    PubMed

    Boieri, Margherita; Shah, Pranali; Jalapothu, Dasaradha; Zaitseva, Olena; Walter, Lutz; Rolstad, Bent; Naper, Christian; Dressel, Ralf; Inngjerdingen, Marit

    2017-02-23

    Acute graft-versus-host disease (aGvHD) remains a significant hurdle to successful treatment of many hematological disorders. The disease is caused by infiltration of allo-activated donor T cells primarily into the gastrointestinal tract and skin. While cytotoxic T cells mediate direct cellular damage, T helper (Th) cells differentially secrete immunoregulatory cytokines. Acute GvHD is thought to be primarily initiated by Th1 cells but a consensus is still lacking regarding the role of Th2 and Th17 cells. The aim of this study was to determine the contribution of distinct T cell subsets to aGvHD in the rat. Acute GvHD was induced by transplanting irradiated rats with T-cell depleted MHC-mismatched bone marrow, followed two weeks later by donor lymphocyte infusion. Near complete donor T cell chimerism was achieved in the blood and lymphatic tissues, in contrast to mixed chimerism in the skin and gut. Skin and gut donor T cells were predominantly CD4(+), in contrast to T cells in blood and lymphatic tissues. Genes associated with Th1 cells were up-regulated in gut, liver, lung, and skin tissues affected by aGvHD. Increased serum levels of CXCL10 and IL-18 preceded symptoms of aGvHD, accompanied by increased responsiveness to CXCL10 by blood CD4(+) T cells. No changes in expression of Th2- or Th17-associated genes were observed, indicating that aGvHD in this rat model is mainly Th1-driven. The rat model of aGvHD could be instrumental for further investigations of donor T cell subsets in the skin and gut, and for exploring therapeutic options to ameliorate symptoms of aGvHD.

  20. Interleukin-23 dependent IL-17 drives Th1 responses following Mycobacterium bovis BCG vaccination

    PubMed Central

    Gopal, Radha; Lin, Yinyao; Obermajer, Nataša; Slight, Samantha; Nuthalapati, Nikhil; Ahmed, Mushtaq; Kalinski, Pawel; Khader, Shabaana A

    2012-01-01

    Generation of effective T helper cell type 1 (Th1) responses are required for immunity against intracellular bacteria. However, some intracellular bacteria require Interleukin (IL)-17 to drive Th1 immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1 responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced Prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1 responses, while simultaneously inducing IL-23 and Th17 differentiation. The ability of IL-17 to down-regulate IL-10 and induce IL-12 production allows the generation of subsequent Th1 responses. Accordingly, BCG-induced Th17 responses precedes generation of Th1 responses in vivo, while absence of IL-23 pathway decreases BCG vaccine-induced Th17 and Th1 immunity and subsequent vaccine-induced protection upon M.tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1 responses occurs in an IL-17-independent manner. These novel data project the IL-23/IL-17 pathway in driving Th1 responses, specifically, to overcome IL-10 mediated inhibition and that in absence of IL-10, the generation of BCG induced Th1 immunity is IL-17-independent. PMID:22101830

  1. PLGA nano/micro particles encapsulated with pertussis toxoid (PTd) enhances Th1/Th17 immune response in a murine model.

    PubMed

    Li, Pan; Asokanathan, Catpagavalli; Liu, Fang; Khaing, Kyi Kyi; Kmiec, Dorota; Wei, Xiaoqing; Song, Bing; Xing, Dorothy; Kong, Deling

    2016-11-20

    Poly(lactic-co-glycolic acid) (PLGA) based nano/micro particles were investigated as a potential vaccine platform for pertussis antigen. Presentation of pertussis toxoid as nano/micro particles (NP/MP) gave similar antigen-specific IgG responses in mice compared to soluble antigen. Notably, in cell line based assays, it was found that PLGA based nano/micro particles enhanced the phagocytosis of fluorescent antigen-nano/micro particles by J774.2 murine monocyte/macrophage cells compared to soluble antigen. More importantly, when mice were immunised with the antigen-nano/micro particles they significantly increased antigen-specific Th1 cytokines INF-γ and IL-17 secretion in splenocytes after in vitro re-stimulation with heat killed Bordetalla pertussis, indicating the induction of a Th1/Th17 response. Also, presentation of pertussis antigen in a NP/MP formulation is able to provide protection against respiratory infection in a murine model. Thus, the NP/MP formulation may provide an alternative to conventional acellular vaccines to achieve a more balanced Th1/Th2 immune response.

  2. TH2 profile in asymptomatic Taenia solium human neurocysticercosis.

    PubMed

    Chavarría, Anahí; Roger, Beatrice; Fragoso, Gladis; Tapia, Graciela; Fleury, Agnes; Dumas, Michel; Dessein, Alain; Larralde, Carlos; Sciutto, Edda

    2003-10-01

    Neurocysticercosis (NC), a parasitic disease caused by Taenia solium, may be either asymptomatic or have mild to severe symptoms due to several factors. In this study, the immunological factors that underlie NC pleomorphism were studied. Ten of the 132 inhabitants of a rural community in Mexico (Tepez) had a computerized tomography (CT) scan compatible with calcified NC, and all were asymptomatic. Their immunological profiles were compared with those of 122 CT scan negative (non-NC) subjects from the same village. NC was associated with a TH2 response (IgG4, IL-4, IL-5, IL-13). Subjects from Tepez had higher levels of specific antibodies (IgG1, IgG2, IgG4, IgE) and specific cell proliferation than subjects from an area with low exposure (Ensenada). This suggests that non-NC subjects from Tepez had been exposed to T. solium and resisted infection in the brain. Distinct immunological profiles in equally exposed individuals differing in outcome of infection support the hypothesis of host-related factors in resistance to and pathogenesis of NC. This is the first study reporting the immunological profile associated with the asymptomatic form of NC.

  3. Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma.

    PubMed

    Fowler, D H; Gress, R E

    2000-07-01

    Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graft rejection; however, T cells also initiate graft-versus-host disease (GVHD). Identification of T cell populations which mediate a GVL effect and prevent rejection with reduced GVHD will likely improve transplantation outcome. T cells exist in four functionally-defined populations, the CD4+, Th1/Th2 and CD8+, Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokines (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differentially secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, with Tc1 cells utilizing both perforin- and fas-based killing pathways, whereas Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to differentially mediate and regulate transplantation responses. These studies demonstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloengraftment. Additional experiments have shown that allospecific donor Tc2 cells result in reduced GVHD, and mediate a significant GVL effect. Thirdly, we have demonstrated that non-host reactive Tc2 cells with veto-like activity can potently abrogate marrow rejection independent of GVHD. Together, these results demonstrate that functionally-defined donor Th2 and Tc2 populations play an important role in the regulation of GVHD, the prevention of graft rejection, and the mediation of GVL effects, and suggest that utilization of Th2 and Tc2 cells in clinical allogeneic SCT may have potential

  4. Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage

    PubMed Central

    Quispe Calla, Nirk E.; Pavelko, Stephen D.; Cherpes, Thomas L.

    2016-01-01

    While ascension of Chlamydia trachomatis into the upper genital tract of women can cause pelvic inflammatory disease and Fallopian tube damage, most infections elicit no symptoms or overt upper genital tract pathology. Consistent with this asymptomatic clinical presentation, genital C. trachomatis infection of women generates robust TH2 immunity. As an animal model that modeled this response would be invaluable for delineating bacterial pathogenesis and human host defenses, herein we explored if pathogen-specific TH2 immunity is similarly elicited by intravaginal (ivag) infection of mice with oculogenital C. trachomatis serovars. Analogous to clinical infection, ascension of primary C. trachomatis infection into the mouse upper genital tract produced no obvious tissue damage. Clearance of ivag challenge infection was mediated by interferon (IFN)-γ-producing CD4+ T cells, while IFN-γ signaling blockade concomitant with a single ivag challenge promoted tissue damage by enhancing Chlamydia-specific TH17 immunity. Likewise, IFN-γ and IL-17 signaling blockade or CD4+ T cell depletion eliminated the genital pathology produced in untreated controls by multiple ivag challenge infections. Conversely, we were unable to detect formation of pathogen-specific TH2 immunity in C. trachomatis-infected mice. Together, our work revealed C. trachomatis infection of mice generates TH1 and TH17 immune responses that promote pathogen clearance and immunopathological tissue damage. Absence of Chlamydia-specific TH2 immunity in these mice newly highlights the need to identify experimental models of C. trachomatis genital infection that more closely recapitulate the human host response. PMID:27606424

  5. Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo.

    PubMed

    Erdmann, Andreas A; Gao, Zhan-Guo; Jung, Unsu; Foley, Jason; Borenstein, Todd; Jacobson, Kenneth A; Fowler, Daniel H

    2005-06-15

    To evaluate the direct effect of adenosine on cytokine-polarized effector T cells, murine type 1 helper T cells (Th1) and type 1 cytotoxic T lymphocytes (Tc1) and Th2/Tc2 cells were generated using an antigen-presenting cell (APC)-free method. Tc1 and Tc2 cells had similar adenosine signaling, as measured by intracellular cyclic AMP (cAMP) increase upon adenosine A(2A) receptor agonism by CGS21680 (CGS). CGS greatly reduced Tc1 and Tc2 cell interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) secretion, with nominal effect on interferon gamma (IFN-gamma) secretion. Tc2 cell IL-4 and IL-5 secretion was not reduced by CGS, and IL-10 secretion was moderately reduced. Agonist-mediated inhibition of IL-2 and TNF-alpha secretion occurred via A(2A) receptors, with no involvement of A(1), A(2B), or A(3) receptors. Adenosine agonist concentrations that abrogated cytokine secretion did not inhibit Tc1 or Tc2 cell cytolytic function. Adenosine modulated effector T cells in vivo, as CGS administration reduced CD4(+)Th1 and CD8(+)Tc1 cell expansion to alloantigen and, in a separate model, reduced antigen-specific CD4(+) Th1 cell numbers. Remarkably, agonist-mediated T-cell inhibition was abrogated by in vivo IL-2 therapy. Adenosine receptor activation therefore preferentially inhibits type I cytokine secretion, most notably IL-2. Modulation of adenosine receptors may thus represent a suitable target primarily for inflammatory conditions mediated by Th1 and Tc1 cells.

  6. High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon FcγR triggering

    PubMed Central

    Radstake, T; van Lent, P L E M; Pesman, G; Blom, A; Sweep, F; Ronnelid, J; Adema, G; Barrera, P; van den Berg, W B

    2004-01-01

    Objective: To assess whether DC from RA produce altered cytokine levels and whether this is regulated by triggering of Fc gamma receptors (FcγR). Methods: The production of proinflammatory (TNFα, IL1, IL6), Th1 (IL12, IFNγ), and Th2 (IL10) cytokine profiles of immature DC (iDC) from patients with RA and healthy subjects upon triggering of FcγR dependent and independent pathways was investigated. iDC, derived from blood monocytes by standardised protocols, were stimulated with immune complexes (IC) at day 6 for 48 hours and, subsequently, for 2 days with LPS in the presence or absence of IC or IFNγ, resulting in fully matured DC (mDC). IL1, IL6, TNFα, IFNγ, IL12, and IL10 levels in supernatants were measured by ELISA and RIA. Results: mDC from patients with RA showed a markedly increased production of IL1, IL6, TNFα, and IL10 compared with DC from healthy donors. Triggering of FcγR decreased the production of proinflammatory cytokines IL1, IL12, and IFNγ by iDC and mDC in RA and controls. The production of IL6 and TNFα decreased in patients with RA, whereas it was increased in controls. Triggering of FcγR independent mechanisms using IFNγ increased the production of proinflammatory and Th1 cytokines, which was more pronounced in RA. Conclusion: FcγR dependent pathways influence cytokine production by DC. A skewed balance towards proinflammatory and Th1 cytokines in RA can, at least partly, be restored by triggering FcγR on DC in RA. Insight into the mechanism which determines the FcγR balance might lead to new strategies to abrogate Th1 driven inflammatory processes in RA. PMID:15140777

  7. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells.

    PubMed

    Amarnath, Shoba; Mangus, Courtney W; Wang, James C M; Wei, Fang; He, Alice; Kapoor, Veena; Foley, Jason E; Massey, Paul R; Felizardo, Tania C; Riley, James L; Levine, Bruce L; June, Carl H; Medin, Jeffrey A; Fowler, Daniel H

    2011-11-30

    Immune surveillance by T helper type 1 (T(H)1) cells is not only critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GVHD) after transplantation. The inhibitory molecule programmed death ligand 1 (PDL1) has been shown to anergize human T(H)1 cells, but other mechanisms of PDL1-mediated T(H)1 inhibition such as the conversion of T(H)1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause T(H)1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET(+) T(H)1 cells into FOXP3(+) regulatory T (T(reg)) cells in vivo, thereby preventing human-into-mouse xenogeneic GVHD (xGVHD). Either blocking PD1 expression on T(H)1 cells by small interfering RNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized T(H)1 cell differentiation during PDL1 challenge and restored the capacity of T(H)1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human T(H)1 cells to manifest in vivo plasticity, resulting in a T(reg) phenotype that severely impairs cell-mediated immunity. Converting human T(H)1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GVHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection.

  8. The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice

    PubMed Central

    Chowdhury, Sayan; Mukherjee, Tulika; Mukhopadhyay, Rupkatha; Mukherjee, Budhaditya; Sengupta, Souvik; Chattopadhyay, Sharmila; Jaisankar, Parasuraman; Roy, Syamal; Majumder, Hemanta K

    2012-01-01

    Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA–protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non-competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA–protein binary complexes and thus stabilizes the ‘cleavable complex’ formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis. PMID:23027614

  9. The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice.

    PubMed

    Chowdhury, Sayan; Mukherjee, Tulika; Mukhopadhyay, Rupkatha; Mukherjee, Budhaditya; Sengupta, Souvik; Chattopadhyay, Sharmila; Jaisankar, Parasuraman; Roy, Syamal; Majumder, Hemanta K

    2012-10-01

    Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA-protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non-competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA-protein binary complexes and thus stabilizes the 'cleavable complex' formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis.

  10. IFNγ and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNγ from Th2 Cells

    PubMed Central

    Coomes, Stephanie M.; Pelly, Victoria S.; Kannan, Yashaswini; Okoye, Isobel S.; Czieso, Stephanie; Entwistle, Lewis J.; Perez-Lloret, Jimena; Nikolov, Nikolay; Potocnik, Alexandre J.; Biró, Judit; Langhorne, Jean; Wilson, Mark S.

    2015-01-01

    Parasitic helminths establish chronic infections in mammalian hosts. Helminth/Plasmodium co-infections occur frequently in endemic areas. However, it is unclear whether Plasmodium infections compromise anti-helminth immunity, contributing to the chronicity of infection. Immunity to Plasmodium or helminths requires divergent CD4+ T cell-driven responses, dominated by IFNγ or IL-4, respectively. Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines. Whether such plasticity occurs during co-infection is unclear. In this study, we observed reduced anti-helminth Th2 cell responses and compromised anti-helminth immunity during Heligmosomoides polygyrus and Plasmodium chabaudi co-infection. Using newly established triple cytokine reporter mice (Il4gfpIfngyfpIl17aFP635), we demonstrated that Il4gfp+ Th2 cells purified from in vitro cultures or isolated ex vivo from helminth-infected mice up-regulated IFNγ following adoptive transfer into Rag1–/– mice infected with P. chabaudi. Functionally, Th2 cells that up-regulated IFNγ were transcriptionally re-wired and protected recipient mice from high parasitemia. Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells. Finally, blockade of IL-12 and IFNγ during co-infection partially preserved anti-helminth Th2 responses. In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection. Consequently, co-infection with Plasmodium spp. may contribute to the chronicity of helminth infection by reducing anti-helminth Th2 cells and converting them into IFNγ-secreting cells. PMID:26147567

  11. Homeopathic medicines cause Th1 predominance and induce spleen and megakaryocytes changes in BALB/c mice infected with Leishmania infantum.

    PubMed

    Cajueiro, Ana Paula Bacellar; Goma, Ester Puna; Dos Santos, Hilton Antônio Mata; Almeida Rodrigues, Igor; Toma, Helena Keiko; Araújo, Silvana Marques; Bonamin, Leoni Villano; Gomes, Nelson Brêtas de Noronha; Castelo-Branco, Morgana Teixeira Lima; de Souza Dias, Edilma Paraguai; Dos Santos Pyrrho, Alexandre; Holandino, Carla

    2017-02-27

    The prevalence of Th1/Th2 response, spleen changes and megakaryocytes were investigated in BALB/c mice (n=138) infected with Leishmania infantum, and treated with Leishmania infantum 30× (10(-30)) biotherapy - BioLi30×. We performed controlled experiments using 8-to-12-week-old mice, infected with 5×10(7)L. infantum promastigotes, divided into eight groups: G1 (healthy), G2 (infected with L. infantum), G3 (BioLi30× pre-treated), G4 (BioLi30× pre/post-treated), G5 (BioLi30× post-treated), G6 (Water 30× post-treated), G7 (Antimonium crudum 30× post-treated) and G8 (Glucantime® post-treated). G3-G7 groups were orally treated with their respective drugs diluted in filtered water (1:10), and G8 received Glucantime® (0.6mg/100µl of PBS), intraperitoneally. Spleen fragments were submitted to double blind histopathological evaluation and the number of megakaryocytes was counted. Besides, animals' serum was measured after 49days of infection, and cytokines (IFN-γ, IL-4, IL-10, IL-12), as well as the Th1/Th2 correlation (IFN-γ/IL-4 and IFN-γ/IL-10), were analyzed. Spleen histological parameters were classified as: healthy appearance (G1); discreet (G3-G7), moderate (G2) and moderate to severe (G8) white pulp hyperplasia; proliferation of megakaryocytes (G2-G8), and intense disruption (G2-G8). All groups, except for G7, showed higher percentages of megakaryocytes per field ranging from 87% to 15%, when compared to healthy animals (G1). Th1 predominance in IFN-γ/IL-4 ratio (comparing to G2) was detected in G4, G5, G6 and G7. Finally, pre/post (BioLi30x) and post-treatment (Antimonium crudum 30x) presented reduction of megakaryocytes/spleen changes due to immunomodulation animal process, controlling the infection process, probably by the Th1 cytokine predominance.

  12. Cyclosporine A enhances Th2 bias at the maternal-fetal interface in early human pregnancy with aid of the interaction between maternal and fetal cells.

    PubMed

    Piao, Hai-Lan; Wang, Song-Cun; Tao, Yu; Zhu, Rui; Sun, Chan; Fu, Qiang; Du, Mei-Rong; Li, Da-Jin

    2012-01-01

    Our previous study has demonstrated that cyclosporine A (CsA) administration in vivo induces Th2 bias at the maternal-fetal interface, leading to improved murine pregnancy outcomes. Here, we investigated how CsA treatment in vitro induced Th2 bias at the human maternal-fetal interface in early pregnancy. The cell co-culture in vitro in different combination of component cells at the maternal-fetal interface was established to investigate the regulation of CsA on cytokine production from the interaction of these cells. It was found that interferon (IFN)-γ was produced only by decidual immune cells (DICs), and not by trophoblasts or decidual stromal cells (DSCs); all these cells secreted interleukin (IL)-4, IL-10, and tumor necrosis factor (TNF)-α. Treatment with CsA completely blocked IFN-γ production in DICs and inhibited TNF-α production in all examined cells. CsA increased IL-10 and IL-4 production in trophoblasts co-cultured with DSCs and DICs although CsA treatment did not affect IL-10 or IL-4 production in any of the cells when cultured alone. These results suggest that CsA promotes Th2 bias at the maternal-fetal interface by increasing Th2-type cytokine production in trophoblasts with the aid of DSCs and DICs, while inhibiting Th1-type cytokine production in DICs and TNF-α production in all investigated cells. Our study might be useful in clinical therapeutics for spontaneous pregnancy wastage and other pregnancy complications.

  13. Different growth factor requirements for human Th2 cells may reflect in vivo induced anergy.

    PubMed Central

    Van Reijsen, F C; Wijburg, O L; Gebhardt, M; Van Ieperen-Van Dijk, A G; Betz, S; Poellabauer, E M; Thepen, T; Bruijnzeel-Koomen, C A; Mudde, G C

    1994-01-01

    We previously reported the isolation of allergen-specific Th2 lines and clones from atopy patch test (APT) sites of atopic dermatitis (AD) patients. Upon stimulation with allergen or anti-CD3+ phorbol myristate acetate (PMA) IL-4 was released with or without IL-5, while no (or extremely low concentrations of) IL-2 and interferon-gamma (IFN-gamma) were detectable. A high IL-4/IFN-gamma ratio facilitates production of allergen-specific IgE, of which high levels are observed in AD patients. Here we show that the above mentioned Th2 cells are notably different from murine Th2 cells. Not IL-4, which is the autocrine acting growth factor for murine Th2 cells, but IL-2 was needed for proliferation of these human APT-derived Th2 lines and clones. Of significance, unless exogenous IL-2 was added, no proliferative response to allergen, presented by Epstein-Barr virus-transformed B (EBV-B) cells, non-T cells or IgE-bearing Langerhans cells (LC), occurred. Lack of proliferation and IL-2 production after full T cell receptor (TCR) triggering is a characteristic first described for in vitro anergized T cells. However, like the clones we describe in this study, anergic T cells may retain production of cytokines other than IL-2. A further resemblance between anergic T cells and the human Th2 clones reported here is that IL-4 can enhance IL-2-driven proliferation, but is not capable of inducing T cell growth by itself. The absence of IL-4-driven proliferation differentiates human Th2 cells from murine Th2 cells. Both produce IL-4 when stimulated in a cognate fashion, but only murine Th2 cells will proliferate. We conclude that the presently reported human Th2 cells are different from murine Th2 cells, in that they need other T cells to produce IL-2 required for their expansion. Moreover, the Th2 cells phenotypically resemble anergic T cells. As yet, however, we have no clue as to whether these features account for the current Th2 cells only or for human Th2 cells in general. We

  14. Gαq Regulates the Development of Rheumatoid Arthritis by Modulating Th1 Differentiation

    PubMed Central

    Wang, Dashan; Liu, Yuan; Li, Yan; Zhang, Jiyun

    2017-01-01

    The Gαq-containing G protein, an important member of Gq/11 class, is ubiquitously expressed in mammalian cells. Gαq has been found to play an important role in immune regulation and development of autoimmune disease such as rheumatoid arthritis (RA). However, how Gαq participates in the pathogenesis of RA is still not fully understood. In the present study, we aimed to find out whether Gαq controls RA via regulation of Th1 differentiation. We observed that the expression of Gαq was negatively correlated with the expression of signature Th1 cytokine (IFN-γ) in RA patients, which suggests a negative role of Gαq in differentiation of Th1 cells. By using Gαq knockout (Gnaq−/−) mice, we demonstrated that loss of Gαq led to enhanced Th1 cell differentiation. Gαq negative regulated the differentiation of Th1 cell by modulating the expression of T-bet and the activity of STAT4. Furthermore, we detected the increased ratio of Th1 cells in Gnaq−/− bone marrow (BM) chimeras spontaneously developing inflammatory arthritis. In conclusion, results presented in the study demonstrate that loss of Gαq promotes the differentiation of Th1 cells and contributes to the pathogenesis of RA. PMID:28197018

  15. Retnla (Relma/Fizz1) suppresses helminth-induced Th2-Type immunity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. Using Retnla deficient (-/-) mice and three helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite...

  16. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal...

  17. Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway.

    PubMed

    Lou, Hongfei; Lu, Jingning; Choi, Eun Byul; Oh, Min Hee; Jeong, Mingeum; Barmettler, Sara; Zhu, Zhou; Zheng, Tao

    2017-04-01

    Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show in the present study that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, downregulation of epidermal differentiation complex genes, and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially upregulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP(+) cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (thymic stromal lymphopoietin and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced thymic stromal lymphopoietin but it also increased the expression of IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway.

  18. Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention

    PubMed Central

    Nocera, Nadia F.; Lee, M. Catherine; De La Cruz, Lucy M.; Rosemblit, Cinthia; Czerniecki, Brian J.

    2016-01-01

    The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer. PMID:27766079

  19. Release from Th1-type immune tolerance in spleen and enhanced production of IL-5 in Peyer's patch by cholera toxin B induce the glomerular deposition of IgA.

    PubMed

    Yamanaka, Takahiro; Tamauchi, Hidekazu; Suzuki, Yusuke; Suzuki, Hitoshi; Horikoshi, Satoshi; Terashima, Masazumi; Iwabuchi, Kazuya; Habu, Sonoko; Okumura, Ko; Tomino, Yasuhiko

    2016-04-01

    We examined the pathogenesis of glomerular damage in Th2 type-dependent GATA-3 transgenic (GATA-3 Tg) mice with IgA nephropathy (IgAN). GATA-3 Tg mice were immunized orally using OVA plus cholera toxin B (CTB), and measurement of the serum IgA antibody level and histopathological examination were performed. Marked increases in the serum levels of OVA-specific IgA antibody, IgA and IgG, C3 deposits analogous to those seen in IgAN, and expansion of the matrix in association with mesangial cell proliferation were observed. Furthermore, glomerular IgA deposits were co-localized with mannan-binding lectin (MBL) deposits, which might actually have been abnormal IgA deposits. In GATA-3/TCR-Tg mice that had been orally sensitized with CTB plus OVA and were re-stimulated with OVA in vitro, cultured Peyer's patch cells showed the enhanced production of IL-5 and supernatants from cultures of spleen cells showed a reduction of TGF-β production with a simultaneous increase in IL-2 production and the recovery of IFN-γ formation. The amount of TGF-β produced by the spleen cells was found to be correlated with the amount of IFN-γ and IL-IL-2 produced by the cells. Also, the percentage of regulatory T cells (Treg) in the spleens of mice sensitized with OVA plus CTB was lower than that in mice orally sensitized with OVA alone. These results suggest that the increased production of IL-5 from Peyer's patch cells (PPc) and the restored Th1-type immune response might cause the production of abnormal IgA and might induce the deposition of IgA in glomeruli.

  20. Oral Treatment with Extract of Agaricus blazei Murill Enhanced Th1 Response through Intestinal Epithelial Cells and Suppressed OVA-Sensitized Allergy in Mice

    PubMed Central

    Bouike, Go; Nishitani, Yosuke; Shiomi, Hideyuki; Yoshida, Masaru; Azuma, Takeshi; Hashimoto, Takashi; Kanazawa, Kazuki; Mizuno, Masashi

    2011-01-01

    To clarify the mechanism of the antiallergic activity of Agaricus blazei Murill extract (ABME), the present paper used an in vivo allergy model and an in vitro intestinal gut model. During OVA sensitization, the serum IgE levels decreased significantly in ABME group. Interleukin (IL)-4 and -5 produced from OVA-restimulated splenocytes was significantly decreased, and anti-CD3ε/CD28 antibody treatment also reduced IL-10, -4, and -5 production and increased IFN-γ production in ABME group. These results suggest that oral administration of ABME improves Th1/Th2 balance. Moreover, a coculture system constructed of Caco-2 cells and splenocytes from OT-II mice or RAW 264.7 cells indicated that the significant increases in IFN-γ production by ABME treatment. Therefore, it was concluded that the antiallergic activity of ABME was due to the activation of macrophages by epithelial cells and the promotion of the differentiation of naïve T cells into Th1 cells in the immune. PMID:20953432

  1. Augmentation of immune response by chicoric acid through the modulation of CD28/CTLA-4 and Th1 pathway in chronically stressed mice.

    PubMed

    Kour, Kiranjeet; Bani, Sarang

    2011-05-01

    This study demonstrates the protective effect of chicoric acid (CA) on chronic restraint stress-induced altered T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental Swiss albino mice. CA has the potential to restore diminished immune response and Th1/Th2 homeostasis in chronically stressed mice as evident by significant increase in lymphocyte proliferation and CD3(+), CD4(+) and CD8(+) T cell population. Interestingly, chicoric acid imparted immunostimulation mainly by upregulating the expression of CD28 and CD80 and downregulating CTLA-4. It exerted stimulatory effect on IL-12, IFN-gamma and IL-2 and suppressed the increased IL-10 levels in chronically stressed mice. It also exhibited a significant lowering effect on raised corticosterone levels and reversed the chronic stress-induced hypertrophy of adrenal glands and atrophy of thymus and spleen, thereby showing its normalizing effect on HPA axis. Our results reveal that CA has the potential to reverse the impact of chronic restraint stress on immune status by normalizing corticosterone levels and augmenting Th1 cytokine profile along with the co-stimulatory molecules particularly CD28/CTLA-4 pathway that plays a very important role in generation of an effective immune response in immune compromised situations.

  2. The Relationship between the Antitumor Effect of the IL-12 Gene Therapy and the Expression of Th1 Cytokines in an HPV16-Positive Murine Tumor Model

    PubMed Central

    García Paz, Flor; Madrid Marina, Vicente; Morales Ortega, Ausencio; Santander González, Abimelec; Peralta Zaragoza, Oscar; Burguete García, Ana; Torres Poveda, Kirvis; Moreno, José; Alcocer González, Juan; Hernandez Marquez, Eva; Bermúdez Morales, Victor

    2014-01-01

    Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12's antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer. PMID:24808638

  3. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

    PubMed Central

    Entwistle, Lewis J.; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R.; Ching-Cheng Huang, Stanley; Pearce, Edward J.; Pedro S. de Carvalho, Luiz; Ley, Steven C.

    2016-01-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8–/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8–/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  4. Ethyl pyruvate ameliorates experimental colitis in mice by inhibiting the HMGB1-Th17 and Th1/Tc1 responses.

    PubMed

    Guo, Xianghua; Guo, Runhua; Luo, Xia; Zhou, Lian

    2015-12-01

    Ethyl pyruvate (EP), a simple lipophilic pyruvate ester, has demonstrated protective effects against murine colitis through inhibition the release of inflammatory factor high-mobility group protein box 1 (HMGB1). HMGB1 has been implicated in several autoimmune diseases by inducing Thl and Thl7 cells activation. This study was designed to investigate whether EP amelioration of murine colitis is related to the blocking of the HMGB1-Th17/Thl pathway. We induced murine colitis by intrarectal administration of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Ethyl pyruvate was injected intraperitoneally once a day for 7days. One week after intrarectal challenge with TNBS, HMGB1, IL-17 and IFN-γ protein levels were remarkably increased following severe colon inflammation. Meanwhile, excessive infiltration of Th17 cells in colonic tissues, and an upregulated proportion of Th17 and Th1/Tc1 cells in the spleen and mesenteric lymph nodes (MLN) were found in the TNBS-treated group compared to the control group. Treatment with the HMGB1 inhibitor EP not only remarkably improved colon pathological damage, but also significantly reduced the number of Th17 cells in the local tissues of the colitis-induced mice. Furthermore, the percentage of Th1/Tc1 and Th17 cells in the spleen and MLN, as well as levels of serum IFN-γ and IL-17A, were all markedly decreased in the EP-treated group. Moreover, in vitro, our results showed that EP in a dose dependent manner inhibited HMGB1 release induced by LPS from CT26 cells (murine colon adenocarcinoma cell line). These results suggest that HMGB1 contributes to the development of murine colitis by promoting the Th17 and Th1/Tc1 responses, and that EP can significantly inhibit HMGB1-Th17 and Thl/Tc1 pathway activation, which may provide better protection to mice with TNBS-induced colitis.

  5. Th1 Cytokine Production Induced by Lactobacillus acidophilus in BALB/c Mice Bearing Transplanted Breast Tumor

    PubMed Central

    Imani Fooladi, Abbas Ali; Yazdi, Mohammad Hossein; Pourmand, Mohammad Reza; Mirshafiey, Abbas; Hassan, Zuhair Mohammad; Azizi, Taghi; Mahdavi, Mehdi; Soltan Dallal, Mohammad Mehdi

    2015-01-01

    Background: The immunomodulative effects of Lactic Acid Bacteria as probiotics have been already demonstrated. Objectives: The current study aimed to evaluate the effect of oral administration of Lactobacillus acidophilus on the immune responses and patterns of cytokine production in the BALB/c mice bearing breast cancer. Materials and Methods: The current study used thirty inbred BALB/c mice, six- to eight-week-old; they were divided into two groups of 15 each. One group was used as control in each assay. The L. acidophilus (ATCC4356) used in the study was inoculated in MRS broth and cultivated overnight at 37°C under anaerobic conditions, then collected by centrifugation, and re-suspended in Phosphate-buffered Saline (PBS) media. After preparation of the proper amount of the suspension, it was orally administered to the mice via gavage and the control mice received an equal volume of PBS in the same manner. Results: The results showed that oral administration of L. acidophilus as a potent immunostimulator agent could motivate the proliferation of immune cells. Moreover, it could increase the production of IFN-γ and decrease the production of IL-4, known as Th2 cytokines, in the spleen cell culture. The results showed that the survival time of the L. acidophilus administered mice significantly increased in comparison to that of the control mice. Conclusions: The current study findings suggested that L. acidophilus can promote immune responses with Th1 bias and may increase the antitumor response. Further, the consumption of this probiotic strain may help to manage the immune response in tumor condition, but more studies are needed to investigate the other mechanisms of this effect. PMID:26034546

  6. T Cell Polarization toward TH2/TFH2 and TH17/TFH17 in Patients with IgG4-Related Disease

    PubMed Central

    Grados, Aurélie; Ebbo, Mikael; Piperoglou, Christelle; Groh, Matthieu; Regent, Alexis; Samson, Maxime; Terrier, Benjamin; Loundou, Anderson; Morel, Nathalie; Audia, Sylvain; Maurier, François; Graveleau, Julie; Hamidou, Mohamed; Forestier, Amandine; Palat, Sylvain; Bernit, Emmanuelle; Bonotte, Bernard; Farnarier, Catherine; Harlé, Jean-Robert; Costedoat-Chalumeau, Nathalie; Vély, Frédéric; Schleinitz, Nicolas

    2017-01-01

    IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease’s pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes’ subsets were analyzed by flow cytometry, with analysis of TH1/TH2/TH17, TFH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjögren’s syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, TH2, TH17, and CD4+CXCR5+PD1+ TFH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. TFH increase was characterized by the specific expansion of TFH2 (CCR6−CXCR3−), and to a lesser extent of TFH17 (CCR6+CXCR3−) cells. Interestingly, CD4+CXCR5+PD1+ TFH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a TH2/TFH2 and TH17/TFH17 polarization. This immunological imbalance might be implicated in the disease’s pathophysiology. Treatment regimens targeting such T cells warrant further evaluation. PMID:28348556

  7. Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity.

    PubMed

    Heijink, Irene H; Kies, P Marcel; Kauffman, Henk F; Postma, Dirkje S; van Oosterhout, Antoon J M; Vellenga, Edo

    2007-06-15

    Airway epithelial cells are well-known producers of thymus- and activation-regulated chemokine (TARC), a Th2 cell-attracting chemokine that may play an important role in the development of allergic airway inflammation. However, the mechanism responsible for up-regulation of TARC in allergy is still unknown. In the asthmatic airways, loss of expression of the cell-cell contact molecule E-cadherin and reduced epithelial barrier function has been observed, which may be the result of an inadequate repair response. Because E-cadherin also suppressed multiple signaling pathways, we studied whether disruption of E-cadherin-mediated cell contact may contribute to increased proallergic activity of epithelial cells, e.g., production of the chemokine TARC. We down-regulated E-cadherin in bronchial epithelial cells by small interference RNA and studied effects on electrical resistance, signaling pathways, and TARC expression (by electric cell-substrate impedance sensing, immunodetection, immunofluorescent staining, and real-time PCR). Small interference RNA silencing of E-cadherin resulted in loss of E-cadherin-mediated junctions, enhanced phosphorylation of epidermal growth factor receptor (EGFR), and the downstream targets MEK/ERK-1/2 and p38 MAPK, finally resulting in up-regulation of TARC as well as thymic stromal lymphopoietin expression. The use of specific inhibitors revealed that the effect on TARC is mediated by EGFR-dependent activation of the MAPK pathways. In contrast to TARC, expression of the Th1/Treg cell-attracting chemokine RANTES was unaffected by E-cadherin down-regulation. In summary, we show that loss of E-cadherin-mediated epithelial cell-cell contact by damaging stimuli, e.g., allergens, may result in reduced suppression of EGFR-dependent signaling pathways and subsequent induction of Th2 cell-attracting molecule TARC. Thus, disruption of intercellular epithelial contacts may specifically promote Th2 cell recruitment in allergic asthma.

  8. Effect of Malnutrition on the Expression of Cytokines Involved in Th1 Cell Differentiation

    PubMed Central

    González-Torres, Cristina; González-Martínez, Haydeé; Miliar, Angel; Nájera, Oralia; Graniel, Jaime; Firo, Verónica; Alvarez, Catalina; Bonilla, Edmundo; Rodríguez, Leonor

    2013-01-01

    Malnutrition is a common cause of secondary immune deficiency and has been linked to an increased susceptibility to infection in humans. Malnutrition specifically affects T-cell-mediated immune responses. The aim of this study was to assess in lymphocytes from malnourished children the expression levels of IL-12, IL-18 and IL-21, molecules that induce the differentiation of T cells related to the immunological cellular response (Th1 response) and the production of cytokines related to the immunological cellular response (Th1 cytokines). We found that the expression levels of IL-12, IL-18 and IL-21 were significantly diminished in malnourished children compared to well-nourished children and were coincident with lower plasmatic levels of IL-2 and IFN-γ (Th1 cytokines). In this study, we show for the first time that the gene expression and intracellular production of cytokines responsible for Th1 cell differentiation (IL-12, IL-18 and IL-21) are diminished in malnourished children. As expected, this finding was related to lower plasmatic levels of IL-2 and IFN-γ. The decreased expression of Th1 cytokines observed in this study may contribute to the deterioration of the immunological Type 1 (cellular) response. We hypothesize that the decreased production of IL-12, IL-18 and IL-21 in malnourished children contributes to their inability to eradicate infections. PMID:23429441

  9. Natural killer cells regulate Th1/Treg and Th17/Treg balance in chlamydial lung infection.

    PubMed

    Li, Jing; Dong, Xiaojing; Zhao, Lei; Wang, Xiao; Wang, Yan; Yang, Xi; Wang, Hong; Zhao, Weiming

    2016-07-01

    Natural killer (NK) cell is an important component in innate immunity, playing a critical role in bridging innate and adaptive immunity by modulating the function of other immune cells including T cells. In this study, we focused on the role of NK cells in regulating Th1/Treg and Th17/Treg balance during chlamydial lung infection. We found that NK cell-depleted mice showed decreased Th1 and Th17 cells, which was correlated with reduced interferon-γ, interleukin (IL)-12, IL-17 and IL-22 production as well as T-bet and receptor-related orphan receptor gamma t expression compared with mice treated with the isotype control antibody. In contrast, NK cell depletion significantly increased Treg in cell number and related transcription factor (Foxp3) expression. The opposite trends of changes of Th1/Th17 and Treg led to significant reduction in the Th1/Treg and Th17/Treg ratios. The data implicate that NK cells play an important role in host defence against chlamydial lung infection, mainly through maintaining Th1/Treg and Th17/Treg balance.

  10. Effect of malnutrition on the expression of cytokines involved in Th1 cell differentiation.

    PubMed

    González-Torres, Cristina; González-Martínez, Haydeé; Miliar, Angel; Nájera, Oralia; Graniel, Jaime; Firo, Verónica; Alvarez, Catalina; Bonilla, Edmundo; Rodríguez, Leonor

    2013-02-19

    Malnutrition is a common cause of secondary immune deficiency and has been linked to an increased susceptibility to infection in humans. Malnutrition specifically affects T-cell-mediated immune responses. The aim of this study was to assess in lymphocytes from malnourished children the expression levels of IL-12, IL-18 and IL-21, molecules that induce the differentiation of T cells related to the immunological cellular response (Th1 response) and the production of cytokines related to the immunological cellular response (Th1 cytokines). We found that the expression levels of IL-12, IL-18 and IL-21 were significantly diminished in malnourished children compared to well-nourished children and were coincident with lower plasmatic levels of IL-2 and IFN-γ (Th1 cytokines). In this study, we show for the first time that the gene expression and intracellular production of cytokines responsible for Th1 cell differentiation (IL-12, IL-18 and IL-21) are diminished in malnourished children. As expected, this finding was related to lower plasmatic levels of IL-2 and IFN-γ. The decreased expression of Th1 cytokines observed in this study may contribute to the deterioration of the immunological Type 1 (cellular) response. We hypothesize that the decreased production of IL-12, IL-18 and IL-21 in malnourished children contributes to their inability to eradicate infections.

  11. Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: Involvement of IL-1β, IL-1α and Th17-associated cytokines and decrease of Th1 and Th2 cytokines.

    PubMed

    Ibrahim, José-Noel; Jounblat, Rania; Delwail, Adriana; Abou-Ghoch, Joelle; Salem, Nabiha; Chouery, Eliane; Megarbane, André; Medlej-Hashim, Myrna; Lecron, Jean-Claude

    2014-10-01

    In order to clarify the inflammatory mechanism underlying familial Mediterranean fever (FMF), we aimed to evaluate the ex vivo cytokine profile of FMF patients during acute attacks and attack-free periods, and compare it with that of healthy controls. The study included 34 FMF patients, of whom 9 were studied during attack and remission and 24 healthy controls. Cytokine levels were evaluated by Luminex technology in serum and supernatants of PBMC (Peripheral Blood Mononuclear Cells) cultures with and without 24h stimulation of monocytes by LPS and T lymphocytes by anti-CD3/CD28 beads. Levels of IL-6 and TNF-α were higher in unstimulated and LPS-stimulated PBMC supernatants of FMF patients in crises compared to controls. In response to LPS stimulation, higher levels of IL-1β and IL-1α were found in PBMC supernatants of patients during crises compared to those in remission and to controls. IFN-γ and IL-4 levels were the lowest in unstimulated and anti-CD3/CD28 stimulated PBMCs supernatants of patients during crises compared to remission and controls. The Th17 cytokines IL-17 and IL-22 were respectively higher in anti-CD3/CD28 stimulated PBMC supernatants of FMF patients during and between crises compared to controls. Amongst cytokines tested in serum, only IL-6 and TNFα were enhanced in FMF patients. The ex vivo study represents an interesting approach to evaluate cytokines' involvement in FMF. Our results suggest an ongoing subclinical inflammation and define an elevated inflammatory cytokine signature, distinctly for M694V homozygous patients. The absence of spontaneous IL-1β release by PBMCs reflects no constitutive activation of the inflammasome in FMF physiopathology.

  12. Participation of MyD88 and Interleukin-33 as Innate Drivers of Th2 Immunity to Trichinella spiralis

    PubMed Central

    Scalfone, Lisa K.; Nel, Hendrik J.; Gagliardo, Lucille F.; Cameron, Jody L.; Al-Shokri, Shaikha; Leifer, Cynthia A.; Fallon, Padraic G.

    2013-01-01

    Trichinella spiralis is a highly destructive parasitic nematode that invades and destroys intestinal epithelial cells, injures many different tissues during its migratory phase, and occupies and transforms myotubes during the final phase of its life cycle. We set out to investigate the role in immunity of innate receptors for potential pathogen- or danger-associated molecular patterns (PAMPs or DAMPs). Focusing on the MyD88-dependent receptors, which include Toll-like receptors (TLRs) and interleukin-1 (IL-1) family members, we found that MyD88-deficient mice expelled worms normally, while TLR2/4-deficient mice showed accelerated worm expulsion, suggesting that MyD88 was active in signaling pathways for more than one receptor during intestinal immunity. A direct role for PAMPs in TLR activation was not supported in a transactivation assay involving a panel of murine and human TLRs. Mice deficient in the IL-1 family receptor for the DAMP, IL-33 (called ST2), displayed reduced intestinal Th2 responses and impaired mast cell activation. IL-33 was constitutively expressed in intestinal epithelial cells, where it became concentrated in nuclei within 2 days of infection. Nuclear localization was an innate response to infection that occurred in intestinal regions where worms were actively migrating. Th2 responses were also compromised in the lymph nodes draining the skeletal muscles of ST2-deficient mice, and this correlated with increased larval burdens in muscle. Our results support a mechanism in which the immune system recognizes and responds to tissue injury in a way that promotes Th2 responses. PMID:23403558

  13. Microbiota-Independent Ameliorative Effects of Antibiotics on Spontaneous Th2-Associated Pathology of the Small Intestine.

    PubMed

    Han, Daehee; Walsh, Matthew C; Kim, Kwang Soon; Hong, Sung-Wook; Lee, Junyoung; Yi, Jaeu; Rivas, Gloriany; Surh, Charles D; Choi, Yongwon

    2015-01-01

    We have previously generated a mouse model of spontaneous Th2-associated disease of the small intestine called TRAF6ΔDC, in which dendritic cell (DC)-intrinsic expression of the signaling mediator TRAF6 is ablated. Interestingly, broad-spectrum antibiotic treatment ameliorates TRAF6ΔDC disease, implying a role for commensal microbiota in disease development. However, the relationship between the drug effects and commensal microbiota status remains to be formally demonstrated. To directly assess this relationship, we have now generated TRAF6ΔDC bone marrow chimera mice under germ-free (GF) conditions lacking commensal microbiota, and found, unexpectedly, that Th2-associated disease is actually exacerbated in GF TRAF6ΔDC mice compared to specific pathogen-free (SPF) TRAF6ΔDC mice. At the same time, broad-spectrum antibiotic treatment of GF TRAF6ΔDC mice has an ameliorative effect similar to that observed in antibiotics-treated SPF TRAF6ΔDC mice, implying a commensal microbiota-independent effect of broad-spectrum antibiotic treatment. We further found that treatment of GF TRAF6ΔDC mice with broad-spectrum antibiotics increases Foxp3+ Treg populations in lymphoid organs and the small intestine, pointing to a possible mechanism by which treatment may directly exert an immunomodulatory effect. To investigate links between the exacerbated phenotype of the small intestines of GF TRAF6ΔDC mice and local microbiota, we performed microbiotic profiling of the luminal contents specifically within the small intestines of diseased TRAF6ΔDC mice, and, when compared to co-housed control mice, found significantly increased total bacterial content characterized by specific increases in Firmicutes Lactobacillus species. These data suggest a protective effect of Firmicutes Lactobacillus against the spontaneous Th2-related inflammation of the small intestine of the TRAF6ΔDC model, and may represent a potential mechanism for related disease phenotypes.

  14. Effects of Psoraleae fructus and its major component psoralen on Th2 response in allergic asthma.

    PubMed

    Jin, Hualiang; Wang, Limin; Xu, Changqing; Li, Bei; Luo, Qingli; Wu, Jinfeng; Lv, Yubao; Wang, Genfa; Dong, Jingcheng

    2014-01-01

    This study is aimed to evaluate the effects of Psoraleae fructus (PF) on Th2 responses in a rat model of asthma in vivo and psoralen, a major constituent in PF, on Th2 responses in vitro. A rat model of asthma was established by sensitization and challenged with ovalbumin (OVA). Airway hyperresponsiveness was detected by direct airway resistance analysis. Lung tissues were examined for cell infiltration and mucus hypersecretion. Bronchoalveolar lavage fluid (BALF) was assessed for cytokine levels. In vitro study, Th2 cytokine production was evaluated in the culture supernatant of D10.G4.1 (D10 cells) followed by the determination of cell viability, meanwhile Th2 transcription factor GATA-3 expression in D10 cells was also determined. The oral administration of PF significantly reduced airway hyperresponsiveness (AHR) to aerosolized methacholine and decreased IL-4 and IL-13 levels in the BALF. Histological studies showed that PF markedly inhibited inflammatory infiltration and mucus secretion in the lung tissues. In vitro study, psoralen significantly suppressed Th2 cytokines of IL-4, IL-5 and IL-13 by ConA-stimulated D10 cells without inhibitory effect on cell viability. Furthermore, GATA-3 protein expression was also markedly reduced by psoralen. This study demonstrated that PF exhibited inhibitory effects on hyperresponsiveness and airway inflammation in a rat model of asthma, which was associated with the suppression of Th2 response. Psoralen, a major constituent of PF, has immunomodulatory properties on Th2 response in vitro, which indicated that psoralen might be a critical component of PF for its therapeutic effects.

  15. Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma.

    PubMed

    Miyagaki, Tomomitsu; Sugaya, Makoto; Fujita, Hideki; Ohmatsu, Hanako; Kakinuma, Takashi; Kadono, Takafumi; Tamaki, Kunihiko; Sato, Shinichi

    2010-09-01

    CC chemokine receptor 3 (CCR3), the sole receptor for eotaxins, is expressed on eosinophils and T helper type 2 (Th2) cells. In Hodgkin's disease, eotaxin-1 secreted by fibroblasts collects Th2 cells and eosinophils within the tissue. Similarly, many Th2 cells infiltrate the lesional skin of cutaneous T-cell lymphoma (CTCL). In this study, we investigated the role of eotaxins in the development of the Th2 environment of CTCL. We revealed that fibroblasts from lesional skin of CTCL expressed higher amounts of eotaxin-3 messenger RNA (mRNA) compared with those from normal skin. Lesional skin of CTCL at advanced stages contained significantly higher levels of eotaxin-3 and CCR3 mRNA, compared with early stages of CTCL. IL-4 mRNA was expressed in some cases at advanced stages. Immunohistochemistry revealed that keratinocytes, endothelial cells, and dermal fibroblasts in lesional skin of CTCL showed a stronger expression of eotaxin-3 than did normal skin. CCR3(+) lymphocytes and IL-4 expression were observed in some cases of advanced CTCL. Furthermore, both serum eotaxin-3 and eotaxin-1 levels of CTCL patients at advanced stages were significantly higher than those of healthy individuals. The concentrations of these chemokines correlated with serum soluble IL-2 receptor levels. These results suggest that interaction of eotaxins and CCR3 regulates the Th2-dominant tumor environment, which is closely related to the development of CTCL.

  16. Foxa2 Regulates Leukotrienes to Inhibit Th2-mediated Pulmonary Inflammation

    PubMed Central

    Tang, Xiaoju; Liu, Xiaojing J.; Tian, Cuijie; Su, Qiaoli; Lei, Yi; Wu, Qingbo; He, Yangyan; Whitsett, Jeffrey A.

    2013-01-01

    Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first 2 weeks after birth, the loss of Foxa2 increases the production of leukotrienes (LTs) and Th2 cytokines in the lungs of Foxa2 gene–targeted mice. Foxa2 expression inhibited 15-lipoxygenase (Alox15) and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene–targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway. PMID:23822876

  17. Salvianolic acid B ameliorates CNS autoimmunity by suppressing Th1 responses.

    PubMed

    Dong, Zhihui; Ma, Dihui; Gong, Ye; Yu, Tingmin; Yao, Gang

    2016-04-21

    Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is a Th1 and Th17 cell-mediated CNS autoimmune disease. Therefore, immune regulation is a key target for therapy. Salvianolic acid B (Sal B) is a major water-soluble bioactive component of the famous traditional Chinese medicine Salvia miltiorrhiza, which is notable for its anti-oxidative and anti-inflammatory effects. Thus Sal B, by impairing Th1 or Th17 responses in EAE/MS, might ameliorate the crippling symptoms. Here we show that the intraperitoneal administration of 30mg/kg Sal B daily for 14 days after the onset of MOG-induced EAE in mice effectively reduced its severity. Additionally, Sal B treatment downgraded the infiltration of inflammatory cells, limited astrogliosis and blocked Th1 responses other than that of Th17. These results indicated that Sal B may serve as an effective therapeutic agent for MS/EAE by inhibiting Th1 cell responses.

  18. HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses in fractionated γ-irradiated mice by modulating the IL-12p70-STAT4 signaling pathway.

    PubMed

    Park, Hae-Ran; Jo, Sung-Kee; Choi, Nam-Hee; Jung, Uhee

    2012-05-01

    Whole body irradiated mice appear to experience a down-regulation of the helper T (Th)1-like immune response, and maintain a persistent immunological imbalance. In the current study, we evaluated the effect of HemoHIM (an herbal product made from Angelica Radix, Cnidium officinale , and Paeonia japonica cultivated in Korea) to ameliorate the immunological imbalance induce in fractionated γ-irradiated mice. The mice were exposed to γ rays twice a week (0.5 Gy fractions) for a total dose of 5 Gy, and HemoHIM was administrated orally from 1 week before the first irradiation to 1 week before the final analysis. All experiments were performed 4 and 6 months after their first exposure. HemoHIM ameliorated the Th1- and Th2-related immune responses normally occur in irradiated mice with or without dinitrophenylated keyhole limpet hemocyanin immunization. HemoHIM also restored the natural killer cell activities without changing the percentage of natural killer cells in irradiated mice. Furthermore, the administration of HemoHIM prevented the reduction in levels of interleukin-12p70 in irradiated mice. Finally, we found that HemoHIM enhanced the phosphorylation of signal transducer and activator of transcription (STAT) 4 that was reduced in irradiated mice. Our findings suggest that HemoHIM ameliorates the persistent down-regulation of Th1-like immune responses by modulating the IL-12p70/pSTAT4 signaling pathway.

  19. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells.

    PubMed

    Abimannan, Thiruvaimozhi; Peroumal, Doureradjou; Parida, Jyoti R; Barik, Prakash K; Padhan, Prasanta; Devadas, Satish

    2016-10-01

    Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Th1 cells or CD4(+) T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL-17A in Th17 and IFN-γ in Th1 cells by reducing the expression of their respective TFs, RORγt and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4(+) T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Th1 mediated disease. In human CD4(+) T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A(+) (Th17), IFN(-)γ(+) (Th1) and IL-17A(+)/IFN(-)γ(+) (Th17/1) cells and also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Th1 cells in autoimmune disorders.

  20. Local expression of antiinflammatory cytokines in cancer.

    PubMed Central

    Yamamura, M; Modlin, R L; Ohmen, J D; Moy, R L

    1993-01-01

    To characterize the nature of the local cytokine response to cancer, we chose to investigate cytokine patterns in biopsy specimens of basal cell carcinoma (BCC). We hypothesized that a distinct pattern of local cytokine production may be characteristic of BCC, a neoplasia of epidermis, in comparison to the pattern of seborrheic keratosis (SK), a benign growth of epidermis. We analyzed cytokine mRNAs in BCC versus SK by performing polymerase chain reaction on mRNA derived from biopsy specimens. The mRNAs encoding cytokines for IL-4, IL-5, IL-10, and granulocyte macrophage colony-stimulating factor were strongly expressed in BCC lesions and weakly expressed in SK lesions. Conversely, IL-2, IFN-gamma, and lymphotoxin mRNAs were strongly expressed in SK lesions and weakly expressed in BCC lesions. The response to malignancy, BCC, was typified by cytokines characteristic of murine TH2 cells. This cytokine pattern favors humoral immunity with concomitant immunosuppression of cell-mediated immune responses. In comparison, the response to the benign growth, SK, was typified by cytokines characteristic of murine TH1 cells that favor cell-mediated immune reactions. The findings of a distinct cytokine pattern in skin cancer provide a framework to develop strategies for immunologic intervention. Images PMID:8450029

  1. Preferential induction of a Th1 immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization.

    PubMed Central

    Raz, E; Tighe, H; Sato, Y; Corr, M; Dudler, J A; Roman, M; Swain, S L; Spiegelberg, H L; Carson, D A

    1996-01-01

    We compared the antigen-specific antibody isotypes and lymphokine secretion by CD4+ T cells in BALB/c mice immunized intradermally with either Escherichia coli beta-galactosidase (beta-gal) or plasmid DNA (pDNA) encoding beta-gal in a cytomegalovirus-based expression vector (pCMV-LacZ). pCMV-LacZ induced mainly IgG2a, whereas beta-gal in saline or alum induced IgG1 and IgE beta-gal-specific antibodies. In addition, splenic CD4+ T helper (Th) cells isolated from pDNA-immunized mice secreted interferon-gamma but not interleukin (IL)-4 and IL-5, whereas Th cells from beta-gal-injected mice secreted IL-4 and IL-5 but not interferon-gamma after in vitro stimulation with antigen. Together these data demonstrate that pDNA immunization induced a T helper type 1 (Th1) response, whereas protein immunization induced a T helper type 2 (Th2) response to the same antigen. Interestingly, priming of mice with pCMV-LacZ prevented IgE antibody formation to a subsequent i.p. beta-gal in alum injection. This effect was antigen-specific, because priming with pCMV-LacZ did not inhibit IgE anti-ovalbumin antibody formation. Most importantly, intradermal immunization with pCMV-LacZ (but not pCMV-OVA) of beta-gal in alum-primed mice caused a 66-75% reduction of the IgE anti-beta-gal titer in 6 weeks. Also, pCMV-LacZ induced specific IgG2a antibody titers and interferon-gamma secretion by Th cells in the beta-gal in alum-primed mice. The data demonstrate that gene immunization induces a Th1 response that dominates over an ongoing protein-induced Th2 response in an antigen-specific manner. This suggests that immunization with pDNA encoding for allergens may provide a novel type of immunotherapy for allergic diseases. PMID:8643542

  2. Dendritic Cell-Secreted Lipocalin2 Induces CD8+ T-Cell Apoptosis, Contributes to T-Cell Priming and Leads to a TH1 Phenotype

    PubMed Central

    Floderer, Melanie; Prchal-Murphy, Michaela; Vizzardelli, Caterina

    2014-01-01

    Lipocalin 2 (LCN2), which is highly expressed by dendritic cells (DCs) when treated with dexamethasone (Dex) and lipopolysaccharide (LPS), plays a key role in the defence against bacteria and is also involved in the autocrine apoptosis of T-cells. However, the function of LCN2 when secreted by DCs is unknown: this is a critical gap in our understanding of the regulation of innate and adaptive immune systems. Tolerance, stimulation and suppression are functions of DCs that facilitate the fine-tuning of the immune responses and which are possibly influenced by LCN2 secretion. We therefore examined the role of LCN2 in DC/T-cell interaction. WT or Lcn2−/− bone marrow-derived DCs were stimulated with LPS or LPS+IFN-γ with and without Dex and subsequently co-cultured with T-cells from ovalbumin-specific TCR transgenic (OT-I and OT-II) mice. We found that CD8+ T-cell apoptosis was highly reduced when Lcn2−/− DCs were compared with WT. An in vivo CTL assay, using LPS-treated DCs, showed diminished killing ability in mice that had received Lcn2−/− DCs compared with WT DCs. As a consequence, we analysed T-cell proliferation and found that LCN2 participates in T-cell-priming in a dose-dependent manner and promotes a TH1 microenvironment. DC-secreted LCN2, whose function has previously been unknown, may in fact have an important role in regulating the balance between TH1 and TH2. Our results yield insights into DC-secreted LCN2 activity, which could play a pivotal role in cellular immune therapy and in regulating immune responses. PMID:25010215

  3. Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse

    PubMed Central

    Bollyky, Paul L; Evanko, Stephen P; Wu, Rebecca P; Potter-Perigo, Susan; Long, S Alice; Kinsella, Brian; Reijonen, Helena; Guebtner, Kelly; Teng, Brandon; Chan, Christina K; Braun, Kathy R; Gebe, John A; Nepom, Gerald T; Wight, Thomas N

    2010-01-01

    Hyaluronan (HA) production by dendritic cells (DCs) is known to promote antigen presentation and to augment T-cell activation and proliferation. We hypothesized that pericellular HA can function as intercellular ‘glue' directly mediating T cell–DC binding. Using primary human cells, we observed HA-dependent binding between T cells and DCs, which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone (4-MU), an agent which blocks HA synthesis. Furthermore, T cells regulate HA production by DCs via T cell-derived cytokines in a T helper (Th) subset-specific manner, as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production. Similar effects were seen upon the addition of exogenous Th1 cytokines, IL-2, interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α). The critical factors which determined the extent of DC–T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA, as T-cell clones which were pre-treated with monensin, added to block cytokine secretion, bound equivalently irrespective of their Th subset. These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA, which in turn affects the extent of DC–T cell binding. We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation. These data point to a pivotal role for HA in DC–T cell interactions at the IS. PMID:20228832

  4. Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse.

    PubMed

    Bollyky, Paul L; Evanko, Stephen P; Wu, Rebecca P; Potter-Perigo, Susan; Long, S Alice; Kinsella, Brian; Reijonen, Helena; Guebtner, Kelly; Teng, Brandon; Chan, Christina K; Braun, Kathy R; Gebe, John A; Nepom, Gerald T; Wight, Thomas N

    2010-05-01

    Hyaluronan (HA) production by dendritic cells (DCs) is known to promote antigen presentation and to augment T-cell activation and proliferation. We hypothesized that pericellular HA can function as intercellular 'glue' directly mediating T cell-DC binding. Using primary human cells, we observed HA-dependent binding between T cells and DCs, which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone (4-MU), an agent which blocks HA synthesis. Furthermore, T cells regulate HA production by DCs via T cell-derived cytokines in a T helper (Th) subset-specific manner, as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production. Similar effects were seen upon the addition of exogenous Th1 cytokines, IL-2, interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). The critical factors which determined the extent of DC-T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA, as T-cell clones which were pre-treated with monensin, added to block cytokine secretion, bound equivalently irrespective of their Th subset. These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA, which in turn affects the extent of DC-T cell binding. We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation. These data point to a pivotal role for HA in DC-T cell interactions at the IS.

  5. Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis.

    PubMed

    Sallin, Michelle A; Sakai, Shunsuke; Kauffman, Keith D; Young, Howard A; Zhu, Jinfang; Barber, Daniel L

    2017-03-28

    Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73(+)CXCR3(+)T-bet(dim) stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1(+)KLRG1(+) Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69(+)CD103(+) tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN-γ inhibits the accumulation of intravascular CX3CR1(+)KLRG1(+) Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis.

  6. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Enteric nematode infection induces a strong Th2 cytokine response and is characterized by increased infiltration of various immune cells including macrophages. The role of these immune cells in host defense against enteric nematode infection, however, remains poorly defined. The present study invest...

  7. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema

    PubMed Central

    Avraham, Tomer; Zampell, Jamie C.; Yan, Alan; Elhadad, Sonia; Weitman, Evan S.; Rockson, Stanley G.; Bromberg, Jacqueline; Mehrara, Babak J.

    2013-01-01

    Lymphedema is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4+ T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4+ cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4+ inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.—Avraham, T., Zampell, J. C., Yan, A., Elhadad, S., Weitman, E. S., Rockson, S. G., Bromberg, J., Mehrara, B. J. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. PMID:23193171

  8. Analysis of Th1, Th17 and regulatory T cells in tuberculosis case contacts.

    PubMed

    García Jacobo, R E; Serrano, C J; Enciso Moreno, J A; Gaspar Ramírez, O; Trujillo Ochoa, J L; Uresti Rivera, E E; Portales Pérez, D P; González-Amaro, R; García Hernández, M H

    2014-01-01

    We have hypothesized that individuals infected with Mycobacteriumtuberculosis that exhibit different patterns of immune reactivity in serial interferon (IFN)-γ release assays (IGRA's) correspond to different status within the immune spectrum of latent tuberculosis (TB). Accordingly, we analyzed the possible association between the consistent results (negative or positive) in an IGRA test and relevant immune parameters, mainly the levels of Th1 and Th17 lymphocytes and T regulatory (Treg) cells in the peripheral blood of TB case contacts. We found that individuals with a persistently positive IGRA showed increased levels of Th1 and Th17 lymphocytes upon in vitro stimulation with MTB antigens. In addition, a significant increase in the proportion of CD4+CTLA-4+ and CD4+Foxp3+ cells was detected in assays with blood samples from these individuals. Our data support that different immune phenotypes can be identified into the spectrum of latent TB, by combining different parameters of immune reactivity against MTB.

  9. Interleukin-6 Induced “Acute” Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics

    PubMed Central

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L.; Yan, Wei; Xu, Lisa X.

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an “acute” phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated “acute” phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86+MHCII+ dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such “acute” environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest “acute” response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated “acute” microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of “acute” and

  10. Type I IFN signaling in CD8– DCs impairs Th1-dependent malaria immunity

    PubMed Central

    Haque, Ashraful; Best, Shannon E.; Montes de Oca, Marcela; James, Kylie R.; Ammerdorffer, Anne; Edwards, Chelsea L.; de Labastida Rivera, Fabian; Amante, Fiona H.; Bunn, Patrick T.; Sheel, Meru; Sebina, Ismail; Koyama, Motoko; Varelias, Antiopi; Hertzog, Paul J.; Kalinke, Ulrich; Gun, Sin Yee; Rénia, Laurent; Ruedl, Christiane; MacDonald, Kelli P.A.; Hill, Geoffrey R.; Engwerda, Christian R.

    2014-01-01

    Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ–producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8– cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8– splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN–inducing pathogens. PMID:24789914

  11. Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B.

    PubMed Central

    Rossol, S; Marinos, G; Carucci, P; Singer, M V; Williams, R; Naoumov, N V

    1997-01-01

    Interleukin-12, a cytokine with an important role against intracellular pathogens, promotes Th1 cell development, cellmediated cytotoxicity, and interferon-gamma production. We investigated the immunoregulatory role of IL-12 in 72 chronic hepatitis B virus (HBV) carriers, 33 of whom were monitored longitudinally during interferon-alpha treatment. Serum levels of IL-12 heterodimer, IL-12 p40 subunit, IL-4, and Th1 cytokines were determined by specific ELISAs, and hepatitis B core antigen-specific T cell response by a proliferation assay. Chronic HBV carriers had higher serum levels of IL-12 and IL-12 p40 in comparison with controls (P < 0.01), suggesting that IL-12 production is not impaired. The longitudinal analysis revealed a further substantial increase (> 2.5x baseline level) of bioactive IL-12 and Th1 cytokines in patients who cleared HBV and seroconverted to anti- hepatitis B e, unlike the 23 nonresponders with persistent HBV replication (P < 0.01). The IL-12 peak followed the peak of hepatocytolysis by 9.8+/-2.8 wk and occurred either before or simultaneously with hepatitis B e seroconversion. Hepatitis B core antigen-specific T cell proliferation closely correlated with hepatocytolysis and increased significantly in all patients (8 responders and 15 nonresponders) who developed hepatitis flare, irrespective of the virological outcome. These results provide in vivo evidence that IL-12 may have an important role for viral clearance in chronic HBV infection. PMID:9185527

  12. Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

    PubMed Central

    Watanabe, Mitsuru; Masaki, Katsuhisa; Yamasaki, Ryo; Kawanokuchi, Jun; Takeuchi, Hideyuki; Matsushita, Takuya; Suzumura, Akio; Kira, Jun-ichi

    2016-01-01

    We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNγ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS. PMID:27929069

  13. Thermophysical and anion diffusion properties of (Ux,Th1−x)O2

    PubMed Central

    Cooper, Michael W. D.; Murphy, Samuel T.; Fossati, Paul C. M.; Rushton, Michael J. D.; Grimes, Robin W.

    2014-01-01

    Using molecular dynamics, the thermophysical properties of the (Ux,Th1−x)O2 system have been investigated between 300 and 3600 K. The thermal dependence of lattice parameter, linear thermal expansion coefficient, enthalpy and specific heat at constant pressure is explained in terms of defect formation and diffusivity on the oxygen sublattice. Vegard's law is approximately observed for solid solution thermal expansion below 2000 K. Different deviations from Vegard's law above this temperature occur owing to the different temperatures at which the solid solutions undergo the superionic transition (2500–3300 K). Similarly, a spike in the specific heat, associated with the superionic transition, occurs at lower temperatures in solid solutions that have a high U content. Correspondingly, oxygen diffusivity is higher in pure UO2 than in pure ThO2. Furthermore, at temperatures below the superionic transition, oxygen mobility is notably higher in solid solutions than in the end members. Enhanced diffusivity is promoted by lower oxygen-defect enthalpies in (Ux,Th1−x)O2 solid solutions. Unlike in UO2 and ThO2, there is considerable variety of oxygen vacancy and oxygen interstitial sites in solid solutions generating a wide range of property values. Trends in the defect enthalpies are discussed in terms of composition and the lattice parameter of (Ux,Th1−x)O2. PMID:25383028

  14. Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers.

    PubMed

    Lyadova, I V; Panteleev, A V

    2015-01-01

    The outcome of Mycobacterium tuberculosis (Mtb) infection ranges from a complete pathogen clearance through asymptomatic latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous spectrum of states with different degrees of pathogen "activity," host pathology, and immune reactivity. Therefore, it is important to differentiate LTBI and active TB and identify active TB stages. CD4(+) T cells play critical role during Mtb infection by mediating protection, contributing to inflammation, and regulating immune response. Th1 and Th17 cells are the main effector CD4(+) T cells during TB. Th1 cells have been shown to contribute to TB protection by secreting IFN-γ and activating antimycobacterial action in macrophages. Th17 induce neutrophilic inflammation, mediate tissue damage, and thus have been implicated in TB pathology. In recent years new findings have accumulated that alter our view on the role of Th1 and Th17 cells during Mtb infection. This review discusses these new results and how they can be implemented for TB diagnosis and monitoring.

  15. Arabidopsis TH2 Encodes the Orphan Enzyme Thiamin Monophosphate Phosphatase[OPEN

    PubMed Central

    Niehaus, Thomas D.; Hasnain, Ghulam; Gidda, Satinder K.; Nguyen, Thuy N.D.; Anderson, Erin M.; Brown, Greg; Yakunin, Alexander F.; de Crécy-Lagard, Valérie; Gregory, Jesse F.

    2016-01-01

    To synthesize the cofactor thiamin diphosphate (ThDP), plants must first hydrolyze thiamin monophosphate (ThMP) to thiamin, but dedicated enzymes for this hydrolysis step were unknown and widely doubted to exist. The classical thiamin-requiring th2-1 mutation in Arabidopsis thaliana was shown to reduce ThDP levels by half and to increase ThMP levels 5-fold, implying that the THIAMIN REQUIRING2 (TH2) gene product could be a dedicated ThMP phosphatase. Genomic and transcriptomic data indicated that TH2 corresponds to At5g32470, encoding a HAD (haloacid dehalogenase) family phosphatase fused to a TenA (thiamin salvage) family protein. Like the th2-1 mutant, an insertional mutant of At5g32470 accumulated ThMP, and the thiamin requirement of the th2-1 mutant was complemented by wild-type At5g32470. Complementation tests in Escherichia coli and enzyme assays with recombinant proteins confirmed that At5g32470 and its maize (Zea mays) orthologs GRMZM2G148896 and GRMZM2G078283 are ThMP-selective phosphatases whose activity resides in the HAD domain and that the At5g32470 TenA domain has the expected thiamin salvage activity. In vitro and in vivo experiments showed that alternative translation start sites direct the At5g32470 protein to the cytosol and potentially also to mitochondria. Our findings establish that plants have a dedicated ThMP phosphatase and indicate that modest (50%) ThDP depletion can produce severe deficiency symptoms. PMID:27677881

  16. Plasmacytoid dendritic cells prevent cigarette smoke and Chlamydophila pneumoniae-induced Th2 inflammatory responses.

    PubMed

    Sorrentino, Rosalinda; Gray, Pearl; Chen, Shuang; Shimada, Kenichi; Crother, Timothy R; Arditi, Moshe

    2010-10-01

    Smoking promotes the development of allergic asthma and pneumonia. Chlamydophila pneumoniae lung infection is associated with an increased risk for asthma, inducing an immune response regulated by dendritic cells (DCs). This study sought to determine whether exposure to cigarette smoke modulates the functional activity of CD11c-positive DCs in the lung, with and without concomitant C. pneumoniae infection. Bone marrow-derived DCs (BMDCs) were exposed in vitro to cigarette smoke extract (CSE) and/or live C. pneumoniae (Cpn), and then adoptively transferred intratracheally into wild-type mice. Although CSE plus Cpn appeared to exert an additive effect on the production of Th2 cytokines in vitro, we did not see this effect in vivo. However, the adoptive transfer of DCs pulsed with both CSE and C. pneumoniae into the lungs of naive mice led to an influx of plasmacytoid DCs (pDCs) that suppressed the Th2 skewing ability of the transferred BMDCs. The depletion of pDCs by antibody restored the Th2 skewing ability of the BMDCs. The expression of indoleamine-2,3-dioxygenase in the lung was reduced after the depletion of pDCs, and blocking IFN-α in vitro prevented the ability of pDCs to inhibit the Th2 responses induced by myeloid DCs (mDCs), suggesting their potential involvement in the mechanism of altered polarization. In conclusion, exposure to cigarette smoke skews C. pneumoniae-induced mDCs responses toward a Th2 bias in the lung, which is prevented by pDCs. We propose that pDCs may play a major role in the immunosuppressive lung environment in smokers with C. pneumoniae infection.

  17. The bioactivity of teleost IL-6: IL-6 protein in orange-spotted grouper (Epinephelus coioides) induces Th2 cell differentiation pathway and antibody production.

    PubMed

    Chen, Hsin-Hung; Lin, Han-Tso; Foung, Yi-Fan; Han-You Lin, John

    2012-10-01

    Interleukin 6 (IL-6) is a protein secreted by T cells and macrophages and plays an important role in immune response. IL-6 regulates the proliferation and differentiation of T cells, and elicits immunoglobulin production in B cells. In this study, the cDNA il-6 (gil-6) sequence of the orange spotted grouper (Epinephelus coioides) was obtained. The deduced IL-6 (gIL-6) protein comprised 223 amino acids, the sequence shared approximately 30% similarity with mammalian IL-6, and between 47% and 69% similarity with other available teleost IL-6. The protein comprises the signal peptide, the IL-6 family signature, and conserved amino acid residues found in IL-6 sequences of other teleost. In order to understand the bioactivity and influence of gIL-6 on humoral immune response, recombinant gIL-6 (rgIL-6) synthesized by prokaryotes was injected into orange spotted groupers, and the immune-related gene expression at various times in various organs was observed. Our results revealed that the Th1 specific transcription factor t-bet was down-regulated and Th2 specific transcription factors gata3, and c-maf were up-regulated in immune organs, following IL-6 stimulation. Additionally, higher levels of igm mRNA and translated protein were detected in rgIL-6 stimulated fish. These results indicate that IL-6 in groupers regulates the differentiation of naїve T helper cells into Th2 cells and elicits the production of antibodies.

  18. Transgenic expression of CXCR3 on T cells enhances susceptibility to cutaneous Leishmania major infection by inhibiting monocyte maturation and promoting a Th2 response.

    PubMed

    Oghumu, Steve; Stock, James C; Varikuti, Sanjay; Dong, Ran; Terrazas, Cesar; Edwards, Jessica A; Rappleye, Chad A; Holovatyk, Ariel; Sharpe, Arlene; Satoskar, Abhay R

    2015-01-01

    Cutaneous leishmaniasis, caused mainly by Leishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused by Leishmania major. Furthermore, T cells from L. major-susceptible BALB/c but not L. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance to L. major infection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes with L. major infection. Contrary to our hypothesis, transgenic expression of CXCR3 (CXCR3(Tg)) on T cells of BALB/c mice resulted in increased lesion sizes and parasite burdens compared to wild-type (WT) littermates after L. major infection. Restimulated lymph node cells from L. major-infected BALB/c-CXCR3(Tg) mice produced more interleukin-4 (IL-4) and IL-10 and less gamma interferon (IFN-γ). Cells in draining lymph nodes from BALB/c-CXCR3(Tg) mice showed enhanced Th2 and reduced Th1 cell accumulation associated with increased neutrophils and inflammatory monocytes. However, monocytes displayed an immature phenotype which correlated with increased parasite burdens. Interestingly, transgenic expression of CXCR3 on T cells did not impact the outcome of L. major infection in C57BL/6 mice, which mounted a predominantly Th1 response and spontaneously resolved their infection similar to WT littermates. Our findings demonstrate that transgenic expression of CXCR3 on T cells increases susceptibility of BALB/c mice to L. major.

  19. The role of PKCζ in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil.

    PubMed

    Harb, Hani; Irvine, James; Amarasekera, Manori; Hii, Charles S; Kesper, Dörthe A; Ma, Yuefang; D'Vaz, Nina; Renz, Harald; Potaczek, Daniel P; Prescott, Susan L; Ferrante, Antonio

    2017-02-03

    While immunodeficiency of immaturity of the neonate has been considered important as the basis for unusual susceptibility to infection, it has also been recognized that the ability to progress from an immature Th2 cytokine predominance to a Th1 profile has relevance in determining whether children will develop allergy, providing an opportunity for epigenetic regulation through environmental pressures. However, this notion remains relatively unexplored. Here we present evidence that there are two major control points to explain the immunodeficiency in cord blood (CB) T-cells, a deficiency in interleukin-12 (IL-12) producing and IL-10 overproducing accessory cells, leading to a decreased interferon-γ (IFNγ) synthesis, and the other an intrinsic defect in T-cell protein kinase C zeta (PKCζ) expression. Importantly was the finding that human CB T-cells rendered deficient in PKCζ, by shRNA knockdown, develop into low tumour necrosis factor-α (TNF α) and IFNγ but increased IL-13 producing cells. Interestingly, we found that the increase in PKCζ levels in CB T-cells caused by prenatal supplementation with fish oil correlated with modifications of histone acetylation at the PKCζ gene (PRKCZ) promoter level. The data demonstrate that PKCζ expression regulates the maturation of neonatal T-cells into specific functional phenotypes and that environmental influences may work via PKCζ to regulate these phenotypes and disease susceptibility.

  20. RHS6-mediated chromosomal looping and nuclear substructure binding is required for Th2 cytokine gene expression.

    PubMed

    Hwang, Soo Seok; Jang, Sung Woong; Lee, Gap Ryol

    2017-03-01

    Subset-specific gene expression is a critical feature of CD4 T cell differentiation. Th2 cells express Th2 cytokine genes including Il4, Il5, and Il13 and mediate the immune response against helminths. The expression of Th2 cytokine genes is regulated by Rad50 hypersensitive site 6 (RHS6) in the Th2 locus control region; however, the molecular mechanisms of RHS6 action at the chromatin level are poorly understood. Here, we demonstrate that RHS6 is crucial for chromosomal interactions and nuclear substructure binding of the Th2 cytokine locus. RHS6-deficient cells had a marked reduction in chromatin remodeling and in intrachromosomal interactions at the Th2 locus. Deficiency of RHS6-binding transcription factors GATA3, SATB1, and IRF4 also caused a great reduction in chromatin remodeling and long-range chromosomal interactions involving the Th2 locus. RHS6 deficiency abrogated association of the Th2 locus with the nuclear substructure and RNA polymerase II. Therefore, RHS6 serves as a crucial cis-acting hub for coordinate regulation of Th2 cytokine genes by forming chromosomal loops and binding to a nuclear substructure.

  1. Id2 reinforces TH1 cell differentiation and inhibits E2A to repress TFH cell differentiation

    PubMed Central

    Shaw, Laura A.; Bélanger, Simon; Omilusik, Kyla D.; Cho, Sunglim; Scott-Browne, James P.; Nance, J. Philip; Goulding, John; Lasorella, Anna; Lu, Li-Fan; Crotty, Shane; Goldrath, Ananda W.

    2016-01-01

    Differentiation of T helper (TH) effector subsets is critical for host protection. E protein transcription factors and Id proteins are important arbiters of T cell development, but their role in differentiation of TH1 and TFH cells is not well understood. TH1 cells showed robust Id2 expression compared to TFH cells, and RNAi depletion of Id2 increased TFH cell frequencies. Further, TH1 cell differentiation was blocked by Id2 deficiency, leading to E protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired generation of TH1 cells following Toxoplasma gondii infection. The TFH-defining transcriptional repressor Bcl6 bound the Id2 locus, providing a mechanism for the bimodal Id2 expression and reciprocal development of TH1 and TFH cell fates. PMID:27213691

  2. Formaldehyde-Induced Aggravation of Pruritus and Dermatitis Is Associated with the Elevated Expression of Th1 Cytokines in a Rat Model of Atopic Dermatitis

    PubMed Central

    Back, Seung Keun; Lee, Hyunkyoung; Lee, JaeHee; Kim, Hye young; Kim, Hee Jin; Na, Heung Sik

    2016-01-01

    Atopic dermatitis is a complex disease of heterogeneous pathogenesis, in particular, genetic predisposition, environmental triggers, and their interactions. Indoor air pollution, increasing with urbanization, plays a role as environmental risk factor in the development of AD. However, we still lack a detailed picture of the role of air pollution in the development of the disease. Here, we examined the effect of formaldehyde (FA) exposure on the manifestation of atopic dermatitis and the underlying molecular mechanism in naive rats and in a rat model of atopic dermatitis (AD) produced by neonatal capsaicin treatment. The AD and naive rats were exposed to 0.8 ppm FA, 1.2 ppm FA, or fresh air (Air) for 6 weeks (2 hours/day and 5 days/week). So, six groups, namely the 1.2 FA-AD, 0.8 FA-AD, Air-AD, 1.2 FA-naive, 0.8 FA-naive and Air-naive groups, were established. Pruritus and dermatitis, two major symptoms of atopic dermatitis, were evaluated every week for 6 weeks. After that, samples of the blood, the skin and the thymus were collected from the 1.2 FA-AD, the Air-AD, the 1.2 FA-naive and the Air-naive groups. Serum IgE levels were quantified with ELISA, and mRNA expression levels of inflammatory cytokines from extracts of the skin and the thymus were calculated with qRT-PCR. The dermatitis and pruritus significantly worsened in 1.2 FA-AD group, but not in 0.8 FA-AD, compared to the Air-AD animals, whereas FA didn't induce any symptoms in naive rats. Consistently, the levels of serum IgE were significantly higher in 1.2 FA-AD than in air-AD, however, there was no significant difference following FA exposure in naive animals. In the skin, mRNA expression levels of Th1 cytokines such as TNF-α and IL-1β were significantly higher in the 1.2 FA-AD rats compared to the air-AD rats, whereas mRNA expression levels of Th2 cytokines (IL-4, IL-5, IL-13), IL-17A and TSLP were significantly higher in 1.2 FA-naive group than in the Air-naive group. These results suggested that 1

  3. TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression.

    PubMed

    Liu, Hou-Pu; Cao, Anthony T; Feng, Ting; Li, Qingjie; Zhang, Wenbo; Yao, Suxia; Dann, Sara M; Elson, Charles O; Cong, Yingzi

    2015-04-01

    Differentiated CD4(+) T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN-γ(+) IL-17(+) CD4(+) T cells, the number of which correlates with severity of colitis. We investigated whether IFN-γ(+) Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN-γ(Thy1.1+) Th1 cells were generated by culturing naïve CD4(+) T cells from IFN-γ(Thy1.1) CBir1 TCR-Tg reporter mice, whose TCR is specific for an immunodominant microbiota antigen, CBir1 flagellin, under Th1 polarizing conditions. IFN-γ(Thy1.1+) Th1 cells induced colitis in Rag(-/-) mice after adoptive transfer and converted into IL-17(+) Th17, but not Foxp3(+) Treg cells in the inflamed intestines. TGF-β and IL-6, but not IL-1β and IL-23, regulated Th1 conversion into Th17 cells. TGF-β induction of transcriptional factor Runx1 is crucial for the conversion, since silencing Runx1 by siRNA inhibited Th1 conversion into Th17 cells. Furthermore, TGF-β enhanced histone H3K9 acetylation but inhibited H3K9 trimethylation of Runx1- and ROR-γt-binding sites on il-17 or rorc gene in Th1 cells. We conclude that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is possibly mediated by TGF-β induction of Runx1.

  4. Differential Activation of Airway Eosinophils Induces IL-13 Mediated Allergic Th2 Pulmonary Responses in Mice

    PubMed Central

    Jacobsen, EA; Doyle, AD; Colbert, DC; Zellner, KR; Protheroe, CA; LeSuer, WE; Lee, NA.; Lee, JJ

    2015-01-01

    Background Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Methods Wild type or cytokine deficient (IL-13−/− or IL-4−/−) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. Results In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophildeficient mice, which induced no immune/inflammatory changes either in the lung or lung draining lymph nodes (LDLNs), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLNs. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4 and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13 whereas IL-4 expression by eosinophils had no significant role. Conclusion The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. PMID:26009788

  5. LOCATION PLAN. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    LOCATION PLAN. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL - STA. 132+00. TEXAS HILL CANAL AND DISTRIBUTION SYSTEM. United States Department of Interior, Bureau of Reclamation; Gila Project, Arizona, Wellton-Mohawk Division. Drawing No. 50-D-3186, dated January 25, 1955, Denver, Colorado - Wellton-Mohawk Irrigation System, Relift Station, Texas Hill Canal 2.5, Northern Terminus of Avenue 51 East, approximately .5 mile south of Union Pacific Railroad, Wellton, Yuma County, AZ

  6. GENERAL ARRANGEMENT AND OUTLINE. T.H. 2.5 PUMPING PLANT. TEXAS HILL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    GENERAL ARRANGEMENT AND OUTLINE. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL - STA. 132+00. TEXAS HILL CANAL AND DISTRIBUTION SYSTEM. United States Department of Interior, Bureau of Reclamation; Gila Project, Arizona, Wellton-Mohawk Division. Drawing No. 50-D-3187, dated January 10, 1955, Denver, Colorado - Wellton-Mohawk Irrigation System, Relift Station, Texas Hill Canal 2.5, Northern Terminus of Avenue 51 East, approximately .5 mile south of Union Pacific Railroad, Wellton, Yuma County, AZ

  7. Early immunological response to German cockroach frass exposure induces a Th2/Th17 environment.

    PubMed

    Page, Kristen; Zhou, Ping; Ledford, John R; Day, Scottie B; Lutfi, Riad; Dienger, Krista; Lewkowich, Ian P

    2011-01-01

    Cockroach exposure is a major risk factor for the development of asthma; however, the early immune events induced by cockroach leading to the Th2 response are not fully understood. Exposure of naïve mice to German cockroach (GC) feces (frass) was sufficient to induce dendritic cell (DC) recruiting and activating chemokines C-C motif ligand 20, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor and macrophage inflammatory protein-1α into the airways. This corresponded with an increase in myeloid DCs (mDCs) in the airways as well as increased expression of CD80 and CD86 on the mDCs. Plasmacytoid DCs in the lung were unchanged. Levels of IL-5, IL-17A and IL-6 cytokines in whole lung cultures were significantly increased 18 h following GC frass exposure demonstrating the early development of a mixed Th2/Th17 response. In addition, GC frass stimulated the production of IL-23, IL-6 and IL-12p70 from bone marrow-derived mDCs. Adoptive transfer of GC frass-pulsed mDCs induced airway reactivity, airway inflammation as well as eosinophilia and induced a strong Th2/Th17 response in the lung. MyD88-deficient bone marrow-derived mDCs did not respond to GC frass treatment, suggesting a functional Toll-like receptor pathway was important to induce the Th2/Th17 response. Together, our data show that GC frass activated the innate immune response to augment DC recruitment and activation of mDCs which promoted robust T cell-skewing cytokines and ultimately drive the development of airway inflammation.

  8. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization

    PubMed Central

    Caballero, Mauricio T.; Serra, M. Elina; Acosta, Patricio L.; Marzec, Jacqui; Gibbons, Luz; Salim, Maximiliano; Rodriguez, Andrea; Reynaldi, Andrea; Garcia, Alejandro; Bado, Daniela; Buchholz, Ursula J.; Hijano, Diego R.; Coviello, Silvina; Newcomb, Dawn; Bellabarba, Miguel; Ferolla, Fausto M.; Libster, Romina; Berenstein, Ada; Siniawaski, Susana; Blumetti, Valeria; Echavarria, Marcela; Pinto, Leonardo; Lawrence, Andrea; Ossorio, M. Fabiana; Grosman, Arnoldo; Mateu, Cecilia G.; Bayle, Carola; Dericco, Alejandra; Pellegrini, Mariana; Igarza, Ignacio; Repetto, Horacio A.; Grimaldi, Luciano Alva; Gudapati, Prathyusha; Polack, Norberto R.; Althabe, Fernando; Shi, Min; Ferrero, Fernando; Bergel, Eduardo; Stein, Renato T.; Peebles, R. Stokes; Boothby, Mark; Kleeberger, Steven R.; Polack, Fernando P.

    2015-01-01

    While 30%–70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention. PMID:25555213

  9. Interleukin-19 contributes as a protective factor in experimental Th2-mediated colitis.

    PubMed

    Fujimoto, Yasuyuki; Azuma, Yasu-Taka; Matsuo, Yukiko; Kuwamura, Mitsuru; Kuramoto, Nobuyuki; Miki, Mariko; Azuma, Naoki; Teramoto, Midori; Nishiyama, Kazuhiro; Izawa, Takeshi; Nakajima, Hidemitsu; Takeuchi, Tadayoshi

    2017-03-01

    Inflammatory bowel disease results from chronic dysregulation of the mucosal immune system and aberrant activation of both the innate and adaptive immune responses. IL-19 is a member of the IL-10 family, and IL-10 plays an important role in inflammatory bowel disease. We have previously shown that IL-19 knockout mice are more susceptible to innate-mediated colitis. Next, we ask whether IL-19 contributes to T cells-mediated colitis. Here, we investigated the role of IL-19 in a mouse model of Th2 cell-mediated colitis. Inflammatory responses in IL-19-deficient mice were assessed using a Th2-mediated colitis induced by oxazolone. The colitis was evaluated by analyzing the body weight loss and histology of the colon. Lymph node cells were cultured in vitro to determine cytokine production. IL-19 knockout mice exacerbated oxazolone-induced colitis by stimulating the transport of inflammatory cells into the colon, and by increasing IgE production and the number of circulating eosinophil. The exacerbation of oxazolone-induced colonic inflammation following IL-19 knockout mice was accompanied by an increased production of IL-4 and IL-9, but no changes in the expression of IL-5 and IL-13 in lymph node cells. IL-19 plays an anti-inflammatory role in the Th2-mediated colitis model, suggesting that IL-19 may represent a potential therapeutic target for reducing colonic inflammation.

  10. Human Bone Marrow-derived Mesenchymal Stem Cells Induce Th2-Polarized Immune Response and Promote Endogenous Repair in Animal Models of Multiple Sclerosis

    PubMed Central

    Bai, L; Lennon, DP; Eaton, V; Maier, K; Caplan, AI; Miller, SD; Miller, RH

    2009-01-01

    Cell based therapies are attractive approaches to promote myelin repair. Recent studies demonstrated a reduction in disease burden in mice with EAE treated with mouse mesenchymal stem cells (MSCs). Here we demonstrated human bone marrow derived MSCs (BM-hMSCs) promote functional recovery in both chronic and relapsing-remitting models of mouse EAE, traced their migration into the injured CNS and assayed their ability to modulate disease progression and the host immune response. Injected BM-hMSCs accumulated in the CNS, reduced the extent of damage and increased oligodendrocyte lineage cells in lesion areas. The increase in oligodendrocytes in lesions may reflect BM-hMSC induced changes in neural fate determination since neurospheres from treated animals gave rise to more oligodendrocytes and less astrocytes than non-treated neurospheres. Host immune responses were also influenced by BM-hMSCs. Inflammatory T-cells including interferon gamma (IFN-γ) producing Th1 cells and IL-17 producing Th17 inflammatory cells and their associated cytokines were reduced along with concomitant increases in IL-4 producing Th2 cells and anti-inflammatory cytokines. Together these data suggest the BM-hMSCs represent a viable option for therapeutic approaches. PMID:19191336

  11. Gold and d-penicillamine induce vasculitis and up-regulate mRNA for IL-4 in the Brown Norway rat: support for a role for Th2 cell activity

    PubMed Central

    QASIM, F J; THIRU, S; GILLESPIE, K

    1997-01-01

    d-penicillamine (DP) and gold salts which are used as immune-modulating agents in the treatment of rheumatoid arthritis are known to be capable of causing autoimmune manifestations. Most autoimmune diseases in man are dominated by Th1-type responses, and one might presume that effective immunotherapy counteracts Th1 activity, perhaps by causing a shift to a Th2 response. The mechanism of action of gold and DP is not clear, but some clues may be obtained from their effects in animal models. DP, gold salts and mercuric chloride (HgCl2) are known to induce Th2-dominated autoimmune syndromes in genetically susceptible rodent strains, and we have demonstrated recently that HgCl2 up-regulates messenger RNA (mRNA) for IL-4 in the Brown Norway (BN) rat. In the BN rat HgCl2 treatment is also associated with the development of vasculitis, and anti-myeloperoxidase (MPO) antibodies are found in the serum. The present study examined and confirmed the hypothesis that, since gold and DP induce an autoimmune syndrome similar to HgCl2 in the BN rat, they may also induce vasculitis and an up-regulation in mRNA for IL-4. Tissue injury was assessed macroscopically and histologically on day 5 and day 15 after the start of injections with gold, DP or HgCl2, serum titres of IgE and presence of anti-MPO antibodies were determined using ELISA, and a semi-quantitative assay using reverse transcription-polymerase chain reaction was used to assay the level of mRNA for IL-4 in spleen and caecum. The relative degree of tissue injury reflected the potency of induction of IgE by the three agents (HgCl2 being most potent and DP least potent). The lesions were identical histologically, supporting the premise that the vasculitis is a manifestation of the autoimmune syndrome rather than non-specific HgCl2 toxicity. Both gold and DP induced less up-regulation of mRNA for IL-4 than HgCl2. HgCl2 (but not gold or DP) induced anti-MPO antibodies. It would be interesting to examine patients treated with

  12. IL-21 is increased in peripheral blood of emphysema mice and promotes Th1/Tc1 cell generation in vitro.

    PubMed

    Duan, Minchao; Huang, Ying; Zhong, Xiaoning; Tang, Haijuan

    2014-06-01

    Interleukin-21 (IL-21) has been reported to be involved in many Th1-associated diseases. However, the alteration and immune regulation of IL-21 in emphysema remains unknown. In this study, we tested the levels of IFN-γ and IL-21 and the frequencies of Th1 and Tc1 in peripheral blood from cigarette smoke (CS)-exposed mice and air-exposed mice and explored the effect of IL-21 on generation of Th1 and Tc1 cells in vitro. It was found that the levels of IFN-γ and IL-21 and the frequencies of Th1, Tc1, CD4(+) IL-21(+), CD4(+) IL-21R(+), and CD8(+) IL-21R(+) T cells were much higher in CS-exposed mice. Moreover, the levels of IL-21 were correlated positively with Th1 cells and with Tc1 cells. Finally, the in vitro experiments showed that IL-21 could promote Th1/Tc1 cell generation in CS-exposed mice. These results indirectly provide evidence that IL-21 produced by CD4(+) T cells could promote Th1/Tc1 response, leading to systemic inflammation in emphysema.

  13. The Role of Neutrophils in the Induction of Specific Th1 and Th17 during Vaccination against Tuberculosis

    PubMed Central

    Trentini, Monalisa M.; de Oliveira, Fábio M.; Kipnis, André; Junqueira-Kipnis, Ana P.

    2016-01-01

    Mycobacterium tuberculosis causes tuberculosis (TB), a disease that killed more than 1.5 million people worldwide in 2014, and the Bacillus Calmette Guérin (BCG) vaccine is the only currently available vaccine against TB. However, it does not protect adults. Th1 and Th17 cells are crucial for TB control, as well as the neutrophils that are directly involved in DC trafficking to the draining lymph nodes and the activation of T lymphocytes during infection. Although several studies have shown the importance of neutrophils during M. tuberculosis infection, none have shown its role in the development of a specific response to a vaccine. The vaccine mc2-CMX was shown to protect mice against M. tuberculosis challenge, mainly due to specific Th1 and Th17 cells. This study evaluated the importance of neutrophils in the generation of the Th1- and Th17-specific responses elicited by this vaccine. The vaccine injection induced a neutrophil rich lesion with a necrotic central area. The IL-17 KO mice did not generate vaccine-specific Th1 cells. The vaccinated IL-22 KO mice exhibited Th1- and Th17-specific responses. Neutrophil depletion during vaccination abrogated the induction of Th1-specific responses and prohibited the bacterial load reduction observed in the vaccinated animals. The results show, for the first time, the role of neutrophils in the generation of specific Th1 and Th17 cells in response to a tuberculosis vaccine. PMID:27375607

  14. Immunization of proteins from Toxascaris leonina adult worm inhibits allergic specific Th2 response.

    PubMed

    Lee, Keun Hee; Park, Hye Kyung; Jeong, Hae Jin; Park, Sang Kyun; Lee, Sun Joo; Choi, Sun Hee; Cho, Min Kyoung; Ock, Mee Sun; Hong, Yeon-Chul; Yu, Hak Sun

    2008-10-01

    Recently, the influence of parasitic infections on the incidence of allergic diseases has become the focus of increased attention. In order to ascertain whether parasite-derived proteins could inhibit the allergic specific Th2 response, we applied excretory-secretory protein (Tl-ES) or total protein (Tl-TP) of the adult worm Toxascaris leonina to asthma model mice prior to or simultaneously with OVA challenge, after which we assessed the OVA-specific Th2 responses. The group subjected to immunization with Tl-ES and Tl-TP (immunized group) evidenced a thinning of the bronchial epithelial and muscle layer, a disruption and shedding of epithelial cells, a reduction in the number of goblet cells, and a reduction in mucus production as compared to the group treated with Tl-ES coupled with OVA challenge (challenge with OVA groups) and the OVA-induced asthma group. The administration of Tl-ES and Tl-TP, regardless of injection time, was shown to inhibit the recruitment of inflammatory cells into the airway, and in particular, macrophages, neutrophils, and lymphocytes were significantly reduced as the result of the parasite proteins. However, the total number of eosinophils was slightly reduced as the result of the administration of parasite proteins. Sensitization and OVA challenge was shown to accelerate the secretion of Th2 cytokines (IL-4 and IL-5) within the lung, but in the immunized groups, those levels were lower. The administration of Tl-TP and OVA challenge group also evidenced a significant reduction in IL-4 levels as compared to the OVA-challenged group. The concentrations of Th2 cytokines in the Tl-ES and OVA challenge group were more similar to those observed in the OVA-challenged group. The concentration of IL-10 and TGF-beta in the lung was decreased substantially in the OVA-only challenge group, but the Tl-TP immunized group exhibited significantly induced IL-10 cytokine. OVA-specific IgG2a, IgG1, and IgE levels in the immunized groups were significantly

  15. Gene Expression Profiles of Human Phosphotyrosine Phosphatases Consequent to Th1 Polarisation and Effector Function

    PubMed Central

    Castro-Sánchez, Patricia; Ramirez-Munoz, Rocio

    2017-01-01

    Phosphotyrosine phosphatases (PTPs) constitute a complex family of enzymes that control the balance of intracellular phosphorylation levels to allow cell responses while avoiding the development of diseases. Despite the relevance of CD4 T cell polarisation and effector function in human autoimmune diseases, the expression profile of PTPs during T helper polarisation and restimulation at inflammatory sites has not been assessed. Here, a systematic analysis of the expression profile of PTPs has been carried out during Th1-polarising conditions and upon PKC activation and intracellular raise of Ca2+ in effector cells. Changes in gene expression levels suggest a previously nonnoted regulatory role of several PTPs in Th1 polarisation and effector function. A substantial change in the spatial compartmentalisation of ERK during T cell responses is proposed based on changes in the dose of cytoplasmic and nuclear MAPK phosphatases. Our study also suggests a regulatory role of autoimmune-related PTPs in controlling T helper polarisation in humans. We expect that those PTPs that regulate T helper polarisation will constitute potential targets for intervening CD4 T cell immune responses in order to generate new therapies for the treatment of autoimmune diseases. PMID:28393080

  16. Interleukin-22 Promotes T Helper 1 (Th1)/Th17 Immunity in Chlamydial Lung Infection

    PubMed Central

    Peng, Ying; Gao, Xiaoling; Yang, Jie; Shekhar, Sudhanshu; Wang, Shuhe; Fan, Yijun; Zhao, Weiming; Yang, Xi

    2014-01-01

    The role of interleukin-22 (IL-22) in intracellular bacterial infections is a controversial issue, although the contribution of this cytokine to host defense against extracellular bacterial pathogens has been well established. In this study, we focused on an intra-cellular bacterium, Chlamydia, and evaluated the production and function of IL-22 in host defense against chlamydial lung infection using a mouse model. We found that Chlamydia muridarum infection elicited quick IL-22 responses in the lung, which increased during infection and were reduced when bacterial loads decreased. More importantly, blockade of endogenous IL-22 using neutralizing anti-IL-22 monoclonal antibodies (mAb) resulted in more severe disease in the mice, leading to significantly higher weight loss and bacterial growth and much more severe pathological changes than treatment with isotype control antibody. Immunological analyses identified significantly lower T helper 1 (Th1) and Th17 responses in the IL-22–neutralized mice. In contrast, intranasal administration of exogenous IL-22 significantly enhanced protection following chlamydial lung infection, which was associated with a significant increase of Th17 response. The data demonstrate that IL-22 is a critical cytokine, mediating host defense against chlamydial lung infection and coordinating the function of distinct Th-cell subsets, particularly Th1 and Th17, in the process. PMID:24531835

  17. Targeted depletion of lymphotoxin-alpha-expressing TH1 and TH17 cells inhibits autoimmune disease.

    PubMed

    Chiang, Eugene Y; Kolumam, Ganesh A; Yu, Xin; Francesco, Michelle; Ivelja, Sinisa; Peng, Ivan; Gribling, Peter; Shu, Jean; Lee, Wyne P; Refino, Canio J; Balazs, Mercedesz; Paler-Martinez, Andres; Nguyen, Allen; Young, Judy; Barck, Kai H; Carano, Richard A D; Ferrando, Ron; Diehl, Lauri; Chatterjea, Devavani; Grogan, Jane L

    2009-07-01

    Uncontrolled T helper type 1 (T(H)1) and T(H)17 cells are associated with autoimmune responses. We identify surface lymphotoxin-alpha (LT-alpha) as common to T(H)0, T(H)1 and T(H)17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-alpha. Depleting LT-alpha-specific mAb inhibited T cell-mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-alpha-specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-gamma and tumor necrosis factor-alpha (TNF-alpha), whereas decoy lymphotoxin-beta receptor (LT-betaR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcgamma receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1beta and TNF-alpha within joints. These data indicate that depleting LT-alpha-expressing lymphocytes with LT-alpha-specific mAb may be beneficial in the treatment of autoimmune disease.

  18. Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

    PubMed Central

    Kolev, Martin; Dimeloe, Sarah; Le Friec, Gaelle; Navarini, Alexander; Arbore, Giuseppina; Povoleri, Giovanni A.; Fischer, Marco; Belle, Réka; Loeliger, Jordan; Develioglu, Leyla; Bantug, Glenn R.; Watson, Julie; Couzi, Lionel; Afzali, Behdad; Lavender, Paul; Hess, Christoph; Kemper, Claudia

    2015-01-01

    Summary Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ T cell effector function. PMID:26084023

  19. Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses.

    PubMed

    Kolev, Martin; Dimeloe, Sarah; Le Friec, Gaelle; Navarini, Alexander; Arbore, Giuseppina; Povoleri, Giovanni A; Fischer, Marco; Belle, Réka; Loeliger, Jordan; Develioglu, Leyla; Bantug, Glenn R; Watson, Julie; Couzi, Lionel; Afzali, Behdad; Lavender, Paul; Hess, Christoph; Kemper, Claudia

    2015-06-16

    Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4(+) T cell effector function.

  20. HP-NAP inhibits the growth of bladder cancer in mice by activating a cytotoxic Th1 response.

    PubMed

    Codolo, Gaia; Fassan, Matteo; Munari, Fabio; Volpe, Andrea; Bassi, Piefrancesco; Rugge, Massimo; Pagano, Francesco; D'Elios, Mario Milco; de Bernard, Marina

    2012-01-01

    Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard treatment for intermediate and high-risk non-muscle-invasive bladder cancer. BCG therapy is the most successful example of immunotherapy in cancer. Unfortunately, the treatment-related side effects are still relevant. Furthermore, non-responder patients are candidate to radical cystectomy in the absence of valuable alternative options. These aspects have prompted the search for newer biological response modifiers (BRM) with a better benefit/side effects ratio. The toll-like receptor (TLR) 2 ligand, Helicobacter pylori protein HP-NAP, has been shown to deserve a potential role as BRM. HP-NAP is capable of driving the differentiation of T helper (Th) 1 cells, both in vitro and in vivo, because of its ability to create an IL-12-enriched milieu. Herein, we report that local administration of HP-NAP decreases tumour growth by triggering tumour necrosis in a mouse model of bladder cancer implant. The effect is accompanied by a significant accumulation of both CD4+ and CD8+ IFN-γ-secreting cells, within tumour and regional lymph nodes. Noteworthy, HP-NAP-treated tumours show also a reduced vascularization due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. Our findings strongly indicate that HP-NAP might become a novel therapeutic "bullet" for the cure of bladder tumours.

  1. Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161+Th1 Cells) to CD161+Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients

    PubMed Central

    Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161+Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161+Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase. PMID:27123445

  2. Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161(+)Th1 Cells) to CD161(+)Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients.

    PubMed

    Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161(+)Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161(+)Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase.

  3. IL-25/IL-33–responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa

    PubMed Central

    Lam, Emily P.S.; Kariyawasam, Harsha H.; Rana, Batika M.J.; Durham, Stephen R.; McKenzie, Andrew N.J.; Powell, Nicholas; Orban, Nara; Lennartz-Walker, Melissa; Hopkins, Claire; Ying, Sun; Rimmer, Joanne; Lund, Valerie J.; Cousins, David J.; Till, Stephen J.

    2016-01-01

    Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown. Objective We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP. Methods Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable β-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. Results IL-25 receptor (IL-17RB)–expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB+CD4+ polyp–derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB+CD4+ T cells, several identical T-cell receptor variable β-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17–producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells. Conclusion IL-25 and IL-33 can interact locally with IL-17RB+ST2+ polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis. PMID:26684290

  4. Induction of a Th1 immune response and suppression of IgE via immunotherapy with a recombinant hybrid molecule encapsulated in liposome-protamine-DNA nanoparticles in a model of experimental allergy.

    PubMed

    Nouri, Hamid Reza; Varasteh, Abdolreza; Jaafari, Mahmoud Reza; Davies, Janet M; Sankian, Mojtaba

    2015-07-01

    Liposome-protamine-DNA nanoparticles (LPD) are safe, effective, and non-toxic adjuvants that induce Th1-like immune responses. We hypothesized that encapsulation of allergens into liposomes could be an appropriate option for immunotherapy. The present study evaluated the immunotherapeutic potential of a recombinant hybrid molecule (rHM) encapsulated in LPD nanoparticles in a murine model of Chenopodium album allergy. BALB/c mice were sensitized with the allergen in alum, and the immunotherapy procedure was performed by subcutaneous injections of LPD-rHM, rHM, or empty LPD at weekly intervals. Sensitized mice developed a Th2-biased immune response characterized by strong specific IgG1 and IgE production, IL-4, and the transcription factor GATA3 in spleen cell cultures. Treatment with the LPD-rHM resulted in a reduction in IgE and a marked increase in IgG2a. The LPD-rHM induced allergen-specific responses with relatively high interferon-gamma production, as well as expression of the transcription factor T-bet in stimulated splenocytes. In addition, lymphoproliferative responses were higher in the LPD-rHM-treated mice than in the other groups. Removal of the nanoparticles from the rHM resulted in a decrease in the allergen's immunogenicity. These results indicate that the rHM complexed with LPD nanoparticles has a marked suppressive effect on the allergic response and caused a shift toward a Th1 pathway.

  5. Parallel algorithms of relative radiometric correction for images of TH-1 satellite

    NASA Astrophysics Data System (ADS)

    Wang, Xiang; Zhang, Tingtao; Cheng, Jiasheng; Yang, Tao

    2014-05-01

    The first generation of transitive stereo-metric satellites in China, TH-1 Satellite, is able to gain stereo images of three-line-array with resolution of 5 meters, multispectral images of 10 meters, and panchromatic high resolution images of 2 meters. The procedure between level 0 and level 1A of high resolution images is so called relative radiometric correction (RRC for short). The processing algorithm of high resolution images, with large volumes of data, is complicated and time consuming. In order to bring up the processing speed, people in industry commonly apply parallel processing techniques based on CPU or GPU. This article firstly introduces the whole process and each step of the algorithm - that is in application - of RRC for high resolution images in level 0; secondly, the theory and characteristics of MPI (Message Passing Interface) and OpenMP (Open Multi-Processing) parallel programming techniques is briefly described, as well as the superiority for parallel technique in image processing field; thirdly, aiming at each step of the algorithm in application and based on MPI+OpenMP hybrid paradigm, the parallelizability and the strategies of parallelism for three processing steps: Radiometric Correction, Splicing Pieces of TDICCD (Time Delay Integration Charge-Coupled Device) and Gray Level Adjustment among pieces of TDICCD are deeply discussed, and furthermore, deducts the theoretical acceleration rates of each step and the one of whole procedure, according to the processing styles and independence of calculation; for the step Splicing Pieces of TDICCD, two different strategies of parallelism are proposed, which are to be chosen with consideration of hardware capabilities; finally, series of experiments are carried out to verify the parallel algorithms by applying 2-meter panchromatic high resolution images of TH-1 Satellite, and the experimental results are analyzed. Strictly on the basis of former parallel algorithms, the programs in the experiments

  6. Interleukin-17 contributes to generation of Th1 immunity and neutrophil recruitment during Chlamydia muridarum genital tract infection but is not required for macrophage influx or normal resolution of infection.

    PubMed

    Scurlock, Amy M; Frazer, Lauren C; Andrews, Charles W; O'Connell, Catherine M; Foote, Isaac P; Bailey, Sarabeth L; Chandra-Kuntal, Kumar; Kolls, Jay K; Darville, Toni

    2011-03-01

    Interleukin 17 (IL-17) contributes to development of Th1 immunity and neutrophil influx during Chlamydia muridarum pulmonary infection, but its role during C. muridarum genital tract infection has not been described. We detected similar numbers of Chlamydia-specific Th17 and Th1 cells in iliac nodes of wild-type mice early during genital C. muridarum infection, while Th1 cells predominated later. il17ra(-/-) mice exhibited a reduced chlamydia-specific Th1 response in draining iliac nodes and decreased local IFN-γ production. Neutrophil influx into the genital tract was also decreased. However, il17ra(-/-) mice resolved infection normally, and no difference in pathology was observed compared to the wild type. Macrophage influx and tumor necrosis factor alpha (TNF-α) production were increased in il17ra(-/-) mice, providing a compensatory mechanism to effectively control chlamydial genital tract infection despite a reduced Th1 response. In ifnγ(-/-) mice, a marked increase in cellular infiltrates and chronic pathology was associated with an increased Th17 response. Although neutralization of IL-17 in ifnγ(-/-) mice decreased neutrophil influx, macrophage infiltration remained intact and the bacterial burden was not increased. Collectively, these results indicate that IL-17 contributes to the generation of Th1 immunity and neutrophil recruitment but is not required for macrophage influx or normal resolution of C. muridarum genital infection. These data highlight the redundant immune mechanisms operative at this mucosal site and the importance of examining site-specific responses to mucosal pathogens.

  7. The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

    SciTech Connect

    Steinmetz, Martin; Ponnuswamy, Padmapriya; Laurans, Ludivine; Esposito, Bruno; Tedgui, Alain; Mallat, Ziad

    2015-08-14

    Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 10{sup 7} OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen

  8. Aerobic Exercise Attenuated Bleomycin-Induced Lung Fibrosis in Th2-Dominant Mice

    PubMed Central

    Oliveira-Junior, Manoel Carneiro; Assumpção-Neto, Erasmo; Brandão-Rangel, Maysa Alves Rodrigues; Damaceno-Rodrigues, Nilsa Regina; Garcia Caldini, Elia; Velosa, Ana Paula Pereira; Teodoro, Walcy Rosolia; Ligeiro de Oliveira, Ana Paula; Dolhnikoff, Marisa; Eickelberg, Oliver; Vieira, Rodolfo Paula

    2016-01-01

    Introduction The aim of this study was to investigate the effect of aerobic exercise (AE) in reducing bleomycin-induced fibrosis in mice of a Th2-dominant immune background (BALB/c). Methods BALB/c mice were distributed into: sedentary, control (CON), Exercise-only (EX), sedentary, bleomycin-treated (BLEO) and bleomycin-treated+exercised (BLEO+EX); (n = 8/group). Following treadmill adaptation, 15 days following a single, oro-tracheal administration of bleomycin (1.5U/kg), AE was performed 5 days/week, 60min/day for 4 weeks at moderate intensity (60% of maximum velocity reached during a physical test) and assessed for pulmonary inflammation and remodeling, and cytokine levels in bronchoalveolar lavage (BAL). Results At 45 days post injury, compared to BLEO, BLEO+EX demonstrated reduced collagen deposition in the airways (p<0.001) and also in the lung parenchyma (p<0.001). In BAL, a decreased number of total leukocytes (p<0.01), eosinophils (p<0.001), lymphocytes (p<0.01), macrophages (p<0.01), and neutrophils (p<0.01), as well as reduced pro-inflammatory cytokines (CXCL-1; p<0.01), (IL-1β; p<0.001), (IL-5; p<0.01), (IL-6; p<0.001), (IL-13; p<0.01) and pro-fibrotic growth factor IGF-1 (p<0.001) were observed. Anti-inflammatory cytokine IL-10 was increased (p<0.001). Conclusion AE attenuated bleomycin-induced collagen deposition, inflammation and cytokines accumulation in the lungs of mice with a predominately Th2-background suggesting that therapeutic AE (15–44 days post injury) attenuates the pro-inflammatory, Th2 immune response and fibrosis in the bleomycin model. PMID:27677175

  9. Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions

    PubMed Central

    Planas, Raquel; Metz, Imke; Ortiz, Yaneth; Vilarrasa, Nuria; Jelčić, Ilijas; Salinas-Riester, Gabriela; Heesen, Christoph; Brück, Wolfgang; Martin, Roland; Sospedra, Mireia

    2015-01-01

    Objective Multiple sclerosis (MS) is a disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Based on infiltrating immune cells, deposition of humoral factors and loss of oligodendrocytes and/or myelin proteins, four lesion patterns have been described. Pattern II is characterized by antibody and complement deposition in addition to T-cell infiltration. MS is considered a T-cell-mediated disease, but until now the study of pathogenic T cells has encountered major challenges, most importantly the limited access of brain-infiltrating T cells. Our objective was to identify, isolate, and characterize brain-infiltrating clonally expanded T cells in pattern II MS lesions. Methods We used next-generation sequencing to identify clonally expanded T cells in demyelinating pattern II brain autopsy lesions, subsequently isolated these as T-cell clones from autologous cerebrospinal fluid and functionally characterized them. Results We identified clonally expanded CD8+ but also CD4+ T cells in demyelinating pattern II lesions and for the first time were able to isolate these as live T-cell clones. The functional characterization shows that T cells releasing Th2 cytokines and able to provide B cell help dominate the T-cell infiltrate in pattern II brain lesions. Interpretation Our data provide the first functional evidence for a putative role of Th2/Tc2 cells in pattern II MS supporting the existence of this pathogenic phenotype and questioning the protective role that is generally ascribed to Th2 cells. Our observations are important to consider for future treatments of pattern II MS patients. PMID:26401510

  10. The TLR4 Agonist Vaccine Adjuvant, GLA-SE, Requires Canonical and Atypical Mechanisms of Action for TH1 Induction.

    PubMed

    Dubois Cauwelaert, Natasha; Desbien, Anthony L; Hudson, Thomas E; Pine, Samuel O; Reed, Steven G; Coler, Rhea N; Orr, Mark T

    2016-01-01

    The Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) promotes strong TH1 and balanced IgG1/IgG2 responses to protein vaccine antigens. This enhanced immunity is sufficient to provide protection against many diseases including tuberculosis and leishmaniasis. To better characterize the adjuvant action it is important to understand how the different cytokines and transcription factors contribute to the initiation of immunity. In the present study using T-bet-/- and IL-12-/- mice and a blocking anti-IFNαR1 monoclonal antibody, we define mechanisms of adjuvant activity of GLA-SE. In accordance with previous studies of TLR4 agonist based adjuvants, we found that TH1 induction via GLA-SE was completely dependent upon T-bet, a key transcription factor for IFNγ production and TH1 differentiation. Consistent with this, deficiency of IL-12, a cytokine canonical to TH1 induction, ablated TH1 induction via GLA-SE. Finally we demonstrate that the innate immune response to GLA-SE, including rapid IFNγ production by memory CD8+ T cells and NK cells, was contingent on type I interferon, a cytokine group whose association with TH1 induction is contextual, and that they contributed to the adjuvant activity of GLA-SE.

  11. DISCHARGE PIPE AND OUTLET TRANSITION. T.H. 2.5 PUMPING PLANT. TEXAS ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    DISCHARGE PIPE AND OUTLET TRANSITION. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL - STA. 132+00.00. TEXAS HILL CANAL AND DISTRIBUTION SYSTEM. United States Department of Interior, Bureau of Reclamation; Gila Project, Arizona, Wellton-Mohawk Division. Drawing No. 50-D-3199, dated January 26, 1955, Denver, Colorado - Wellton-Mohawk Irrigation System, Relift Station, Texas Hill Canal 2.5, Northern Terminus of Avenue 51 East, approximately .5 mile south of Union Pacific Railroad, Wellton, Yuma County, AZ

  12. INLET TRANSITION WEIR SPILLWAY OUTLET STRUCTURE. T.H. 2.5 PUMPING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    INLET TRANSITION - WEIR SPILLWAY OUTLET STRUCTURE. T.H. 2.5 PUMPING PLANT. TEXAS HILL CANAL - STA. 132+00.00. TEXAS HILL CANAL AND DISTRIBUTION SYSTEM. United States Department of Interior, Bureau of Reclamation; Gila Project, Arizona, Wellton-Mohawk Division. Drawing No. 50-D-3198, dated January 24, 1955, Denver, Colorado - Wellton-Mohawk Irrigation System, Relift Station, Texas Hill Canal 2.5, Northern Terminus of Avenue 51 East, approximately .5 mile south of Union Pacific Railroad, Wellton, Yuma County, AZ

  13. Aeromonas caviae strain induces Th1 cytokine response in mouse intestinal tract

    SciTech Connect

    Hayes, S L; Lye, D J; McKinstry, Craig A.; Vesper, Sephen J.

    2010-01-01

    Aeromonas caviae has been associated with human gastrointestinal disease. Strains of this species typically lack virulence factors (VFs) such as enterotoxins and hemolysins that are produced by other human pathogens of the Aeromonas genus. Microarray profiling of murine small intestinal extracts, 24 hours after oral infection with an A. caviae strain, provides evidence of a Th1 type immune response. A large number of gamma-interferon (γ-IFN) induced genes are up-regulated as well as several tumor necrosis factor-alpha (TNF-α) transcripts. A. caviae has always been considered as opportunistic pathogen because it lacks obvious virulence factors. This current effort suggests that an A. caviae strain can colonize the murine intestinal tract and cause what has been described by others as a dysregulatory cytokine response. This response could explain why a number of diarrheal waterborne disease cases have been attributed to A. caviae even though it lacks obvious enteropathogenic properties.

  14. Thymic Low Affinity/Avidity Interaction Selects Natural Th1 Cells

    PubMed Central

    Kang, Byung Hyun; Park, Hyo Jin; Yum, Hye In; Park, Seung Pyo; Park, Jin Kyun; Kang, Eun Ha; Lee, Jae-Il; Lee, Eun Bong; Park, Chung-Gyu

    2015-01-01

    Identification of intrathymic eomesodermin+ (Eomes+) CD4 T cells creates a novel idea that there is more than one way for the generation of innate CD4 T cells. Promyelocytic leukemia zinc finger protein+ T cells and natural Th17 cells are known to be generated by sensing a high and persistent TCR strength, whereas this is not the case for Eomes+ CD4 T cells. These cells go through low-level signal during the entire maturation pathway, which subsequently leads to induction of high susceptibility to cytokine IL-4. This event seems to be a major determinant for the generation of this type of cell. These T cells are functionally equivalent to Th1 cells that are present in the periphery, and this event takes place both in transgenic and in wild-type mice. There is additional evidence that this type of Eomes+ innate CD4 T cell is also present in human cord blood. PMID:25972479

  15. Ex vivo rapamycin generates donor Th2 cells that potently inhibit graft-versus-host disease and graft-versus-tumor effects via an IL-4-dependent mechanism.

    PubMed

    Foley, Jason E; Jung, Unsu; Miera, Angel; Borenstein, Todd; Mariotti, Jacopo; Eckhaus, Michael; Bierer, Barbara E; Fowler, Daniel H

    2005-11-01

    Rapamycin (sirolimus) inhibits graft-vs-host disease (GVHD) and polarizes T cells toward Th2 cytokine secretion after allogeneic bone marrow transplantation (BMT). Therefore, we reasoned that ex vivo rapamycin might enhance the generation of donor Th2 cells capable of preventing GVHD after fully MHC-disparate murine BMT. Using anti-CD3 and anti-CD28 costimulation, CD4+ Th2 cell expansion was preserved partially in high-dose rapamycin (10 microM; Th2.rapa cells). Th2.rapa cells secreted IL-4 yet had reduced IL-5, IL-10, and IL-13 secretion relative to control Th2 cells. BMT cohorts receiving wild-type (WT) Th2.rapa cells, but not Th2.rapa cells generated from IL-4-deficient (knockout) donors, had marked Th2 skewing post-BMT and greatly reduced donor anti-host T cell alloreactivity. Histologic studies demonstrated that Th2.rapa cell recipients had near complete abrogation of skin, liver, and gut GVHD. Overall survival in recipients of WT Th2.rapa cells, but not IL-4 knockout Th2.rapa cells, was constrained due to marked attenuation of an allogeneic graft-vs-tumor (GVT) effect against host-type breast cancer cells. Delay in Th2.rapa cell administration until day 4, 7, or 14 post-BMT enhanced GVT effects, moderated GVHD, and improved overall survival. Therefore, ex vivo rapamycin generates enhanced donor Th2 cells for attempts to balance GVHD and GVT effects.

  16. Blood Stem Cell Activity Is Arrested by Th1-Mediated Injury Preventing Engraftment following Nonmyeloablative Conditioning

    PubMed Central

    Florek, Mareike; Kohrt, Holbrook E. K.; Küpper, Natascha J.; Filatenkov, Alexander; Linderman, Jessica A.; Hadeiba, Husein; Negrin, Robert S.

    2016-01-01

    T cells are widely used to promote engraftment of hematopoietic stem cells (HSCs) during an allogeneic hematopoietic cell transplantation. Their role in overcoming barriers to HSC engraftment is thought to be particularly critical when patients receive reduced doses of preparative chemotherapy and/or radiation compared with standard transplantations. In this study, we sought to delineate the effects CD4+ cells on engraftment and blood formation in a model that simulates clinical hematopoietic cell transplantation by transplanting MHC-matched, minor histocompatibility–mismatched grafts composed of purified HSCs, HSCs plus bulk T cells, or HSCs plus T cell subsets into mice conditioned with low-dose irradiation. Grafts containing conventional CD4+ T cells caused marrow inflammation and inhibited HSC engraftment and blood formation. Posttransplantation, the marrows of HSCs plus CD4+ cell recipients contained IL-12–secreting CD11c+ cells and IFN-γ–expressing donor Th1 cells. In this setting, host HSCs arrested at the short-term stem cell stage and remained in the marrow in a quiescent cell cycling state (G0). As a consequence, donor HSCs failed to engraft and hematopoiesis was suppressed. Our data show that Th1 cells included in a hematopoietic allograft can negatively impact HSC activity, blood reconstitution, and engraftment of donor HSCs. This potential negative effect of donor T cells is not considered in clinical transplantation in which bulk T cells are transplanted. Our findings shed new light on the effects of CD4+ T cells on HSC biology and are applicable to other pathogenic states in which immune activation in the bone marrow occurs such as aplastic anemia and certain infectious conditions. PMID:27815446

  17. Coumestrol inhibits autoantibody production through modulating Th1 response in experimental autoimmune thyroiditis

    PubMed Central

    Zhao, Xuemin; Jin, Qian; Fan, Chenling; Li, Jing; Shan, Zhongyan; Teng, Weiping

    2016-01-01

    Coumestrol is a common phytoestrogen found in plants and Chinese medicinal herbs. Its influences on experimental autoimmune thyroiditis (EAT) were investigated in this study. Female adult CBA/J mice were fed with drinking water containing 1% Tween80 only (Control group), 0.8 mg/l (L group) and 8 mg/l coumestrol (H group) from 6 to 15 weeks of age, respectively. Their serum coumestrol concentrations were determined by high performance liquid chromatography, which were undetectable, 43.70 ± 21.74 ng/ml and 135.07 ± 70.40 ng/ml, respectively. In addition, the mice (n = 14–16/group) were immunized twice with thyroglobulin (Tg) and Freund's adjuvant to induce EAT during the meantime. Although no overt changes in the extent of intrathyroidal mononuclear cell infiltration were shown in the two coumestrol-treated groups as compared with the controls, serum anti-Tg IgG2a, IgG3 and IgG1 titers, ratio of IgG2a to IgG1 and the percentage of T helper (Th)1 cells in the splenocytes were significantly reduced in the L group. Another consistent change was the significantly decreased expression of splenic IFN-γ mRNA after low dose of coumestrol exposure. Uterine weight was also markedly reduced in the mice of L group. These findings suggest that coumestrol treatment may have some beneficial actions against thyroid-specific autoantibody production in the development of autoimmune thyroiditis through suppression of Th1 response due to its anti-estrogenic activity. PMID:27384679

  18. DISCOVERY OF COLLIMATED BIPOLAR OUTFLOWS IN THE PLANETARY NEBULA TH 2-A

    SciTech Connect

    Danehkar, A.

    2015-12-10

    We present a comprehensive set of spatially resolved, integral field spectroscopic mapping of the Wolf–Rayet planetary nebula Th 2-A, obtained using the Wide Field Spectrograph on the Australian National University 2.3-m telescope. Velocity-resolved Hα channel maps with a resolution of 20 km s{sup −1} allow us to identify different kinematic components within the nebula. This information is used to develop a three-dimensional morpho-kinematic model of the nebula using the interactive kinematic modeling tool shape. These results suggest that Th 2-A has a thick toroidal shell with an expansion velocity of 40 ± 10 km s{sup −1}, and a thin prolate ellipsoid with collimated bipolar outflows toward its axis reaching velocities in the range of 70–110 km s{sup −1}, with respect to the central star. The relationship between its morpho-kinematic structure and peculiar [WO]-type stellar characteristics deserves further investigation.

  19. TLR2 signaling and Th2 responses drive Tannerella forsythia-induced periodontal bone loss.

    PubMed

    Myneni, Srinivas R; Settem, Rajendra P; Connell, Terry D; Keegan, Achsah D; Gaffen, Sarah L; Sharma, Ashu

    2011-07-01

    Periodontal disease (PD) is a chronic inflammation of the tooth-supporting soft tissue and alveolar bone due to infection by a select group of gram-negative microbes, which leads to tooth loss if untreated. Because mice deficient in CD4(+) cells are resistant to infection-induced alveolar bone loss, Th cells have been implicated in bone-destructive processes during PD. However, the extent to which different Th cell subtypes play roles in pathogenesis or host protection remains to be defined and is likely to vary depending on the dominant microorganism involved. By far, Porphyromonas gingivalis is the best-studied periodontal microbe in PD. Although the gram-negative anaerobe Tannerella forsythia is also a vital contributor to periodontal bone loss, almost nothing is known about immune responses to this organism. Previous studies from our laboratory revealed that T. forsythia induces periodontal bone loss in mice and that this bone loss depends on the bacterially expressed BspA protein. In this study, we showed that T. forsythia activates murine APCs primarily through TLR2-dependent signaling via BspA. Furthermore, T. forsythia infection causes a pronounced Th2 bias, evidenced by T cell expression of IL-5, but not IFN-γ or IL-17, in draining lymph nodes. Consistently, deficiencies in TLR2 or STAT6 result in resistance to T. forsythia-induced alveolar bone loss. Thus, TLR2 signaling and Th2 cells play pathogenic roles in T. forsythia-induced alveolar bone destruction.

  20. Rapamycin generates anti-apoptotic human Th1/Tc1 cells via autophagy for induction of xenogeneic GVHD.

    PubMed

    Amarnath, Shoba; Flomerfelt, Francis A; Costanzo, Carliann M; Foley, Jason E; Mariotti, Jacopo; Konecki, Daniel M; Gangopadhyay, Anu; Eckhaus, Michael; Wong, Susan; Levine, Bruce L; June, Carl H; Fowler, Daniel H

    2010-05-01

    Murine T cells exposed to rapamycin maintain flexibility towards Th1/Tc1 differentiation, thereby indicating that rapamycin promotion of regulatory T cells (Tregs) is conditional. The degree to which rapamycin might inhibit human Th1/Tc1 differentiation has not been evaluated. In the presence of rapamycin, T cell costimulation and polarization with IL-12 or IFN-α permitted human CD4+ and CD8+ T cell differentiation towards a Th1/Tc1 phenotype; activation of STAT1 and STAT4 pathways essential for Th1/Tc1 polarity was preserved during mTOR blockade but instead abrogated by PI3 kinase inhibition. Such rapamycin-resistant human Th1/Tc1 cells: (1) were generated through autophagy (increased LC3BII expression; phenotype reversion by autophagy inhibition via 3-MA or siRNA for Beclin1); (2) expressed anti-apoptotic bcl-2 family members (reduced Bax, Bak; increased phospho-Bad); (3) maintained mitochondrial membrane potentials; and (4) displayed reduced apoptosis. In vivo, type I polarized and rapamycin-resistant human T cells caused increased xenogeneic graft-versus-host disease (x-GVHD). Murine recipients of rapamycin-resistant human Th1/Tc1 cells had: (1) persistent T cell engraftment; (2) increased T cell cytokine and cytolytic effector function; and (3) T cell infiltration of skin, gut, and liver. Rapamycin therefore does not impair human T cell capacity for type I differentiation. Rather, rapamycin yields an anti-apoptotic Th1/Tc1 effector phenotype by promoting autophagy.

  1. Bach2–Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop

    PubMed Central

    Kuwahara, Makoto; Ise, Wataru; Ochi, Mizuki; Suzuki, Junpei; Kometani, Kohei; Maruyama, Saho; Izumoto, Maya; Matsumoto, Akira; Takemori, Nobuaki; Takemori, Ayako; Shinoda, Kenta; Nakayama, Toshinori; Ohara, Osamu; Yasukawa, Masaki; Sawasaki, Tatsuya; Kurosaki, Tomohiro; Yamashita, Masakatsu

    2016-01-01

    Although Bach2 has an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2–Batf complex antagonizes the recruitment of the Batf–Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we find that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production. Second, the Bach2–Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf–Irf4 complex. These findings suggest that IL-4 and Batf form a positive feedback amplification loop to induce Th2 cell differentiation and the subsequent Th2-type immune response, and Bach2–Batf interactions are required to prevent an excessive Th2 response. PMID:27581382

  2. Ascaris lumbricoides pseudocoelomic body fluid induces a partially activated dendritic cell phenotype with Th2 promoting ability in vivo.

    PubMed

    Dowling, David J; Noone, Cariosa M; Adams, Paul N; Vukman, Krisztina V; Molloy, Sile F; Forde, Jessica; Asaolu, Samuel; O'Neill, Sandra M

    2011-02-01

    Dendritic cells (DCs) matured with helminth-derived molecules that promote Th2 immune responses do not follow conventional definitions of DC maturation processes. While a number of models of DC maturation by Th2 stimuli are postulated, further studies are required if we are to clearly define DC maturation processes that lead to Th2 immune responses. In this study, we examine the interaction of Th2-inducing molecules from the parasitic helminth Ascaris lumbricoides with the maturation processes and function of DCs. Here we show that murine bone marrow-derived DCs are partially matured by A. lumbricoides pseudocoelomic body fluid (ABF) as characterised by the production of IL-6, IL-12p40 and macrophage inflammatory protein 2 (MIP-2) but no enhanced expression of cluster of differentiation (CD)-14, T-cell co-stimulatory markers CD80, CD86, CD40, OX40L and major histocompatibility complex class II was observed. Despite these phenotypic characteristics, ABF-stimulated DCs displayed the functional hallmarks of fully matured cells, enhancing DC phagocytosis and promoting Th2-type responses in skin-draining lymph node cells in vivo. ABF activated Th2-associated extracellular signal-regulated kinase-1 and nuclear factor-kB intracellular signalling pathways independently of toll-like receptor 4. Taken together, we believe this is the first paper to demonstrate A. lumbricoides murine DC-Th cell-driven responses shedding further light on DC maturation processes by helminth antigens.

  3. miR-146a in PBMCs modulates Th1 function in patients with acute coronary syndrome.

    PubMed

    Guo, Min; Mao, Xiaobo; Ji, Qingwei; Lang, Mingjian; Li, Songnan; Peng, Yudong; Zhou, Wei; Xiong, Bo; Zeng, Qiutang

    2010-07-01

    The upregulation of Th1 cells has been suggested to have an essential function in the development of atherosclerosis (AS). Recent studies indicate that miR-146a is a microRNA specifically and highly expressed in Th1-driven autoimmune disease. The aim of the study was to investigate the possible mechanisms of the miR-146a in the onset of acute coronary syndrome (ACS). The results showed that the expression of miR-146a in peripheral blood mononuclear cells (PBMCs) was significantly increased in patients with ACS. We showed that overexpression of miR-146a in PBMCs could significantly upregulate the function of Th1 cells. Furthermore, we showed that miR-146a treatment could modulate the Th1 differentiation through posttranscriptional enhancing the T-bet pathway in PBMCs. In addition, this study also provided evidence that miR-146a treatment in vitro could induce the protein expression of TNF-alpha, MCP-1, NF-kappaB p65, which are key pro-inflammatory cytokines and critical transcription factor in AS. In contrast, miR-146a inhibitor could attenuate these phenomena significantly. The results support the concept that miR-146a may be a novel regulatory factor in Th1 differentiation and a new therapeutic target for AS and ACS.

  4. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis.

    PubMed

    Harbour, Stacey N; Maynard, Craig L; Zindl, Carlene L; Schoeb, Trenton R; Weaver, Casey T

    2015-06-02

    Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A(+) phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to "Th1-like" cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-γ-deficient Th17 cells retained an IL-17A(+) phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-γ receptors. Moreover, Th17 cells could provide "help" for the development of pathogenic Th1 cells from naïve precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.

  5. Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

    PubMed Central

    Reinert-Hartwall, Linnea; Honkanen, Jarno; Salo, Harri M.; Nieminen, Janne K.; Luopajärvi, Kristiina; Härkönen, Taina; Veijola, Riitta; Simell, Olli; Ilonen, Jorma; Peet, Aleksandr; Tillmann, Vallo; Knip, Mikael; Knip, Mikael; Koski, Katriina; Koski, Matti; Härkönen, Taina; Ryhänen, Samppa; Hämäläinen, Anu-Maaria; Ormisson, Anne; Peet, Aleksandr; Tillmann, Vallo; Ulich, Valentina; Kuzmicheva, Elena; Mokurov, Sergei; Markova, Svetlana; Pylova, Svetlana; Isakova, Marina; Shakurova, Elena; Petrov, Vladimir; Dorshakova, Natalya V.; Karapetyan, Tatyana; Varlamova, Tatyana; Ilonen, Jorma; Kiviniemi, Minna; Alnek, Kristi; Janson, Helis; Uibo, Raivo; Salum, Tiit; von Mutius, Erika; Weber, Juliane; Ahlfors, Helena; Kallionpää, Henna; Laajala, Essi; Lahesmaa, Riitta; Lähdesmäki, Harri; Moulder, Robert; Nieminen, Janne; Ruohtula, Terhi; Vaarala, Outi; Honkanen, Hanna; Hyöty, Heikki; Kondrashova, Anita; Oikarinen, Sami; Harmsen, Hermie J. M.; De Goffau, Marcus C.; Welling, Gjalt; Alahuhta, Kirsi; Virtanen, Suvi M.

    2015-01-01

    Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions. PMID:25480564

  6. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza

    PubMed Central

    2009-01-01

    and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness. PMID:20003352

  7. Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease

    PubMed Central

    Furukawa, Sachiko; Moriyama, Masafumi; Miyake, Kensuke; Nakashima, Hitoshi; Tanaka, Akihiko; Maehara, Takashi; Iizuka-Koga, Mana; Tsuboi, Hiroto; Hayashida, Jun-Nosuke; Ishiguro, Noriko; Yamauchi, Masaki; Sumida, Takayuki; Nakamura, Seiji

    2017-01-01

    IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and marked infiltration of IgG4-positive cells in multiple organs. Interleukin-33 (IL-33) is a recently described cytokine that is secreted by damaged epithelial cells, macrophages, and dendritic cells, and potently activates helper T type 2 (Th2) immune responses, which have been suggested to play a major role in IgG4 production of IgG4-RD. Here, we assessed the expression of IL-33 and related molecules in the salivary glands (SGs) of patients with IgG4-RD versus that in patients with Sjögren’s syndrome (SS) and controls. Expression of IL-33 and its receptor (ST2) was strongly detected around ectopic germinal centers (GCs) in the SGs from patients with IgG4-RD, whereas IL-33 was expressed only in epithelial cells in patients with SS and controls. Moreover, IL-33 and CD68+/CD163+ macrophages were mainly distributed around ectopic GCs in patients with IgG4-RD. Double immunofluorescence staining showed that IL-33 expression co-localized with CD68+/CD163+ macrophages. Finally, mRNA expression levels of IL-33 showed a positive correlation to those of Th2 cytokines (IL-4 and IL-13) in patients with IgG4-RD. Our data suggest that IL-33 produced by M2 macrophages might contribute to the pathogenesis of IgG4-RD via aberrant activation of Th2 immune responses. PMID:28205524

  8. HIV-specific Th2 and Th17 responses predict HIV vaccine protection efficacy

    PubMed Central

    Sauce, Delphine; Gorochov, Guy; Larsen, Martin

    2016-01-01

    Understanding the factors that delineate the efficacy of T-cell responses towards pathogens is crucial for our ability to develop potent therapies and vaccines against infectious diseases, such as HIV. Here we show that a recently developed analytical tool, the polyfunctionality index (PI), not only enables prediction of protection after vaccination against HIV, but also allows identification of the immunological pathways involved. Our data suggest that induction of a synergistic network of CD4+ T-cell subsets is implicated in HIV-protection. Accordingly, we provide evidence that vaccine-induced protection is associated with CD40L expressing Th2 cells and IL-2 secreting Th17 cells. In conclusion, we describe a novel approach that is widely applicable and readily interpretable in a biological and clinical context. This approach could greatly impact our fundamental understanding of T-cell immunity as well as the search for effective vaccines. PMID:27324186

  9. Tim-3 induces Th2-biased immunity and alternative macrophage activation during Schistosoma japonicum infection.

    PubMed

    Hou, Nan; Piao, Xianyu; Liu, Shuai; Wu, Chuang; Chen, Qijun

    2015-08-01

    T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected with Schistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response against S. japonicum infection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4(+) and CD8(+) T cells, NK1.1(+) cells, and CD11b(+) cells from the livers of S. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8(+) T cells or CD11b(+) cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbers in vitro and in vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b(+) cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection.

  10. Tim-3 Induces Th2-Biased Immunity and Alternative Macrophage Activation during Schistosoma japonicum Infection

    PubMed Central

    Hou, Nan; Piao, Xianyu; Liu, Shuai; Wu, Chuang

    2015-01-01

    T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected with Schistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response against S. japonicum infection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4+ and CD8+ T cells, NK1.1+ cells, and CD11b+ cells from the livers of S. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8+ T cells or CD11b+ cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbers in vitro and in vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b+ cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection. PMID:25987707

  11. Triclosan Induces Thymic Stromal Lymphopoietin in Skin Promoting Th2 Allergic Responses.

    PubMed

    Marshall, Nikki B; Lukomska, Ewa; Long, Carrie M; Kashon, Michael L; Sharpnack, Douglas D; Nayak, Ajay P; Anderson, Katie L; Jean Meade, B; Anderson, Stacey E

    2015-09-01

    Triclosan is an antimicrobial chemical incorporated into many personal, medical and household products. Approximately, 75% of the U.S. population has detectable levels of triclosan in their urine, and although it is not typically considered a contact sensitizer, recent studies have begun to link triclosan exposure with augmented allergic disease. We examined the effects of dermal triclosan exposure on the skin and lymph nodes of mice and in a human skin model to identify mechanisms for augmenting allergic responses. Triclosan (0%-3%) was applied topically at 24-h intervals to the ear pinnae of OVA-sensitized BALB/c mice. Skin and draining lymph nodes were evaluated for cellular responses and cytokine expression over time. The effects of triclosan (0%-0.75%) on cytokine expression in a human skin tissue model were also examined. Exposure to triclosan increased the expression of TSLP, IL-1β, and TNF-α in the skin with concomitant decreases in IL-25, IL-33, and IL-1α. Similar changes in TSLP, IL1B, and IL33 expression occurred in human skin. Topical application of triclosan also increased draining lymph node cellularity consisting of activated CD86(+)GL-7(+) B cells, CD80(+)CD86(+) dendritic cells, GATA-3(+)OX-40(+)IL-4(+)IL-13(+) Th2 cells and IL-17 A(+) CD4 T cells. In vivo antibody blockade of TSLP reduced skin irritation, IL-1β expression, lymph node cellularity, and Th2 responses augmented by triclosan. Repeated dermal exposure to triclosan induces TSLP expression in skin tissue as a potential mechanism for augmenting allergic responses.

  12. Th2-polarized CD4+ T cells and macrophages limit efficacy of radiation therapy

    PubMed Central

    Shiao, Stephen L.; Ruffell, Brian; DeNardo, David G.; Faddegon, Bruce A.; Park, Catherine C.; Coussens, Lisa M.

    2015-01-01

    Radiation therapy (RT) and chemotherapy (CTX) following surgery are mainstays of treatment for breast cancer (BC). While multiple studies have recently revealed the significance of immune cells as mediators of CTX response in BC, less is known regarding roles for leukocytes as mediating outcomes following RT. To address this, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to RT could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor-bearing mice with either a neutralizing monoclonal antibody (mAb) to colony-stimulating factor-1 (CSF-1) or a small molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following RT. Delayed tumor growth in this setting was associated with increased presence of CD8+ T cells, and reduced presence of CD4+ T cells, the main source of the Th2 cytokine interleukin (IL)4 in mammary tumors. Selective depletion of CD4+ T cells or neutralization of IL4 in combination with RT, phenocopied results following macrophage depletion, whereas depletion of CD8+ T cells abrogated improved response to RT following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the CTX paclitaxel resulted in slowed primary mammary tumor growth by CD8+ T cell-dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant Th2-based programs driving protumorigenic and immune suppressive pathways in mammary (breast) tumors to improve outcomes. PMID:25716473

  13. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells

    PubMed Central

    Chen, Xi; Madar, Aviv; Carpenito, Carmine; McGettigan, Shannon E.; Frigault, Matthew J.; Lee, Jihyun; Posey, Avery D.; Scholler, John; Scholler, Nathalie; Bonneau, Richard

    2014-01-01

    With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of TH17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization. When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARs mediated efficient antitumor responses and showed enhanced persistence compared with CD28- or 4-1BB-based CAR T cells. Thus, redirection of TH17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies. PMID:24986688

  14. Mycobacterium tuberculosislpdC, Rv0462, induces dendritic cell maturation and Th1 polarization

    SciTech Connect

    Heo, Deok Rim; Shin, Sung Jae; Kim, Woo Sik; Noh, Kyung Tae; Park, Jin Wook; Son, Kwang Hee; Park, Won Sun; Lee, Min-Goo; Kim, Daejin; Shin, Yong Kyoo; Jung, In Duk; Park, Yeong-Min

    2011-08-05

    Highlights: {yields} Treatment with Rv0462 induces the expression of surface molecules and the production of cytokines in DCs. {yields} Rv0462 induces the activation of MAPKs. {yields} Rv0462-treated DCs enhances the proliferation of CD4{sup +} T cells. -- Abstract: Mycobacterium tuberculosis, the etiological factor of pulmonary tuberculosis, causes significant morbidity and mortality worldwide. Activation of host immune responses for containment of mycobacterial infections involves participation of innate immune cells, such as dendritic cells (DCs). In this study, we demonstrated that the gene encoding lipoamide dehydrogenase C (lpdC) from M. tuberculosis, Rv0462, induce maturation and activation of DCs involved in the MAPKs signaling pathway. Moreover, Rv0462-treated DCs activated naive T cells, polarized CD4{sup +} and CD8{sup +} T cells to secrete IFN-{gamma} in syngeneic mixed lymphocyte reactions, which would be expected to contribute to Th1 polarization of the immune response. Our results suggest that Rv0462 can contribute to the innate and adaptive immune responses during tuberculosis infection, and thus modulate the clinical course of tuberculosis.

  15. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells.

    PubMed

    Guedan, Sonia; Chen, Xi; Madar, Aviv; Carpenito, Carmine; McGettigan, Shannon E; Frigault, Matthew J; Lee, Jihyun; Posey, Avery D; Scholler, John; Scholler, Nathalie; Bonneau, Richard; June, Carl H

    2014-08-14

    With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of TH17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization. When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARs mediated efficient antitumor responses and showed enhanced persistence compared with CD28- or 4-1BB-based CAR T cells. Thus, redirection of TH17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies.

  16. Ship-borne journey induces Th1 cytokines level in antarctic summer expeditioners.

    PubMed

    Mishra, Kamla Prasad; Yadav, Anand Prakash; Shweta; Chanda, Sudipta; Ganju, Lilly; Majumdar, Dhurjati; Ilavazhagan, Govindasamy

    2010-01-01

    It has become apparent that extreme environmental conditions of Antarctic continent alters many immune responses. The present study was conducted on 28th Indian Antarctic expeditioners. The investigations were carried out to explore the effect of multiple stresses like isolation, cold and UV exposure on human immunity. Thirty blood samples were collected between 6 and 7 AM, after an overnight fast at different stages of the expedition - viz. the pre-exposure sample was collected at Delhi on 25(th) October 2008. The expedition started its ship journey from Capetown, on 6(th) January, 2009 and on-board blood was collected on 31(st) January 2009. After 1 month stay at Maitri, blood was collected on 3(rd) March 2009. Different parameters studied included levels of cytokines, chemokines and cortisol. The ship-borne journey induced a dramatic increase in TNF-α, IFN-γ, and B cell activating factor (BAFF) levels and moderate decreases in TGF-β and cortisol levels. However, after being off board for 1 month at Maitri station, levels of above cytokines, cortisol and BAFF were decreased but MIP-1α was significantly increased. These data for the first time suggest that ship-borne journey to the Antarctic continent results in tremendous stress to the body, which eventually resulted in increased TH1-biased immunity.

  17. Ganoderma lucidum polysaccharides encapsulated in liposome as an adjuvant to promote Th1-bias immune response.

    PubMed

    Liu, Zhenguang; Xing, Jie; Zheng, Sisi; Bo, Ruonan; Luo, Li; Huang, Yee; Niu, Yale; Li, Zhihua; Wang, Deyun; Hu, Yuanliang; Liu, Jiaguo; Wu, Yi

    2016-05-20

    Liposome-based vaccine delivery systems are known to enhance immune responses. Ganoderma lucidum polysaccharides (GLP) have been widely studied as immunomodulator and it could be as inducers of strong immune responses. In the research, GLP and ovalbumin (OVA) were encapsulated into liposome as vaccine and inoculated to mice. The magnitude and kinetics of the humoral and cellular immune responses were investigated. The results showed that GLP-OVA-loaded liposomes (GLPL/OVA) could induce more powerful antigen-specific immune responses than each single-component formulation. Mice immunized with GLPL/OVA displayed higher antigen-specific IgG antibodies, better splenocytes proliferation, higher cytokine secretion by splenocytes and significant activation of CD3+CD4+ and CD3+CD8+ T cells. Thus the GLPL/OVA formulation produced a heightened humoral and cellular immune response, with an overall Th1 bias. Enhanced immune responses elicited by the GLPL/OVA formulation might be attributed to effective activation and mature of DC in draining lymph nodes. Overall, these findings indicate that GLPL have the potential to enhance immune responses as vaccine delivery systems.

  18. Modulation of redox balance leaves murine diabetogenic TH1 T cells "LAG-3-ing" behind.

    PubMed

    Delmastro, Meghan M; Styche, Alexis J; Trucco, Massimo M; Workman, Creg J; Vignali, Dario A A; Piganelli, Jon D

    2012-07-01

    Preventing activation of diabetogenic T cells is critical for delaying type 1 diabetes onset. The inhibitory molecule lymphocyte activation gene 3 (LAG-3) and metalloprotease tumor necrosis factor-α converting enzyme (TACE) work together to regulate TH1 responses. The aim of this study was to determine if regulating redox using a catalytic antioxidant (CA) could modulate TACE-mediated LAG-3 shedding to impede diabetogenic T-cell activation and progression to disease. A combination of in vitro experiments and in vivo analyses using NOD mouse strains was conducted to test the effect of redox modulation on LAG-3 shedding, TACE enzymatic function, and disease onset. Systemic treatment of NOD mice significantly delayed type 1 diabetes onset. Disease prevention correlated with decreased activation, proliferation, and effector function of diabetogenic T cells; reduced insulin-specific T-cell frequency; and enhanced LAG-3(+) cells. Redox modulation also affected TACE activation, diminishing LAG-3 cleavage. Furthermore, disease progression was monitored by measuring serum soluble LAG-3, which decreased in CA-treated mice. Therefore, affecting redox balance by CA treatment reduces the activation of diabetogenic T cells and impedes type 1 diabetes onset via decreasing T-cell effector function and LAG-3 cleavage. Moreover, soluble LAG-3 can serve as an early T-cell-specific biomarker for type 1 diabetes onset and immunomodulation.

  19. Th1-Induced CD106 Expression Mediates Leukocytes Adhesion on Synovial Fibroblasts from Juvenile Idiopathic Arthritis Patients

    PubMed Central

    Luciani, Cristina; Capone, Manuela; Rossi, Maria Caterina; Chillà, Anastasia; Santarlasci, Veronica; Mazzoni, Alessio; Cimaz, Rolando; Liotta, Francesco; Maggi, Enrico; Cosmi, Lorenzo; Del Rosso, Mario; Annunziato, Francesco

    2016-01-01

    This study tested the hypothesis that subsets of human T helper cells can orchestrate leukocyte adhesion to synovial fibroblasts (SFbs), thus regulating the retention of leukocytes in the joints of juvenile idiopathic arthritis (JIA) patients. Several cell types, such as monocytes/macrophages, granulocytes, T and B lymphocytes, SFbs and osteoclasts participate in joint tissue damage JIA. Among T cells, an enrichment of classic and non-classic Th1 subsets, has been found in JIA synovial fluid (SF), compared to peripheral blood (PB). Moreover, it has been shown that IL-12 in the SF of inflamed joints mediates the shift of Th17 lymphocytes towards the non-classic Th1 subset. Culture supernatants of Th17, classic and non-classic Th1 clones, have been tested for their ability to stimulate proliferation, and to induce expression of adhesion molecules on SFbs, obtained from healthy donors. Culture supernatants of both classic and non-classic Th1, but not of Th17, clones, were able to induce CD106 (VCAM-1) up-regulation on SFbs. This effect, mediated by tumor necrosis factor (TNF)-α, was crucial for the adhesion of circulating leukocytes on SFbs. Finally, we found that SFbs derived from SF of JIA patients expressed higher levels of CD106 than those from healthy donors, resembling the phenotype of SFbs activated in vitro with Th1-clones supernatants. On the basis of these findings, we conclude that classic and non-classic Th1 cells induce CD106 expression on SFbs through TNF-α, an effect that could play a role in leukocytes retention in inflamed joints. PMID:27123929

  20. The schistosome glutathione S-transferase P28GST, a unique helminth protein, prevents intestinal inflammation in experimental colitis through a Th2-type response with mucosal eosinophils

    PubMed Central

    Driss, V; El Nady, M; Delbeke, M; Rousseaux, C; Dubuquoy, C; Sarazin, A; Gatault, S; Dendooven, A; Riveau, G; Colombel, J F; Desreumaux, P; Dubuquoy, L; Capron, M

    2016-01-01

    Intestinal helminth parasites are potent inducers of T helper type 2 (Th2) response and have a regulatory role, notably on intestinal inflammation. As infection with schistosomes is unlikely to provide a reliable treatment of inflammatory bowel diseases, we have investigated the beneficial effect of a schistosome enzymatic protein, the 28-kDa glutathione S-transferase (P28GST), on the modulation of disease activity and immune responses in experimental colitis. Our results showed that immunization with recombinant P28GST is at least as efficient as established schistosome infection to reduce colitis lesions and expression of pro-inflammatory cytokines. Considering underlying mechanisms, the decrease of inflammatory parameters was associated with the polarization of the immune system toward a Th2 profile, with local and systemic increases of interleukin (IL)-13 and IL-5. Dense eosinophil infiltration was observed in the colons of P28GST-immunized rats and mice. Depletion of eosinophils by treatment with an anti-Siglec-F monoclonal antibody and use of IL-5-deficient mice led to the loss of therapeutic effect, suggesting the crucial role for eosinophils in colitis prevention by P28GST. These findings reveal that immunization with P28GST, a unique recombinant schistosome enzyme, ameliorates intestinal inflammation through eosinophil-dependent modulation of harmful type 1 responses, representing a new immuno-regulatory strategy against inflammatory bowel diseases. PMID:26174763

  1. The schistosome glutathione S-transferase P28GST, a unique helminth protein, prevents intestinal inflammation in experimental colitis through a Th2-type response with mucosal eosinophils.

    PubMed

    Driss, V; El Nady, M; Delbeke, M; Rousseaux, C; Dubuquoy, C; Sarazin, A; Gatault, S; Dendooven, A; Riveau, G; Colombel, J F; Desreumaux, P; Dubuquoy, L; Capron, M

    2016-03-01

    Intestinal helminth parasites are potent inducers of T helper type 2 (Th2) response and have a regulatory role, notably on intestinal inflammation. As infection with schistosomes is unlikely to provide a reliable treatment of inflammatory bowel diseases, we have investigated the beneficial effect of a schistosome enzymatic protein, the 28-kDa glutathione S-transferase (P28GST), on the modulation of disease activity and immune responses in experimental colitis. Our results showed that immunization with recombinant P28GST is at least as efficient as established schistosome infection to reduce colitis lesions and expression of pro-inflammatory cytokines. Considering underlying mechanisms, the decrease of inflammatory parameters was associated with the polarization of the immune system toward a Th2 profile, with local and systemic increases of interleukin (IL)-13 and IL-5. Dense eosinophil infiltration was observed in the colons of P28GST-immunized rats and mice. Depletion of eosinophils by treatment with an anti-Siglec-F monoclonal antibody and use of IL-5-deficient mice led to the loss of therapeutic effect, suggesting the crucial role for eosinophils in colitis prevention by P28GST. These findings reveal that immunization with P28GST, a unique recombinant schistosome enzyme, ameliorates intestinal inflammation through eosinophil-dependent modulation of harmful type 1 responses, representing a new immuno-regulatory strategy against inflammatory bowel diseases.

  2. Uropathogenic Escherichia coli modulates innate immunity to suppress Th1-mediated inflammatory responses during infectious epididymitis.

    PubMed

    Lang, Tali; Hudemann, Christoph; Tchatalbachev, Svetlin; Stammler, Angelika; Michel, Vera; Aslani, Ferial; Bhushan, Sudhanshu; Chakraborty, Trinad; Renz, Harald; Meinhardt, Andreas

    2014-03-01

    Infectious epididymitis in men, a frequent entity in urological outpatient settings, is commonly caused by bacteria originating from the anal region ascending the genitourinary tract. One of the most prevalent pathogens associated with epididymitis is Escherichia coli. In our previous study, we showed that semen quality is compromised in men following epididymitis associated with specific E. coli pathovars. Thus, our aim was to investigate possible differences in immune responses elicited during epididymitis following infection with the uropathogenic E. coli (UPEC) strain CFT073 and the nonpathogenic enteric E. coli (NPEC) strain 470. Employing an in vivo experimental epididymitis model, C57BL/6 mice were infected with UPEC CFT073, NPEC 470, or phosphate-buffered saline (PBS) as a sham control for up to 7 days. After infection with NPEC 470, the expression of proinflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha in the epididymis was significantly increased. Conversely, UPEC CFT073-challenged mice displayed inflammatory gene expression at levels comparable to sham PBS-treated animals. Moreover, by day 7 only NPEC-infected animals showed activation of adaptive immunity evident by a substantial influx of CD3+ and F4/80+ cells in the epididymal interstitium. This correlated with enhanced production of Th1-associated cytokines IL-2 and gamma interferon (IFN-γ). Furthermore, splenocytes isolated from UPEC-infected mice exhibited diminished T-cell responses with significantly reduced secretion of IL-2 and IFN-γ in contrast to NPEC-infected animals. Overall, these findings provide new insights into understanding pathogen-specific modulation of host immunity during acute phases of epididymitis, which may influence severity of disease and clinical outcomes.

  3. Basophil-associated OX40 Ligand Participates in the Initiation of Th2 Responses during Airway Inflammation*

    PubMed Central

    Di, Caixia; Lin, Xiaoliang; Zhang, Yanjie; Zhong, Wenwei; Yuan, Yufan; Zhou, Tong; Liu, Junling; Xia, Zhenwei

    2015-01-01

    Asthma is characterized by increased airway submucosal infiltration of T helper (Th) cells and myeloid cells that co-conspire to sustain a chronic inflammation. While recent studies have demonstrated that the myeloid basophils promote Th2 cells in response to various types of allergens, the underlying mechanisms are poorly understood. Here, we found for the first time that in a mouse model of allergic asthma basophils highly expressed OX40 ligand (OX40L) after activation. Interestingly, blockade of OX40-OX40L interaction suppressed basophils-primed Th2 cell differentiation in vitro and ameliorated ovalbumin (OVA)-induced allergic eosinophilic inflammation mediated by Th2 activation. In accordance, the adoptive transfer of basophils derived from mediastinal lymph nodes (MLN) of OVA-immunized mice triggered a robust Th2 response and eosinophilic inflammation in wild-type mice but largely muted in OX40−/− mice and mice receiving OX40L-blocked basophils. Taken together, our results reveal a critical role of OX40L presented by the activated basophils to initiate Th2 responses in an allergic asthma model, implicating OX40-OX40L signaling as a potential therapeutic target in the treatment of allergic airway inflammation. PMID:25839234

  4. NK cell deficiency predisposes to viral-induced Th2-type allergic inflammation via epithelial-derived IL-25.

    PubMed

    Kaiko, Gerard E; Phipps, Simon; Angkasekwinai, Pornpimon; Dong, Chen; Foster, Paul S

    2010-10-15

    Severe respiratory syncytial virus (RSV) infection has long been associated with an increased risk for the development of childhood asthma and exacerbations of this disorder. Despite much research into the induction of Th2 responses by allergens and helminths, the factors associated with viral infection that predispose to Th2-regulated asthma remain unknown. Recently, clinical studies have shown reduced numbers of NK cells in infants suffering from a severe RSV infection. Here we demonstrate that NK cell deficiency during primary RSV infection of BALB/c mice results in the suppression of IFN-γ production and the development of an RSV-specific Th2 response and subsequent allergic lung disease. The outgrowth of the Th2 responses was dependent on airway epithelial cell-derived IL-25, which induced the upregulation of the notch ligand Jagged1 on dendritic cells. This study identifies a novel pathway underlying viral-driven Th2 responses that may have functional relevance to viral-associated asthma.

  5. Regulation of T Cell Receptor Signaling by DENND1B in TH2 Cells and Allergic Disease.

    PubMed

    Yang, Chiao-Wen; Hojer, Caroline D; Zhou, Meijuan; Wu, Xiumin; Wuster, Arthur; Lee, Wyne P; Yaspan, Brian L; Chan, Andrew C

    2016-01-14

    The DENN domain is an evolutionary conserved protein module found in all eukaryotes and serves as an exchange factor for Rab-GTPases to regulate diverse cellular functions. Variants in DENND1B are associated with development of childhood asthma and other immune disorders. To understand how DENND1B may contribute to human disease, Dennd1b(-/-) mice were generated and exhibit hyper-allergic responses following antigen challenge. Dennd1b(-/-) TH2, but not other TH cells, exhibit delayed receptor-induced T cell receptor (TCR) downmodulation, enhanced TCR signaling, and increased production of effector cytokines. As DENND1B interacts with AP-2 and Rab35, TH2 cells deficient in AP-2 or Rab35 also exhibit enhanced TCR-mediated effector functions. Moreover, human TH2 cells carrying asthma-associated DENND1B variants express less DENND1B and phenocopy Dennd1b(-/-) TH2 cells. These results provide a molecular basis for how DENND1B, a previously unrecognized regulator of TCR downmodulation in TH2 cells, contributes to asthma pathogenesis and how DENN-domain-containing proteins may contribute to other human disorders.

  6. Treatment of mice with fenbendazole attenuates allergic airways inflammation and Th2 cytokine production in a model of asthma.

    PubMed

    Cai, Yeping; Zhou, Jiansheng; Webb, Dianne C

    2009-01-01

    Mouse models have provided a significant insight into the role of T-helper (Th) 2 cytokines such as IL-5 and IL-13 in regulating eosinophilia and other key features of asthma. However, the validity of these models can be compromised by inadvertent infection of experimental mouse colonies with pathogens such as oxyurid parasites (pinworms). While the benzimidazole derivative, fenbendazole (FBZ), is commonly used to treat such outbreaks, the effects of FBZ on mouse models of Th2 disease are largely unknown. In this investigation, we show that mice fed FBZ-supplemented food during the in utero and post-weaning period developed attenuated lung eosinophilia, antigen-specific IgG1 and Th2 cytokine responses in a model of asthma. Treatment of the mediastinal lymph node cells from allergic mice with FBZ in vitro attenuated cell proliferation, IL-5 and IL-13 production and expression of the early lymphocyte activation marker, CD69 on CD4(+) T cells and CD19(+) B cells. In addition, eosinophilia and Th2 responses remained attenuated after a 4-week withholding period in allergic mice treated preweaning with FBZ. Thus, FBZ modulates the amplitude of Th2 responses both in vivo and in vitro.

  7. The Alteration and Clinical Significance of Th22/Th17/Th1 Cells in Patients with Chronic Myeloid Leukemia

    PubMed Central

    Chen, Ping; Wang, Min; Li, Daqi; Jia, Yan; He, Na; Li, Wei; Ma, Daoxin; Ji, Chunyan

    2015-01-01

    T helper- (Th-) cell immunodeficiency plays important roles in tumor development and their effects in chronic myeloid leukemia (CML) remain unclear. In the present study, we mainly investigated the role of Th22, Th17, and Th1 cell and their related cytokines (IL-22, IL-17, and IFN-r) in the pathophysiology of CML. Bone marrow (BM) and peripheral blood (PB) were extracted from newly diagnosed (ND), chronic phase- (CP-) CML patients, and controls. Th subsets were examined by flow cytometry. Plasma IL-22, IL-17, and IFN-r concentrations were measured by ELISA. AHR and RORC mRNA expressions were examined by RT-PCR. The frequencies of Th22, Th17, and Th1 cells, along with the expression of specific transcription factors RORC and AHR, were significantly decreased in ND patients compared with healthy controls, while all these abnormality recovered in CP patients. In addition, there existed a significantly positive relationship between Th22 and Th17 cells in PB or BM. A significantly negative relationship was found between Th cells (Th22, Th17, or Th1) and BCR-ABL (%) IS or the number of PB white blood cells. All these results demonstrated that Th22, Th17, and Th1 cells might be important therapeutic targets in CML and could facilitate a better outcome for tumor immunotherapy. PMID:26000313

  8. Molecular and Morphological Characterization of Inflammatory Infiltrate in Rosacea Reveals Activation of Th1/Th17 Pathways.

    PubMed

    Buhl, Timo; Sulk, Mathias; Nowak, Pawel; Buddenkotte, Jörg; McDonald, Ian; Aubert, Jérôme; Carlavan, Isabelle; Déret, Sophie; Reiniche, Pascale; Rivier, Michel; Voegel, Johannes J; Steinhoff, Martin

    2015-09-01

    Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, quantitative real-time reverse-transcriptase-PCR, and quantitative immunohistochemistry o