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Sample records for aggressive adult t-cell

  1. Association of Childhood Chronic Physical Aggression with a DNA Methylation Signature in Adult Human T Cells

    PubMed Central

    Guillemin, Claire; Vitaro, Frank; Côté, Sylvana M.; Hallett, Michael; Tremblay, Richard E.; Szyf, Moshe

    2014-01-01

    Background Chronic physical aggression (CPA) is characterized by frequent use of physical aggression from early childhood to adolescence. Observed in approximately 5% of males, CPA is associated with early childhood adverse environments and long-term negative consequences. Alterations in DNA methylation, a covalent modification of DNA that regulates genome function, have been associated with early childhood adversity. Aims To test the hypothesis that a trajectory of chronic physical aggression during childhood is associated with a distinct DNA methylation profile during adulthood. Methods We analyzed genome-wide promoter DNA methylation profiles of T cells from two groups of adult males assessed annually for frequency of physical aggression between 6 and 15 years of age: a group with CPA and a control group. Methylation profiles covering the promoter regions of 20 000 genes and 400 microRNAs were generated using MeDIP followed by hybridization to microarrays. Results In total, 448 distinct gene promoters were differentially methylated in CPA. Functionally, many of these genes have previously been shown to play a role in aggression and were enriched in biological pathways affected by behavior. Their locations in the genome tended to form clusters spanning millions of bases in the genome. Conclusions This study provides evidence of clustered and genome-wide variation in promoter DNA methylation in young adults that associates with a history of chronic physical aggression from 6 to 15 years of age. However, longitudinal studies of methylation during early childhood will be necessary to determine if and how this methylation variation in T cells DNA plays a role in early development of chronic physical aggression. PMID:24691403

  2. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma

    PubMed Central

    Ishitsuka, Kenji; Utsunomiya, Atae; Katsuya, Hiroo; Takeuchi, Shogo; Takatsuka, Yoshifusa; Hidaka, Michihiro; Sakai, Tatsunori; Yoshimitsu, Makoto; Ishida, Takashi; Tamura, Kazuo

    2015-01-01

    Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18–106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients. PMID:26179770

  3. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma.

    PubMed

    Ishitsuka, Kenji; Utsunomiya, Atae; Katsuya, Hiroo; Takeuchi, Shogo; Takatsuka, Yoshifusa; Hidaka, Michihiro; Sakai, Tatsunori; Yoshimitsu, Makoto; Ishida, Takashi; Tamura, Kazuo

    2015-09-01

    Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18-106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

  4. Characterization of patients with aggressive adult T-cell leukemia-lymphoma in Okinawa, Japan: a retrospective analysis of a large cohort.

    PubMed

    Nishi, Yukiko; Fukushima, Takuya; Nomura, Shogo; Tomoyose, Takeaki; Nakachi, Sawako; Morichika, Kazuho; Tedokon, Iori; Tamaki, Keita; Shimabukuro, Natsuki; Taira, Naoya; Miyagi, Takashi; Karimata, Kaori; Ohama, Masayo; Yamanoha, Atsushi; Tamaki, Kazumitsu; Hayashi, Masaki; Arakaki, Hitoshi; Uchihara, Jun-Nosuke; Ohshiro, Kazuiku; Asakura, Yoshitaka; Kuba-Miyara, Megumi; Karube, Kennosuke; Masuzaki, Hiroaki

    2016-10-01

    Okinawa Prefecture, located in the subtropics, is an area of endemic adult T-cell leukemia-lymphoma (ATL) in Japan. We retrospectively analyzed 659 patients with aggressive ATL in seven institutions in Okinawa between 2002 and 2011. The median patient age was 68 years. More patients were aged ≥90 years (2.6 %), in this study, than in a nationwide survey (<1 %). The median survival time (MST) of the entire cohort was 6.5 months. Of the 217 patients who had a clinical status similar to that stated in the eligibility criteria of JCOG9801 (a randomized phase III study comparing VCAP-AMP-VECP with CHOP-14), 147 who received the CHOP regimen had a poorer MST than those in the CHOP-14 arm of JCOG9801 (8 vs 11 months). The prevalence of strongyloidiasis in the ATL patients was much higher (12.4 %) than in the historical cohort who visited the University of the Ryukyus Hospital (3.4 %). Furthermore, strongyloidiasis may be associated with ATL-related deaths. These findings suggest that, compared with other areas in Japan, in Okinawa, the proportion of patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease is associated with a higher prevalence of strongyloidiasis.

  5. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study.

    PubMed

    Ishida, Takashi; Jo, Tatsuro; Takemoto, Shigeki; Suzushima, Hitoshi; Uozumi, Kimiharu; Yamamoto, Kazuhito; Uike, Naokuni; Saburi, Yoshio; Nosaka, Kisato; Utsunomiya, Atae; Tobinai, Kensei; Fujiwara, Hiroshi; Ishitsuka, Kenji; Yoshida, Shinichiro; Taira, Naoya; Moriuchi, Yukiyoshi; Imada, Kazunori; Miyamoto, Toshihiro; Akinaga, Shiro; Tomonaga, Masao; Ueda, Ryuzo

    2015-06-01

    This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887. PMID:25733162

  6. Adult T-cell leukemia-lymphoma.

    PubMed

    Tsukasaki, Kunihiro

    2012-04-01

    Adult T-cell leukemia-lymphoma (ATL) was first described in 1977 as a distinct clinico-pathological entity with a suspected viral etiology. Subsequently, a novel RNA retrovirus, human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) was isolated from a cell line established from the leukemic cells of an ATL patient, and the finding of a clear association with ATL led to its inclusion among human carcinogenic pathogens. The three major routes of HTLV-1 transmission are mother-to-child infections via breast milk, sexual intercourse, and blood transfusions. HTLV-1 infection early in life, presumably from breast feeding, is crucial in the development of ATL. The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into four categories, acute, lymphoma, chronic, and smoldering types defined by organ involvement, and LDH and calcium values. In cases of acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL), intensive chemotherapy such as VCAP-AMP-VECP is usually recommended. In cases of favorable chronic or smoldering ATL (indolent ATL), watchful waiting until disease progression has been recommended although the long term prognosis was inferior to those of, for instance, chronic lymphoid leukemia. Retrospective analysis suggested that the combination of interferon alpha and zidovudine was apparently promising for the treatment of ATL, especially for types with leukemic manifestation. Allogeneic hematopoietic stem cell transplantation is also promising for the treatment of aggressive ATL possibly reflecting graft vs. ATL effect. Several new agent-trials for ATL are ongoing and in preparation, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody. Two steps should be considered for the prevention of HTLV-1-associated ATL. The first is the prevention of HTLV-1 infections and the second is the prevention of ATL among HTLV-1 carriers. So far, no agent has been found to be

  7. DNA Methylation Signature of Childhood Chronic Physical Aggression in T Cells of Both Men and Women

    PubMed Central

    Guillemin, Claire; Provençal, Nadine; Suderman, Matthew; Côté, Sylvana M.; Vitaro, Frank; Hallett, Michael; Tremblay, Richard E.; Szyf, Moshe

    2014-01-01

    Background High frequency of physical aggression is the central feature of severe conduct disorder and is associated with a wide range of social, mental and physical health problems. We have previously tested the hypothesis that differential DNA methylation signatures in peripheral T cells are associated with a chronic aggression trajectory in males. Despite the fact that sex differences appear to play a pivotal role in determining the development, magnitude and frequency of aggression, most of previous studies focused on males, so little is known about female chronic physical aggression. We therefore tested here whether or not there is a signature of physical aggression in female DNA methylation and, if there is, how it relates to the signature observed in males. Methodology/Principal Findings Methylation profiles were created using the method of methylated DNA immunoprecipitation (MeDIP) followed by microarray hybridization and statistical and bioinformatic analyses on T cell DNA obtained from adult women who were found to be on a chronic physical aggression trajectory (CPA) between 6 and 12 years of age compared to women who followed a normal physical aggression trajectory. We confirmed the existence of a well-defined, genome-wide signature of DNA methylation associated with chronic physical aggression in the peripheral T cells of adult females that includes many of the genes similarly associated with physical aggression in the same cell types of adult males. Conclusions This study in a small number of women presents preliminary evidence for a genome-wide variation in promoter DNA methylation that associates with CPA in women that warrant larger studies for further verification. A significant proportion of these associations were previously observed in men with CPA supporting the hypothesis that the epigenetic signature of early life aggression in females is composed of a component specific to females and another common to both males and females. PMID:24475181

  8. Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells.

    PubMed

    Hiwarkar, Prashant; Qasim, Waseem; Ricciardelli, Ida; Gilmour, Kimberly; Quezada, Sergio; Saudemont, Aurore; Amrolia, Persis; Veys, Paul

    2015-12-24

    Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk hematologic malignancies. Following T-replete CBT, naïve CB T cells undergo rapid peripheral expansion with memory-effector differentiation. Emerging data suggest that unrelated CBT, particularly in the context of HLA mismatch and a T-replete graft, may reduce leukemic relapse. To study the role of CB T cells in mediating graft-versus-tumor responses and dissect the underlying immune mechanisms for this, we compared the ability of HLA-mismatched CB and adult peripheral blood (PB) T cells to eliminate Epstein-Barr virus (EBV)-driven human B-cell lymphoma in a xenogeneic NOD/SCID/IL2rg(null) mouse model. CB T cells mediated enhanced tumor rejection compared with equal numbers of PB T cells, leading to improved survival in the CB group (P < .0003). Comparison of CB T cells that were autologous vs allogeneic to the lymphoma demonstrated that this antitumor effect was mediated by alloreactive rather than EBV-specific T cells. Analysis of tumor-infiltrating lymphocytes demonstrated that CB T cells mediated this enhanced antitumor effect by rapid infiltration of the tumor with CCR7(+)CD8(+) T cells and prompt induction of cytotoxic CD8(+) and CD4(+) T-helper (Th1) T cells in the tumor microenvironment. In contrast, in the PB group, this antilymphoma effect is impaired because of delayed tumoral infiltration of PB T cells and a relative bias toward suppressive Th2 and T-regulatory cells. Our data suggest that, despite being naturally programmed toward tolerance, reconstituting T cells after unrelated T-replete CBT may provide superior Tc1-Th1 antitumor effects against high-risk hematologic malignancies.

  9. Clinical Impact of a Humanized CCR4 Antibody (Mogamulizumab) in 14 Patients with Aggressive Adult T-cell Leukemia-lymphoma Treated at a Single Institution During a Three-year Period (2012-2014).

    PubMed

    Kawano, Noriaki; Kuriyama, Takuro; Sonoda, Koh-Hei; Yoshida, Shuro; Yamashita, Kiyoshi; Ochiai, Hidenobu; Shimoda, Kazuya; Ishikawa, Fumihiko; Ueda, Akira; Kikuchi, Ikuo

    2016-01-01

    Objective We elucidated the effectiveness of a humanized CCR4 antibody (mogamulizumab) on adult T-cell leukemia-lymphoma (ATL), which typically has a poor outcome. Methods We retrospectively analyzed 14 patients with aggressive ATL who had been treated at our institution with weekly cycles of mogamulizumab for eight weeks from 2012-2014. Results The patients (median age: 63 years old) were classified as having acute- (n=10) or lymphoma-type (n=4) ATL. The prior treatment regimens consisted of CHOP, VCAP-AMP-VECP, DeVIC and CHASE, with an average of two courses (range: 1-4). The prior disease responses were partial remission (n=3) and progressive disease (n=11). The treatment was administered in the primary refractory setting (n=8), for relapse (n=2), or as bridging therapy before hematopoietic stem cell transplantation (n=4). The overall response rates were 64% and 43% after four and eight cycles (or after the final cycles), respectively. The median overall survival (OS), OS rate at six months and OS rate at 12 months were 66 days, 41.7% and 20.8%, respectively. All of the patients with acute-type ATL who showed a response to treatment had an early response. Notably, six of the 14 ATL patients showed somewhat prolonged survival (>100 days). However, relapse or disease progression in the peripheral blood, central nervous system, lymph nodes, skin, and/or bone occurred within a relatively short period after treatment. The adverse effects were tolerable, and included lymphopenia, cytomegalovirus infection and skin rash. Conclusion Mogamulizumab therapy resulted in an early and high remission rate and somewhat prolonged survival in patients with refractory ATL. However, the duration of remission was short, and there was early relapse and disease progression. This study may show the current impact of mogamulizumab in clinical practice. PMID:27250049

  10. Tax fingerprint in adult T-cell leukemia.

    PubMed

    Bazarbachi, Ali

    2016-04-01

    In this issue of Blood, Fujikawa et al demonstrate that the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax induces an epigenetic-dependent global modification of host gene expression in adult T-cell leukemia-lymphoma (ATL). Hence, the fingerprint of Tax is all over ATL and this may be used for finally capturing ATL. PMID:27056993

  11. [Molecular pathogenesis of peripheral T cell lymphoma (2): extranodal NK/T cell lymphoma, nasal type, adult T cell leukemia/lymphoma and enteropathy associated T cell lymphoma].

    PubMed

    Couronné, Lucile; Bastard, Christian; Gaulard, Philippe; Hermine, Olivier; Bernard, Olivier

    2015-11-01

    Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T /NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of histologic subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. The first part published in the October issue was focused on the three more frequent entities, i.e. angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second part presented herein will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma. PMID:26576610

  12. Adult T-Cell Leukemia: A Review of Epidemiological Evidence

    PubMed Central

    Iwanaga, Masako; Watanabe, Toshiki; Yamaguchi, Kazunari

    2012-01-01

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1) infection and often occurs in HTLV-1-endemic areas, such as southwestern Japan, the Caribbean islands, Central and South America, Intertropical Africa, and Middle East. To date, many epidemiological studies have been conducted to investigate the incidence of ATL among general population or HTLV-1 carriers and to identify a variety of laboratory, molecular, and host-specific markers to be possible predictive factors for developing ATL because HTLV-1 infection alone is not sufficient to develop ATL. This literature review focuses on the epidemiology of ATL and the risk factors for the development of ATL from HTLV-1 carriers, while keeping information on the epidemiology of HTLV-1 to a minimum. The main lines of epidemiological evidence are: (1) ATL occurs mostly in adults, at least 20–30 years after the HTLV-1 infection, (2) age at onset differs across geographic areas: the average age in the Central and South America (around 40 years old) is younger than that in Japan (around 60 years old), (3) ATL occurs in those infected in childhood, but seldom occurs in those infected in adulthood, (4) male carriers have about a three- to fivefold higher risk of developing ATL than female, (5) the estimated lifetime risk of developing ATL in HTLV-1 carriers is 6–7% for men and 2–3% for women in Japan, (6) a low anti-Tax reactivity, a high soluble interleukin-2 receptor level, a high anti-HTLV-1 titer, and high levels of circulating abnormal lymphocytes and white blood cell count are accepted risk factors for the development of ATL, and (7) a higher proviral load (more than 4 copies/100 peripheral blood mononuclear cells) is an independent risk factor for progression of ATL. Nevertheless, the current epidemiological evidence is insufficient to fully understand the oncogenesis of ATL. Further well-designed epidemiological studies are needed. PMID

  13. Integrated molecular analysis of adult T cell leukemia/lymphoma.

    PubMed

    Kataoka, Keisuke; Nagata, Yasunobu; Kitanaka, Akira; Shiraishi, Yuichi; Shimamura, Teppei; Yasunaga, Jun-Ichirou; Totoki, Yasushi; Chiba, Kenichi; Sato-Otsubo, Aiko; Nagae, Genta; Ishii, Ryohei; Muto, Satsuki; Kotani, Shinichi; Watatani, Yosaku; Takeda, June; Sanada, Masashi; Tanaka, Hiroko; Suzuki, Hiromichi; Sato, Yusuke; Shiozawa, Yusuke; Yoshizato, Tetsuichi; Yoshida, Kenichi; Makishima, Hideki; Iwanaga, Masako; Ma, Guangyong; Nosaka, Kisato; Hishizawa, Masakatsu; Itonaga, Hidehiro; Imaizumi, Yoshitaka; Munakata, Wataru; Ogasawara, Hideaki; Sato, Toshitaka; Sasai, Ken; Muramoto, Kenzo; Penova, Marina; Kawaguchi, Takahisa; Nakamura, Hiromi; Hama, Natsuko; Shide, Kotaro; Kubuki, Yoko; Hidaka, Tomonori; Kameda, Takuro; Nakamaki, Tsuyoshi; Ishiyama, Ken; Miyawaki, Shuichi; Yoon, Sung-Soo; Tobinai, Kensei; Miyazaki, Yasushi; Takaori-Kondo, Akifumi; Matsuda, Fumihiko; Takeuchi, Kengo; Nureki, Osamu; Aburatani, Hiroyuki; Watanabe, Toshiki; Shibata, Tatsuhiro; Matsuoka, Masao; Miyano, Satoru; Shimoda, Kazuya; Ogawa, Seishi

    2015-11-01

    Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor. PMID:26437031

  14. Recent Advances in Therapeutic Approaches for Adult T-cell Leukemia/Lymphoma

    PubMed Central

    Kato, Koji; Akashi, Koichi

    2015-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia/lymphoma virus type 1 (HTLV-1). ATLL occurs in approximately 3%–5% of HTLV-1 carriers during their lifetime and follows a heterogeneous clinical course. The Shimoyama classification has been frequently used for treatment decisions in ATLL patients, and antiviral therapy has been reportedly promising, particularly in patients with indolent type ATLL; however, the prognosis continues to be dismal for patients with aggressive-type ATLL. Recent efforts to improve treatment outcomes have been focused on the development of prognostic stratification and improved dosage, timing, and combination of therapeutic modalities, such as antiviral therapy, chemotherapy, allogeneic hematopoietic stem cell transplantation, and molecular targeted therapy. PMID:26694446

  15. Molecular Pathology of Adult T-Cell Leukemia/Lymphoma.

    PubMed

    Ohshima, Koichi

    2015-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm of highly pleomorphic lymphoid cells. ATLL is usually widely disseminated, and it is caused by human T-cell leukemia virus type 1 (HTLV-1). It is a disease with a long latency, and affected individuals are usually exposed to the virus very early in life. The cumulative incidence of ATLL is estimated to be 2.5% among HTLV-1 carriers. ATLL cells express CD2, CD3, CD5, CD4, and CD25, as well as CCR4 and FoxP3 of the regulatory T-cell marker. HTLV-1 is causally linked to ATLL, but infection alone is not sufficient to result in neoplastic transformation. A significant finding in this connection is that the Tax viral protein leads to transcriptional activation of many genes, while the HTLV-1 basic leucine zipper factor is thought to be important for T-cell proliferation and oncogenesis. Half of ATLL cases retain the ability to express HTLV-1 Tax, which is a target of HTLV-1-specific cytotoxic T lymphocytes (CTL). An increase in HTLV-1-specific CTL responses is observed in some asymptomatic HTLV-1 carriers. Although HTLV-1-specific CTL are also present in the peripheral blood of ATLL patients, they do not expand sufficiently. We investigated the clinicopathological features and analyzed the staining of Tax-specific CTL and FoxP3. Tax-specific CTL correlated inversely with FoxP3, an increase in the ratio of CD163+ tumor-associated macrophages was associated with worse clinical prognosis, and ATLL cell lines proliferated significantly following direct co-culture with M2 macrophages. Several clinical variants of ATLL have been identified: acute, lymphomatous, chronic, and smoldering. Oligo-array comparative genomic hybridization revealed that genomic loss of 9p21.3 was a significant characteristic of acute-type, but not of chronic-type ATLL. Furthermore, we found that genomic alteration of CD58, which is implicated in immune escape, is more frequently observed in acute than in chronic ATLL. Interestingly

  16. Adult T-cell leukemia-lymphoma in a pregnant woman diagnosed as a human T-cell lymphotropic virus type 1 carrier.

    PubMed

    Fuchi, Naoki; Miura, Kiyonori; Imaizumi, Yoshitaka; Hasegawa, Hiroo; Yanagihara, Katsunori; Miyazaki, Yasushi; Masuzaki, Hideaki

    2016-03-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia-lymphoma (ATL), which is difficult to cure. In Japan, a nationwide HTLV-1 screening test in pregnant women has been recommended since 2011. A 30-year-old woman was diagnosed as being an HTLV-1 carrier in her previous pregnancy. During the current pregnancy, she had persistent fever and cough. Although she had treatment with antibiotics, peripheral white blood cell count remained high, with an abnormal lymphocyte count. Given that she was an HTLV-1 carrier, she was diagnosed with unfavorable chronic ATL (aggressive ATL) at 12 weeks gestation. After pregnancy termination, her ATL status became favorable chronic ATL (indolent ATL). Therefore, watchful waiting was performed until disease progression. This is the first case report of chronic ATL in early pregnancy, in a woman already diagnosed as an HTLV-1 carrier on screening test. PMID:26663442

  17. Optimizing Management of Patients with Adult T Cell Leukemia-Lymphoma

    PubMed Central

    Yared, Jean A.; Kimball, Amy S.

    2015-01-01

    Adult T cell leukemia-lymphoma is a rare disease with a high mortality rate, and is challenging for the clinician. Early allogeneic stem cell transplant can confer durable remission. As novel therapeutic agents become available to treat T cell malignancies, it is increasingly important that medical oncologists, hematologists, and hematopathologists recognize and accurately diagnose adult T cell leukemia-lymphoma. There is no uniform standard of treatment of adult T cell leukemia-lymphoma, and clinical trials remain critical to improving outcomes. Here we present one management approach based on the recent advances in treatment for adult T cell leukemia-lymphoma patients. PMID:26610571

  18. Abacavir, an anti–HIV-1 drug, targets TDP1-deficient adult T cell leukemia

    PubMed Central

    Tada, Kohei; Kobayashi, Masayuki; Takiuchi, Yoko; Iwai, Fumie; Sakamoto, Takashi; Nagata, Kayoko; Shinohara, Masanobu; Io, Katsuhiro; Shirakawa, Kotaro; Hishizawa, Masakatsu; Shindo, Keisuke; Kadowaki, Norimitsu; Hirota, Kouji; Yamamoto, Junpei; Iwai, Shigenori; Sasanuma, Hiroyuki; Takeda, Shunichi; Takaori-Kondo, Akifumi

    2015-01-01

    Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL. PMID:26601161

  19. Transition of adult T-cell leukemia/lymphoma clones during clinical progression.

    PubMed

    Aoki, Sakura; Firouzi, Sanaz; López, Yosvany; Yamochi, Tadanori; Nakano, Kazumi; Uchimaru, Kaoru; Utusnomiya, Atae; Iwanaga, Masako; Watanabe, Toshiki

    2016-09-01

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm caused by the transformation of HTLV-1-infected T cells. ATLL, especially its aggressive form, is known for its poor prognosis, even with intensive chemotherapy. ATLL cells are considered to be monoclonal; however, multiclonal proliferation or emergence of a new clone over time has been reported based on Southern blot analysis, although direct molecular evidence remains elusive. Furthermore, it is thought that clonal change may be a cause of early drug resistance in ATLL. To directly analyze potential clonal changes in ATLL during its clinical course, we used inverse PCR to detect integration sites in combination with a newly developed method using next-generation sequencing, and compared ATLL cell clonality at different time points. The results of inverse PCR indicated that the major clone was altered in three of 19 patients. Together with results from five patients, using this new method, we found direct evidence of clonal change occurring during the clinical course or in response to chemotherapy in ATLL. These results also highlight the importance of clonality analysis for understanding the mechanisms of ATLL development and drug resistance. PMID:27383637

  20. Langerhans cells increase in the dermal lesions of adult T cell leukaemia in Japan

    PubMed Central

    Shamoto, M

    1983-01-01

    In cases of adult T cell leukaemia neoplastic T cell infiltration in the skin was accompanied by an increase in Langerhans cells. This is in keeping with the view that Langerhans cells may induce antigen-specific and allogenic T cell activation. Images PMID:6600750

  1. Adult T-Cell Leukemia/Lymphoma (HTLV-1)

    MedlinePlus

    ... gentic material made of DNA, but instead carry RNA. These viruses selectively infect only T-cells. Only ... potential to inject its genetic material (DNA or RNA) into normal cells. Once inside the normal cells, ...

  2. Self-Antigen Presentation by Keratinocytes in the Inflamed Adult Skin Modulates T-Cell Auto-Reactivity.

    PubMed

    Meister, Michael; Tounsi, Amel; Gaffal, Evelyn; Bald, Tobias; Papatriantafyllou, Maria; Ludwig, Julia; Pougialis, Georg; Bestvater, Felix; Klotz, Luisa; Moldenhauer, Gerhard; Tüting, Thomas; Hämmerling, Günter J; Arnold, Bernd; Oelert, Thilo

    2015-08-01

    Keratinocytes have a pivotal role in the regulation of immune responses, but the impact of antigen presentation by these cells is still poorly understood, particularly in a situation where the antigen will be presented only in adult life. Here, we generated a transgenic mouse model in which keratinocytes exclusively present a myelin basic protein (MBP) peptide covalently linked to the major histocompatibility complex class II β-chain, solely under inflammatory conditions. In these mice, inflammation caused by epicutaneous contact sensitizer treatment resulted in keratinocyte-mediated expansion of MBP-specific CD4(+) T cells in the skin. Moreover, repeated contact sensitizer application preceding a systemic MBP immunization reduced the reactivity of the respective CD4(+) T cells and lowered the symptoms of the resulting experimental autoimmune encephalomyelitis. This downregulation was CD4(+) T-cell-mediated and dependent on the presence of the immune modulator Dickkopf-3. Thus, presentation of a neo self-antigen by keratinocytes in the inflamed, adult skin can modulate CD4(+) T-cell auto-aggression at a distal organ. PMID:25835957

  3. Human T-cell lymphotropic virus type I-associated adult T-cell leukemia-lymphoma: new directions in clinical research.

    PubMed

    Tsukasaki, Kunihiro; Tobinai, Kensei

    2014-10-15

    Adult T-cell leukemia-lymphoma (ATL) is a distinct malignancy of regulatory T cell (Treg)/TH2 cells caused by human T-cell lymphotropic virus type I (HTLV-1), with a high frequency of expression of CD3/CD4/CD25/CCR4 and FoxP3 in about half of the cells. However, in primary ATL cells, although expression of the virus, including the Tax oncoprotein, appears just after an in vitro culture, integration sites of the provirus into the host genome are random, and chromosomal/genetic abnormalities are complex. ATL is thus a single disease entity that is caused by HTLV-1 and possesses diverse molecular features. The clinical features and prognosis of ATL vary, and this has led to subtypes classified into four categories: acute, lymphomatous, chronic, and smoldering types, based on lactate dehydrogenase and calcium values and organ involvement. Approximately 15 to 20 million individuals are infected with HTLV-1 worldwide, 1.1 million of whom reside in Japan, and the annual incidence of ATL has been estimated to be approximately 1,000. HTLV-1 infection early in life, mainly from breast feeding, is crucial for the development of ATL. The age-specific occurrence of ATL and complex genome abnormalities that accumulate with disease progression suggest a multistep carcinogenesis model following HTLV-1 infection. Various treatment options are available for ATL and consist of watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation for aggressive ATL, and a combination of IFNα and zidovudine for ATL with leukemic manifestation. Several promising new agents, including an anti-CCR4 antibody, are currently undergoing clinical trials associated with translational research. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID:25320371

  4. Characterization of a novel canine T-cell line established from a spontaneously occurring aggressive T-cell lymphoma with large granular cell morphology.

    PubMed

    Bonnefont-Rebeix, Catherine; Fournel-Fleury, Corinne; Ponce, Frédérique; Belluco, Sara; Watrelot, Dorothée; Bouteille, Sylvie E; Rapiteau, Sylvie; Razanajaona-Doll, Diane; Pin, Jean-Jacques; Leroux, Caroline; Marchal, Thierry

    2016-01-01

    Dogs with lymphoma are established as good model for human non-Hodgkin lymphoma studies. Canine cell lines derived from lymphomas may be valuable tools for testing new therapeutic drugs. In this context, we established a canine T-cell line, PER-VAS, from a primary aggressive T-cell lymphoma with large granular morphology. Flow cytometric analysis revealed a stable immunophenotype: PER-VAS cells were positively labelled for CD5, CD45, MHC II and TLR3, and were negative for CD3, CD4 and CD8 expression. Although unstable along the culture process, IL-17 and MMP12 proteins were detectable as late as at passages 280 and 325i.e. respectively 24 and 29 months post isolation. At passage 325, PER-VAS cells maintained the expression of IL-17, CD3, CD56, IFNγ and TNFα mRNAs as shown by RT-PCR analysis. Stable rearrangement of the TCRγ gene has been evidenced by PCR. PER-VAS cells have a high proliferation index with a doubling time of 16.5h and were tumorigenic in Nude mice. Compared to the canine cell lines already reported, PER-VAS cells display an original expression pattern, close to NKT cells, which makes them valuable tools for in vitro comparative research on lymphomas. PMID:26345430

  5. Bronchoalveolar CD4+ T cell responses to respiratory antigens are impaired in HIV-infected adults

    PubMed Central

    Sepako, Enoch; Fullerton, Duncan G; Mzinza, David; Glennie, Sarah; Wright, Adam K; Heyderman, Robert S; Gordon, Stephen B

    2011-01-01

    Rationale HIV-infected adults are at an increased risk of lower respiratory tract infections. HIV infection impairs systemic acquired immunity, but there is limited information in humans on HIV-related cell-mediated immune defects in the lung. Objective To investigate antigen-specific CD4+ T cell responses to influenza virus, Streptococcus pneumoniae and Mycobacterium tuberculosis antigens in bronchoalveolar lavage (BAL) and peripheral blood between HIV-infected individuals and HIV-uninfected Malawian adults. Methods We obtained BAL fluid and blood from HIV-infected individuals (n=21) and HIV-uninfected adults (n=24). We determined the proportion of T cell subsets including naive, memory and regulatory T cells using flow cytometry, and used intracellular cytokine staining to identify CD4+ T cells recognising influenza virus-, S pneumoniae- and M tuberculosis-antigens. Main results CD4+ T cells in BAL were predominantly of effector memory phenotype compared to blood, irrespective of HIV status (p<0.001). There was immune compartmentalisation with a higher frequency of antigen-specific CD4+ T cells against influenza virus, S pneumoniae and M tuberculosis retained in BAL compared to blood in HIV-uninfected adults (p<0.001 in each case). Influenza virus- and M tuberculosis-specific CD4+ T cell responses in BAL were impaired in HIV-infected individuals: proportions of total antigen-specific CD4+ T cells and of polyfunctional IFN-γ and TNF-α-secreting cells were lower in HIV-infected individuals than in HIV-uninfected adults (p<0.05 in each case). Conclusions BAL antigen-specific CD4+ T cell responses against important viral and bacterial respiratory pathogens are impaired in HIV-infected adults. This might contribute to the susceptibility of HIV-infected adults to lower respiratory tract infections such as pneumonia and tuberculosis. PMID:21357587

  6. Impaired CD4 T Cell Memory Response to Streptococcus pneumoniae Precedes CD4 T Cell Depletion in HIV-Infected Malawian Adults

    PubMed Central

    Mzinza, David; Harawa, Visopo; Miles, David J. C.; Jambo, Kondwani C.; Gordon, Stephen B.; Williams, Neil A.; Heyderman, Robert S.

    2011-01-01

    Objective Invasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African adults. CD4 T cell depletion may partially explain this high disease burden but those with relatively preserved T cell numbers are still at increased risk of IPD. This study evaluated the extent of pneumococcal-specific T cell memory dysfunction in asymptomatic HIV infection early on in the evolution of the disease. Methods Peripheral blood mononuclear cells were isolated from asymptomatic HIV-infected and HIV-uninfected Malawian adults and stained to characterize the underlying degree of CD4 T cell immune activation, senescence and regulation. Pneumococcal-specific T cell proliferation, IFN-γ, IL-17 production and CD154 expression was assessed using flow cytometry and ELISpot. Results We find that in asymptomatic HIV-infected Malawian adults, there is considerable immune disruption with an increase in activated and senescent CD4+CD38+PD-1+ and CD4+CD25highFoxp3+ Treg cells. In the context of high pneumococcal exposure and therefore immune stimulation, show a failure in pneumococcal-specific memory T cell proliferation, skewing of T cell cytokine production with preservation of interleukin-17 but decreased interferon-gamma responses, and failure of activated T cells to express the co-stimulatory molecule CD154. Conclusion Asymptomatic HIV-infected Malawian adults show early signs of pneumococcal- specific immune dysregulation with a shift in the balance of CD4 memory, T helper 17 cells and Treg. Together these data offer a mechanistic understanding of how antigen-specific T cell dysfunction occurs prior to T cell depletion and may explain the early susceptibility to IPD in those with relatively preserved CD4 T cell numbers. PMID:21980502

  7. Pathways to Relationship Aggression between Adult Partners

    ERIC Educational Resources Information Center

    Busby, Dean M.; Holman, Thomas B.; Walker, Eric

    2008-01-01

    In this study, the pathways to adult aggression beginning in the family of origin (FOO) and continuing through adult relationships were investigated. With a sample of 30,600 individuals, a comprehensive model was evaluated that included the unique influences of violent victimization in the family, witnessing parental violence, perpetrating…

  8. Direct Ex-Vivo Evaluation of Pneumococcal Specific T-Cells in Healthy Adults

    PubMed Central

    Aslam, Aamir; Chapel, Helen; Ogg, Graham

    2011-01-01

    Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. The nasopharynxes of children are believed to be the natural reservoir of pneumococcus and by adulthood nasopharyngeal carriage is infrequent; such infrequency may be due to demonstrable pneumococcal specific T and B-cell responses. HLA Class 2 tetrameric complexes have been used to characterise antigen specific T-cell responses in a variety of models of infection. We therefore sought to determine the frequency and phenotype of pneumococcal specific T-cells, using a novel HLA-DRB1*1501 tetramer complex incorporating a recently defined T-cell epitope derived from the conserved pneumococcal serine/threonine kinase (StkP). We were able to detect direct ex-vivo StkP446–60-tetramer binding in HLA-DRB1*1501 adults. These StkP446–60-tetramer binding T-cells had increased CD38 expression and were enriched in CCR7- CD45RA+ expression indicating recent and on-going activation and differentiation. Furthermore, these StkP446–60-tetramer binding T-cells demonstrated rapid effector function by secreting interferon-gamma on stimulation with recombinant StkP. This is the first study to directly enumerate and characterise pneumococcal specific T-cells using HLA class 2 tetrameric complexes. We found that ex-vivo pneumococcal-specific T cells were detectable in healthy adults and that they were enriched with cell surface markers associated with recent antigen exposure and later stages of antigen-driven differentiation. It is likely that these activated pneumococcal specific T-cells reflect recent immunostimulatory pneumococcal exposure in the nasopharynx and it is possible that they may be preventing subsequent colonisation and disease. PMID:22039412

  9. Normative beliefs about aggression and cyber aggression among young adults: a longitudinal investigation.

    PubMed

    Wright, Michelle F; Li, Yan

    2013-01-01

    This longitudinal study examined normative beliefs about aggression (e.g., face-to-face, cyber) in relation to the engagement in cyber aggression 6 months later among 126 (69 women) young adults. Participants completed electronically administered measures assessing their normative beliefs, face-to-face and cyber aggression at Time 1, and cyber aggression 6 months later (Time 2). We found that men reported more cyber relational and verbal aggression when compared to women. After controlling for each other, Time 1 face-to-face relational aggression was positively related to Time 2 cyber relational aggression, whereas Time 1 face-to-face verbal aggression was positively related to Time 2 cyber verbal aggression. Normative beliefs regarding cyber aggression was positively related to both forms of cyber aggression 6 months later, after controlling for normative beliefs about face-to-face aggression. Furthermore, a significant two-way interaction between Time 1 cyber relational aggression and normative beliefs about cyber relational aggression was found. Follow-up analysis showed that Time 1 cyber relational aggression was more strongly related to Time 2 cyber relational aggression when young adults held higher normative beliefs about cyber relational aggression. A similar two-way interaction was found for cyber verbal aggression such that the association between Time 1 and Time 2 cyber verbal aggression was stronger at higher levels of normative beliefs about cyber verbal aggression. Results are discussed in terms of the social cognitive and behavioral mechanisms associated with the engagement of cyber aggression.

  10. Normative beliefs about aggression and cyber aggression among young adults: a longitudinal investigation.

    PubMed

    Wright, Michelle F; Li, Yan

    2013-01-01

    This longitudinal study examined normative beliefs about aggression (e.g., face-to-face, cyber) in relation to the engagement in cyber aggression 6 months later among 126 (69 women) young adults. Participants completed electronically administered measures assessing their normative beliefs, face-to-face and cyber aggression at Time 1, and cyber aggression 6 months later (Time 2). We found that men reported more cyber relational and verbal aggression when compared to women. After controlling for each other, Time 1 face-to-face relational aggression was positively related to Time 2 cyber relational aggression, whereas Time 1 face-to-face verbal aggression was positively related to Time 2 cyber verbal aggression. Normative beliefs regarding cyber aggression was positively related to both forms of cyber aggression 6 months later, after controlling for normative beliefs about face-to-face aggression. Furthermore, a significant two-way interaction between Time 1 cyber relational aggression and normative beliefs about cyber relational aggression was found. Follow-up analysis showed that Time 1 cyber relational aggression was more strongly related to Time 2 cyber relational aggression when young adults held higher normative beliefs about cyber relational aggression. A similar two-way interaction was found for cyber verbal aggression such that the association between Time 1 and Time 2 cyber verbal aggression was stronger at higher levels of normative beliefs about cyber verbal aggression. Results are discussed in terms of the social cognitive and behavioral mechanisms associated with the engagement of cyber aggression. PMID:23440595

  11. Subpopulations of human T lymphocytes. XVI. Maldistribution of T cell subsets associated with abnormal locomotion of T cells in untreated adult patients with Hodgkin's disease

    PubMed Central

    Gupta, S.

    1980-01-01

    Peripheral blood and splenic T cells from adult patients with Hodgkin's disease were examined for the proportions and numbers of T cells with receptors for IgM (Tμ) or IgG (Tγ) and their locomotor responses to chemotactic stimuli of casein and endotoxin-activated serum (EAS). Thirty per cent of patients had absolute lymphopenia in the peripheral blood. The proportion of Tμ cells was comparable but the proportion of Tγ cells was significantly increased (P<0·001) resulting in an abnormally low ratio of Tμ/Tγ cells when compared to those for age- and sex-matched controls. In the spleens, the proportions of T cells and Tμ cells were significantly increased (P<0·001) and Tγ cells significantly decreased (P<0·001) resulting in an abnormally high ratio of Tμ/Tγ cells when compared with normal spleens. In the peripheral blood both Tμ and Tγ cells were increased and T cells lacking either receptor (Tφ) were significantly decreased in patients in whom spleens were involved by the tumour when compared to those in whom spleens were not involved by the tumour. Peripheral blood T cells from patients with Hodgkin's disease responded poorly to the chemotactic stimuli when compared to T cells from normal controls or T cells from the spleens of the same patients. Tμ cell proportions in patients with combined stages III and IV were significantly lower (P<0·025) than those in the peripheral blood of patients in combined stages I and II. No correlation was observed between the above parameters and histopathological types of Hodgkin's disease. This study demonstrates an abnormal distribution of T cell subsets and abnormality of locomotion of T cells between peripheral blood and spleens in patients with Hodgkin's disease. This might explain the cellular basis of at least certain immunodeficiencies so commonly associated with Hodgkin's disease. PMID:6970098

  12. Bay 11-7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells.

    PubMed

    Mori, Naoki; Yamada, Yasuaki; Ikeda, Shuichi; Yamasaki, Yoshihiro; Tsukasaki, Kunihiro; Tanaka, Yuetsu; Tomonaga, Masao; Yamamoto, Naoki; Fujii, Masahiro

    2002-09-01

    Human T-cell leukemia virus type I (HTLV-I) is the causative agent of an aggressive form of leukemia designated adult T-cell leukemia (ATL). We have previously demonstrated that all T-cell lines infected with HTLV-I and primary leukemic cells from ATL patients display constitutively high activity of transcription factor NF-kappaB. In this study we showed that Bay 11-7082, an inhibitor of NF-kappaB, induced apoptosis of HTLV-I-infected T-cell lines but only negligible apoptosis of HTLV-I-negative T cells. Bay 11-7082 rapidly and efficiently reduced the DNA binding of NF-kappaB in HTLV-I-infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-x(L), regulated by NF-kappaB, whereas it had little effect on the DNA binding of another transcription factor, AP-1. Although the viral protein Tax is an activator of NF-kappaB, Bay 11-7082-induced apoptosis of HTLV-I-infected cells was not associated with reduced expression of Tax. Furthermore, Bay 11-7082- induced apoptosis of primary ATL cells was more prominent than that of normal peripheral blood mononuclear cells, and apoptosis of these cells was also associated with down-regulation of NF-kappaB activity. Our results indicate that NF-kappaB plays a crucial role in the pathogenesis and survival of HTLV-I-infected leukemic cells and that it is a suitable target for the prevention and treatment of ATL.

  13. New mouse model of acute adult T-cell leukemia generated by transplantation of AKT, BCLxL, and HBZ-transduced T cells.

    PubMed

    Kasugai, Yumiko; Yoshida, Noriaki; Ohshima, Koichi; Matsuo, Keitaro; Seto, Masao; Tsuzuki, Shinobu

    2016-08-01

    Adult T-cell leukemia/lymphoma (ATL) develops in human T-cell leukemia virus type 1 (HTLV-1) carriers. Although the HTLV-1-encoded HBZ gene is critically involved, HBZ alone is insufficient and additional, cooperative "hits" are required for the development of ATL. Candidate cooperative hits are being defined, but methods to rapidly explore their roles in ATL development in collaboration with HBZ are lacking. Here, we present a new mouse model of acute type ATL that can be generated rapidly by transplanting in vitro-induced T cells that have been retrovirally transduced with HBZ and two cooperative genes, BCLxL and AKT, into mice. Co-transduction of HBZ and BCLxL/AKT allowed these T cells to grow in vitro in the absence of cytokines (Flt3-ligand and interleukin-7), which did not occur with any two-gene combination. Although transplanted T cells were a mixture of cells transduced with different combinations of the genes, tumors that developed in mice were composed of HBZ/BCLxL/AKT triply transduced T cells, showing the synergistic effect of the three genes. The genetic/epigenetic landscape of ATL has only recently been elucidated, and the roles of additional "hits" in ATL pathogenesis remain to be explored. Our model provides a versatile tool to examine the roles of these hits, in collaboration with HBZ, in the development of acute ATL. PMID:27223899

  14. T-Cell Subsets Predict Mortality in Malnourished Zambian Adults Initiating Antiretroviral Therapy

    PubMed Central

    Chisenga, Caroline C.; Filteau, Suzanne; Siame, Joshua; Chisenga, Molly; Prendergast, Andrew J.; Kelly, Paul

    2015-01-01

    Objective To estimate the prognostic value of T-cell subsets in Zambian patients initiating antiretroviral therapy (ART), and to assess the impact of a nutritional intervention on T-cell subsets. Methods This was a sub-study of a randomised clinical trial of a nutritional intervention for malnourished adults initiating ART. Participants in a randomised controlled trial (NUSTART trial) were enrolled between April and December 2012. Participants received lipid-based nutritional supplement either with or without additional vitamins and minerals. Immunophenotyping was undertaken at baseline and, in survivors, after 12 weeks of ART to characterize T-cell subsets using the markers CD3, CD4, CD8, CD45RA, CCR7, CD28, CD57, CD31, α4β7, Ki67, CD25 and HLA-DR. Univariate and multivariate survival analysis was performed, and responses to treatment were analysed using the Wicoxon rank-sum test. Results Among 181 adults, 36 (20%) died by 12 weeks after starting ART. In univariate analysis, patients who died had fewer proliferating, more naïve and fewer gut homing CD4+ T-cells compared to survivors; and more senescent and fewer proliferating CD8+ T-cells. In a multivariate Cox regression model high naïve CD4+, low proliferating CD4+, high senescent CD8+ and low proliferating CD8+ subsets were independently associated with increased risk of death. Recent CD4+ thymic emigrants increased less between recruitment and 12 weeks of ART in the intervention group compared to the control group. Conclusions Specific CD4+ T-cell subsets are of considerable prognostic significance for patients initiating ART in Zambia, but only thymic output responded to this nutritional intervention. PMID:26083409

  15. Universal cytotoxic activity of a HTLV-1 Tax-specific T cell clone from an HLA-A*24:02⁺ patient with adult T-cell leukemia against a variety of HTLV-I-infected T-cells.

    PubMed

    Tanaka, Yukie; Yamazaki, Rie; Terasako-Saito, Kiriko; Nakasone, Hideki; Akahoshi, Yu; Nakano, Hirofumi; Ugai, Tomotaka; Wada, Hidenori; Yamasaki, Ryoko; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Ashizawa, Masahiro; Sato, Miki; Kimura, Shun-ichi; Kikuchi, Misato; Kako, Shinichi; Kanda, Junya; Tanihara, Aki; Nishida, Junji; Kanda, Yoshinobu

    2014-01-01

    Adult T cell leukemia/lymphoma (ATL) is an aggressive mature T cell malignancy that is causally associated with human T cell lymphotropic virus type 1 (HTLV-1) infection. The HTLV-1 regulatory protein Tax aggressively accelerates the proliferation of host cells and is also an important target antigen for CD8(+) cytotoxic T cells (CTLs). We previously reported that several predominant HLA-A*24:02-restricted HTLV-1 Tax301-309-specific CTL clones commonly expressed a particular amino acid sequence motif (P-D-R) in complementarity-determining region 3 of T-cell receptor (TCR)-β chain among unrelated ATL patients who underwent allogeneic stem cell transplantation (allo-HSCT). Furthermore, a PDR-motif(+) CTL clone persistently existed in a long-term survivor as a central CTL clone with strong CTL activities after HSCT. Although a larger analysis of the relationship between PDR-motif(+) CTLs and the clinical course is required, the expression of PDR-motif(+) TCR on CD8(+) T cells may play a critical role in the management of anti-HTLV-1 activities for HLA-A24:02(+) ATL patients. Therefore, in this study, we prepared an HTLV-1 Tax301-309 peptide-specific CTL clone (HT-9) expressing PDR-motif(+) TCR isolated from a long-term survivor after HSCT, and evaluated its CTL activity against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients. Before the assay of CTL function, we confirmed that HT-9 expressed less-differentiated effector-memory phenotypes (CD45RA(-)CCR7(-)CD27(+)CD28(+/-)CD57(+/-)) and T-cell exhaustion marker PD-1(+). In assays of CTL function, HT-9 recognized HTLV-1 Tax in an HLA-restricted fashion and demonstrated strong CTL activities against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients regardless of whether the sources were autologous or allogeneic, but not normal cells. These data indicate that PDR-motif(+) TCR could be an important TCR candidate for TCR-gene immunotherapy for HLA-A24:02(+) ATL patients, provided

  16. Virus-specific CD4+ memory phenotype T cells are abundant in unexposed adults

    PubMed Central

    Su, Laura F.; Kidd, Brian A.; Han, Arnold; Kotzin, Jonathan J.; Davis, Mark M.

    2013-01-01

    While T cell memory is generally thought to require direct antigen exposure, we find an abundance of memory phenotype cells (20–90%, averaging over 50%) of CD4+ T cells specific for viral antigens in adults that have never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. This contrasts with newborns where the same T cell receptor (TCR) specificities are almost entirely naïve, which may explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens and in support of this we find extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and the expansion of one of these following influenza vaccination. Thus the presence of these memory phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments. PMID:23395677

  17. T cell subset profile in healthy Zambian adults at the University Teaching Hospital

    PubMed Central

    Chisenga, Caroline Cleopatra; Kelly, Paul

    2016-01-01

    Introduction Symptom-free human immunodeficiency virus antibody-negative Zambian adults (51 subjects, aged 20 to 62 years, 33.3% women and 66.7% men) were studied to establish T cell subset reference ranges. Methods We carried out across sectional study at the University Teaching Hospital, Lusaka. Blood samples were collected from healthy donor volunteers from hospital health care staff, between February and March 2015. Immunopheno typing was undertaken to characterize Tcell subsets using the markers CD3, CD4, CD8, α4β7, Ki67, CD25, CCR7, CD54RA, CD57, CD28, CD27 and HLA-DR. Results Among 51 volunteers, Women had significantly higher absolute CD4 count (median 1042; IQR 864, 1270) than in men (671; 545, 899) (p=0.003). Women also had more CD4 cells expressing homing, naïve, effector and effector memory T cell subsets compared to men. However, in the CD8 population, only the effector cells were significantly different with women expressing more than the males. Conclusion We provide early reference range for T cell subsets in Zambian adults and conclude that among the African women some T cell subsets are higher than men. PMID:27231509

  18. Suppressor T cells prevent in vitro expression of IgM rheumatoid factor in some healthy adults

    SciTech Connect

    Koopman, W.J.

    1981-12-01

    Peripheral blood mononuclear leukocytes (MNL) from 11 of 30 healthy adults elaborated detectable IgM RF when stimulated with pokeweed mitogen. The influence of T cells on IgM RF production by autologous B Cells prepared from donors whose unfractionated MNL synthesized IgM RF in response to PMW was investigated. Untreated T cells supported IgM RF production by autologous B cells with optimal synthesis observed at T:B cell ratios of 2:1 at higher T:B cell ratios a decline in IgM RF production occurred. In contrast, at higher T:B cell ratios irradiated T cells supported consistently higher levels of IgM RF production than untreated T cells suggesting the presence of radiosensitive suppressor T cells for IgM RF in these individuals. Irridiated T cells were compared to untreated T cells for capacity to support IgM RF production by autologous B cells from 12 randomly selected donors at T:B cell ratios of 3:1. Untreated T cells from 4 of 12 individuals were capable of cooperating in induction of IgM RF production by autologous B cells, whereas irradiated T cells supported IgM RF production in 6 of 12 individuals. Levels of IgM RF production in all 6 individuals were significantly higher with irradiated T cells than with untreated T cells; in 2 individuals IgM RF synthesis by autologous B cells was observed only in the presence of irradiated T cells. In 4 of 6 individuals increases in the ratio of IgM RF total IgM synthesis occured with irradiated T cells (when compared to untreated T cells), suggesting disproportionate suppression of RF production. These results indicate the presence of radiosensitive T cells capable of suppressing IgM RF production in a significant fraction of healthy adults and raise the possibility that these cells may regulate in vivo expression of RF.

  19. TIM-3 expression in lymphoma cells predicts chemoresistance in patients with adult T-cell leukemia/lymphoma

    PubMed Central

    Horlad, Hasita; Ohnishi, Koji; Ma, Chaoya; Fujiwara, Yukio; Niino, Daisuke; Ohshima, Koichi; Jinushi, Masahisa; Matsuoka, Masao; Takeya, Motohiro; Komohara, Yoshihiro

    2016-01-01

    Adult T-cell leukemia/lymphoma (ATLL), an aggressive type of malignant lymphoma, is highly resistant to chemotherapy. However, the detailed mechanisms of the chemoresistance of ATLL have never been elucidated. We previously demonstrated that direct cell-cell interaction between macrophages and lymphoma cells was significantly associated with lymphoma progression in patients with ATLL. The present study aimed to further analyze the effects of cell-cell interaction between macrophages and ATLL cells by means of cell culture studies and immunohistochemical analysis using human ATLL samples. It was found that direct co-culture with macrophages induced chemoresistance in the ATLL ATN-1 cell line, but not in other cell lines, including TL-Mor, ED and ATL-2S. It was also found that expression of the T cell Ig and mucin domain-containing molecule-3 (TIM-3) was induced in ATN-1 cells by their long-term co-culture with macrophages. TIM-3 gene transfection induced chemoresistance in the ATN-1 cells. Immunostaining of ATLL tissues showed TIM-3 expression in 25 out of 58 ATLL cases. Although TIM-3 expression was not associated with overall survival or T classification, it was associated with resistance to chemotherapy. TIM-3 expression is therefore considered to be a marker for predicting the efficacy of chemotherapy, and TIM-3-associated signals may be a therapeutic target for patients with ATLL. PMID:27446463

  20. Altered regulatory T cell phenotype in latent autoimmune diabetes of the adults (LADA).

    PubMed

    Radenkovic, M; Silver, C; Arvastsson, J; Lynch, K; Lernmark, Å; Harris, R A; Agardh, C-D; Cilio, C M

    2016-10-01

    Latent autoimmune diabetes of the adults (LADA) accounts for up to 12% of all patients with diabetes. Initially the disease resembles type 2 diabetes (T2D); however, the typical presence of β cell autoantibodies indicates an autoimmune basis of LADA. While dysfunctional regulatory T cells (Tregs ) have been implicated in autoimmune diabetes, these cells have been scarcely studied in LADA. The aim of this study was to investigate the frequency and phenotype of circulating Tregs in LADA patients early during disease progression. Flow cytometric analysis was performed on whole blood and peripheral mononuclear cells (PBMC) from patients diagnosed with LADA prior to insulin deficiency (n = 39) and from healthy volunteers (n = 20). Overall, we found the frequency and activation status of peripheral putative Tregs to be altered in LADA patients compared to healthy controls. While total T cells and CD4(+) T cells expressing high levels of CD25 (CD4(+) CD25(hi) ) were unchanged, the frequency and total numbers of CD4(+) T cells expressing an intermediate level of CD25 (CD4(+) CD25(int) ) were decreased in LADA patients. Interestingly, the expression of the Treg -specific marker forkhead box protein 3 (FoxP3), as well as the activation and memory makers CD69, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), CCR4 and CD45RO were increased in CD4(+) CD25(+) T cells of the patients. Our data depict phenotypical changes in T cells of LADA patients that may reflect a derangement in peripheral immune regulation contributing to the slow process leading to insulin-dependent diabetes in these patients.

  1. Norovirus-Specific Memory T Cell Responses in Adult Human Donors

    PubMed Central

    Malm, Maria; Tamminen, Kirsi; Vesikari, Timo; Blazevic, Vesna

    2016-01-01

    Norovirus (NoV) is a leading cause of acute gastroenteritis in people of all ages worldwide. NoV-specific serum antibodies which block the binding of NoV virus-like particles (VLPs) to the cell receptors have been thoroughly investigated. In contrast, only a few publications are available on the NoV capsid VP1 protein-specific T cell responses in humans naturally infected with the virus. Freshly isolated peripheral blood mononuclear cells of eight healthy adult human donors previously exposed to NoV were stimulated with purified VLPs derived from NoV GII.4-1999, GII.4-2012 (Sydney), and GI.3, and IFN-γ production was measured by an ELISPOT assay. In addition, 76 overlapping synthetic peptides spanning the entire 539-amino acid sequence of GII.4 VP1 were pooled into two-dimensional matrices and used to identify putative T cell epitopes. Seven of the eight subjects produced IFN-γ in response to the peptides and five subjects produced IFN-γ in response to the VLPs of the same origin. In general, stronger T cell responses were induced with the peptides in each donor compared to the VLPs. A CD8+ T cell epitope in the shell domain of the VP1 (134SPSQVTMFPHIIVDVRQL151) was identified in two subjects, both having human leukocyte antigen (HLA)-A∗02:01 allele. To our knowledge, this is the first report using synthetic peptides to study NoV-specific T cell responses in human subjects and identify T cell epitopes. PMID:27752254

  2. Altered regulatory T cell phenotype in latent autoimmune diabetes of the adults (LADA).

    PubMed

    Radenkovic, M; Silver, C; Arvastsson, J; Lynch, K; Lernmark, Å; Harris, R A; Agardh, C-D; Cilio, C M

    2016-10-01

    Latent autoimmune diabetes of the adults (LADA) accounts for up to 12% of all patients with diabetes. Initially the disease resembles type 2 diabetes (T2D); however, the typical presence of β cell autoantibodies indicates an autoimmune basis of LADA. While dysfunctional regulatory T cells (Tregs ) have been implicated in autoimmune diabetes, these cells have been scarcely studied in LADA. The aim of this study was to investigate the frequency and phenotype of circulating Tregs in LADA patients early during disease progression. Flow cytometric analysis was performed on whole blood and peripheral mononuclear cells (PBMC) from patients diagnosed with LADA prior to insulin deficiency (n = 39) and from healthy volunteers (n = 20). Overall, we found the frequency and activation status of peripheral putative Tregs to be altered in LADA patients compared to healthy controls. While total T cells and CD4(+) T cells expressing high levels of CD25 (CD4(+) CD25(hi) ) were unchanged, the frequency and total numbers of CD4(+) T cells expressing an intermediate level of CD25 (CD4(+) CD25(int) ) were decreased in LADA patients. Interestingly, the expression of the Treg -specific marker forkhead box protein 3 (FoxP3), as well as the activation and memory makers CD69, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), CCR4 and CD45RO were increased in CD4(+) CD25(+) T cells of the patients. Our data depict phenotypical changes in T cells of LADA patients that may reflect a derangement in peripheral immune regulation contributing to the slow process leading to insulin-dependent diabetes in these patients. PMID:27357431

  3. T-Cell Lymphoma

    MedlinePlus

    ... are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing). Lymphomas are ... also be involved. This group of PTCLs is aggressive and requires combination chemotherapy upon diagnosis. For more ...

  4. Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

    PubMed

    Kozako, Tomohiro; Soeda, Shuhei; Yoshimitsu, Makoto; Arima, Naomichi; Kuroki, Ayako; Hirata, Shinya; Tanaka, Hiroaki; Imakyure, Osamu; Tone, Nanako; Honda, Shin-Ichiro; Soeda, Shinji

    2016-05-01

    Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients. PMID:27419050

  5. Persistent changes in circulating and intestinal γδ T cell subsets, invariant natural killer T cells and mucosal-associated invariant T cells in children and adults with coeliac disease.

    PubMed

    Dunne, Margaret R; Elliott, Louise; Hussey, Seamus; Mahmud, Nasir; Kelly, Jacinta; Doherty, Derek G; Feighery, Conleth F

    2013-01-01

    Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets), natural killer cells, CD56(+) T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity. PMID:24124528

  6. Persistent changes in circulating and intestinal γδ T cell subsets, invariant natural killer T cells and mucosal-associated invariant T cells in children and adults with coeliac disease.

    PubMed

    Dunne, Margaret R; Elliott, Louise; Hussey, Seamus; Mahmud, Nasir; Kelly, Jacinta; Doherty, Derek G; Feighery, Conleth F

    2013-01-01

    Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets), natural killer cells, CD56(+) T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity.

  7. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients

    PubMed Central

    Turtle, Cameron J.; Hanafi, Laïla-Aïcha; Berger, Carolina; Gooley, Theodore A.; Cherian, Sindhu; Hudecek, Michael; Sommermeyer, Daniel; Melville, Katherine; Pender, Barbara; Budiarto, Tanya M.; Robinson, Emily; Steevens, Natalia N.; Chaney, Colette; Soma, Lorinda; Chen, Xueyan; Li, Daniel; Cao, Jianhong; Heimfeld, Shelly; Jensen, Michael C.; Riddell, Stanley R.; Maloney, David G.

    2016-01-01

    BACKGROUND. T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR–T cell products were prepared from unselected T cells. METHODS. We conducted a clinical trial to evaluate CD19 CAR–T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy. RESULTS. The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR–T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR–T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell–mediated anti-CAR transgene product immune responses developed after CAR–T cell infusion in some patients, limited CAR–T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR–T cell persistence and disease-free survival. CONCLUSION. Immunotherapy with a CAR–T cell product of defined composition enabled identification of factors that correlated with CAR–T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR–T cell dosing strategies that mitigated toxicity and improved disease-free survival. TRIAL REGISTRATION. ClinicalTrials.gov NCT01865617. FUNDING. R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation. PMID:27111235

  8. Regulatory T cells-derived IL-35 promotes the growth of adult acute myeloid leukemia blasts.

    PubMed

    Tao, Qianshan; Pan, Ying; Wang, Yiping; Wang, Huiping; Xiong, Shudao; Li, Qing; Wang, Jia; Tao, Lili; Wang, Zhitao; Wu, Fan; Zhang, Rui; Zhai, Zhimin

    2015-11-15

    Tumor immune escape mechanism mediated by CD4+CD25+regulatory T cells (Tregs) is a key factor in the pathogenesis of acute myeloid leukemia (AML). IL-35, as a novel inhibitory cytokine, is produced by Tregs specially and regulates functions of Tregs in murine. However, IL-35 expression of Tregs in human is still disputed, and its role in AML is yet to be elucidated. In this study, we found that IL-35 was expressed highly in peripheral blood plasma of adult patients with AML and significantly correlated with the clinical stages of malignancy. Tregs-derived from adult AML patients produced IL-35 in a stimulation-dependent manner. IL-35 promoted AML blasts immune escape by expanding Tregs and inhibiting CD4+CD25-effector T cells (Teffs). Furthermore, IL-35 directly promoted the proliferation of AML blasts and reduced the apoptosis of AML blasts. Together, our study demonstrates that IL-35-derived from Tregs promotes the growth of adult AML blasts, suggesting that IL-35 has an important role in the pathogenesis of AML.

  9. Induction of Adult T-Cell Leukemia-Like Lymphoproliferative Disease and Its Inhibition by Adoptive Immunotherapy in T-Cell-Deficient Nude Rats Inoculated with Syngeneic Human T-Cell Leukemia Virus Type 1-Immortalized Cells

    PubMed Central

    Ohashi, Takashi; Hanabuchi, Shino; Kato, Hirotomo; Koya, Yoshihiro; Takemura, Fumiyo; Hirokawa, Katsuiku; Yoshiki, Takashi; Tanaka, Yuetsu; Fujii, Masahiro; Kannagi, Mari

    1999-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) has been shown to be the etiologic agent of adult T-cell leukemia (ATL), but the in vivo mechanism by which the virus causes the malignant transformation is largely unknown. In order to investigate the mechanisms of HTLV-1 leukemogenesis, we developed a rat model system in which ATL-like disease was reproducibly observed, following inoculation of various rat HTLV-1-immortalized cell lines. When previously established cell lines, F344-S1 and TARS-1, but not TART-1 or W7TM-1, were inoculated, systemic multiple tumor development was observed in adult nude (nu/nu) rats. FPM1 cells, newly established from a heterozygous (nu/+) rat syngeneic to nu/nu rats, caused transient tumors only at the injection site in adult nu/nu rats, but could progressively grow in newborn nu/nu rats and metastasize in lymph nodes. The derivative cell line (FPM1-V1AX) serially passed through newborn nu/nu rats acquired the potency to grow in adult nu/nu rats. These results indicated that only some with additional changes but not all of the in vitro HTLV-1-immortalized cell lines possessed in vivo tumorigenicity. Using the syngeneic system, we further showed the inhibition of tumor development by transferring splenic T cells from immunized rats, suggesting the involvement of T cells in the regression of tumors. This novel and reproducible nude rat model of human ATL would be useful for investigation of leukemogenesis and antitumor immune responses in HTLV-1 infection. PMID:10364355

  10. Polycomb-dependent epigenetic landscape in adult T-cell leukemia.

    PubMed

    Fujikawa, Dai; Nakagawa, Shota; Hori, Makoto; Kurokawa, Naoya; Soejima, Ai; Nakano, Kazumi; Yamochi, Tadanori; Nakashima, Makoto; Kobayashi, Seiichiro; Tanaka, Yuetsu; Iwanaga, Masako; Utsunomiya, Atae; Uchimaru, Kaoru; Yamagishi, Makoto; Watanabe, Toshiki

    2016-04-01

    Adult T-cell leukemia-lymphoma (ATL) shows global gene expression alterations that confer cellular characteristics and unfavorable prognosis. However, molecular mechanisms of the sustained expression changes are largely unknown, because there is no study addressing the relationship between landscapes of the gene expression and epigenetic modifications. Here, we analyzed ATL epigenome and integrated it with transcriptome from primary ATL cells and those from corresponding normal CD4(+)T cells to decipher ATL-specific "epigenetic code" that was critical for cell identity. We found that polycomb-repressive complex 2 (PRC2)-mediated trimethylation at histone H3Lys27 (H3K27me3) was significantly and frequently reprogrammed at half of genes in ATL cells. A large proportion of the abnormal gene downregulation was detected at the early stage of disease progression and was explained by H3K27me3 accumulation. The global H3K27me3 alterations involved ATL-specific gene expression changes that included several tumor suppressors, transcription factors, epigenetic modifiers, miRNAs, and developmental genes, suggesting diverse outcomes by the PRC2-dependent hierarchical regulation. Interestingly, a key enzyme, EZH2, was sensitive to promiscuous signaling network including the NF-κB pathway and was functionally affected by human T-cell leukemia virus type I (HTLV-1) Tax. The Tax-dependent immortalized cells showed H3K27me3 reprogramming that was significantly similar to that of ATL cells. Of note, a majority of the epigenetic silencing has occurred in leukemic cells from indolent ATL and also in HTLV-1-infected T cells from asymptomatic HTLV-1 carriers. Because pharmacologic inhibition of EZH2 reversed epigenetic disruption and selectively eliminated leukemic and HTLV-1-infected cells, targeting the epigenetic elements will hold great promise in treatment and prevention of the onset of ATL and HTLV-1-related diseases. PMID:26773042

  11. Differentiation between cutaneous form of adult T cell leukemia/lymphoma and cutaneous T cell lymphoma by in situ hybridization using a human T cell leukemia virus-1 DNA probe.

    PubMed Central

    Arai, E.; Chow, K. C.; Li, C. Y.; Tokunaga, M.; Katayama, I.

    1994-01-01

    Adult T cell leukemia/lymphoma (ATLL) shares overlapping clinicopathological features with cutaneous T cell lymphoma (CTCL), requiring detection of monoclonal integration of proviral DNA of type 1 human T cell leukemia virus for its differential diagnosis from the latter. We applied in situ hybridization (ISH) and polymerase chain reaction (PCR) to paraffin sections from 63 Japanese autopsy cases that had been diagnosed as CTCL in earlier years when ATLL was still not widely known. Eleven and two cases with confirmed diagnoses of ATLL and CTCL served as positive and negative controls, respectively. It was found that ISH was positive in 7 of 63 test cases and 10 of 11 positive controls, whereas PCR was positive in none of the test cases and eight of the positive control cases. Two negative controls were negative for both ISH and PCR. We conclude that ISH is superior to PCR for detecting type 1 human T cell leukemia virus proviral DNA on paraffin sections and that the ISH method is useful for differentiating CTCL from the cutaneous form of ATLL. Images Figure 1 PMID:8291605

  12. Induction of apoptosis by HBI-8000 in adult T-cell leukemia/lymphoma is associated with activation of Bim and NLRP3.

    PubMed

    Hasegawa, Hiroo; Bissonnette, Reid P; Gillings, Mireille; Sasaki, Daisuke; Taniguchi, Hiroaki; Kitanosono, Hideaki; Tsuruda, Kazuto; Kosai, Kousuke; Uno, Naoki; Morinaga, Yoshitomo; Imaizumi, Yoshitaka; Miyazaki, Yasushi; Yanagihara, Katsunori

    2016-08-01

    Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy caused by human T-cell lymphotropic virus 1. Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti-chemokine (C-C motif) receptor 4 antibody, although most patients still have a poor prognosis and there is a clear need for additional options. HBI-8000 is a novel oral histone deacetylase inhibitor with proven efficacy for treatment of T-cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI-8000 on ATL-derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI-8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested Bim activation and, interestingly, the contribution of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome pathway in HBI-8000-induced ATL cell death. Further investigations using siRNAs confirmed that Bim contributes to HBI-8000-induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI-8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI-8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway. PMID:27193821

  13. Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas

    PubMed Central

    Friedberg, Jonathan W.; Mahadevan, Daruka; Cebula, Erin; Persky, Daniel; Lossos, Izidore; Agarwal, Amit B.; Jung, JungAh; Burack, Richard; Zhou, Xiaofei; Leonard, E. Jane; Fingert, Howard; Danaee, Hadi; Bernstein, Steven H.

    2014-01-01

    Purpose Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. Patients and Methods Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. Results We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event–related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. Conclusion The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated. PMID:24043741

  14. Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia

    PubMed Central

    Ge, Zheng; Li, Min; Zhao, Gang; Xiao, Lichan; Gu, Yan; Zhou, Xilian; Yu, Michael D.; Li, Jianyong; Dovat, Sinisa; Song, Chunhua

    2016-01-01

    Genetic mutations on signaling pathways are found in patients with T-cell acute lymphoblastic leukemia (T-ALL) and act as markers of high-risk leukemia. Mutations in dynamin 2 (DNM2) have been reported in T-ALL, particularly in early T-cell precursor-ALL. In the present study, DNM2 mutations were screened by sequencing DNM2 exons obtained by polymerase chain reaction amplification and gel purification in adult T-ALL patients. A total of 4 novel DNM2 mutations were identified in adult T-ALL patients, with a mutation rate of 9.5%, and the DNM2 mutations were found to co-exist with NOTCH1 and PHD finger protein 6, and were also associated with high-risk leukemia. A high rate of silent mutation was also found in the patients, but no significant association was found between the silent mutations and patients' clinical features. The present findings suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.

  15. High Expression of Intestinal Homing Receptor CD103 in Adult T-Cell Leukemia/Lymphoma, Similar to 2 Other CD8+ T-Cell Lymphomas.

    PubMed

    Ishibashi, Hideki; Nimura, Satoshi; Ishitsuka, Kenji; Mihashi, Yasuhito; Mizoguchi, Mikio; Nakamura, Shotaro; Okamura, Seiichi; Momosaki, Seiya; Aoyagi, Kunihiko; Sakisaka, Shotaro; Takeshita, Morishige

    2016-04-01

    We investigated the expression of the αEβ7 integrin (CD103)-intestinal homing receptor of T-intraepithelial lymphocytes (IELs) in 130 cases of adult T-cell leukemia/lymphoma (ATLL). We detected CD103 lymphoma cells in 55% (31/56) of mainly gastrointestinal (GI)-involved ATLL cases. Among them, lymphoma cells of 18 cases located in other involved organs had similar CD103 expression patterns. Histologically, we found (a) increased reactive IELs in non-neoplastic mucosal layers in 28% (5/18) of surgical and mucosal resection cases, (b) preserved epithelial glands, and (c) numerous small intraepithelial ATLL nests in involved lesions in 36 (69%) and 21 (40%), respectively, of the 52 examined cases. These 3 patterns were common in intestinal type II enteropathy-associated T-cell lymphoma but were rare in intestinal EBV nasal-type/like T/natural killer (NK)-cell lymphoma. We detected CD103 tumor cells in 41% (16/39) of lymph node-involved ATLL, in 31% (11/35) of skin-involved ATLL, in 68% (21/31) of type II CD4 enteropathy-associated T-cell lymphoma cases, in 36% (8/22) of primary gastric T/NK-cell lymphomas, and in 77% (7/9) of CD8 epidermotropic mycosis fungoides. CD103 ATLL prefers involving the GI tract over the skin (P<0.05). CD103 expression in GI-involved and/or total ATLL cases was significantly higher than in other 9 T/NK-cell lymphoma groups (P<0.05 or 0.01). Only ATLL cases were commonly CD103 in CD4 T/NK-cell lymphoma groups (P<0.05 or 0.01). Human T-lymphotropic virus-1-infected CD103 T-IELs and mucosal T cells may be important sources of ATLL. PMID:26813744

  16. Regulatory T cells are decreased in acute RHDV lethal infection of adult rabbits.

    PubMed

    Teixeira, Luzia; Marques, Raquel M; Aguas, Artur P; Ferreira, Paula G

    2012-08-15

    Rabbit hemorrhagic disease virus (RHDV) is the etiologic agent of rabbit hemorrhagic disease (RHD), an acute lethal infection that kills 90% of adult rabbits due to severe acute liver inflammation. Interestingly, young rabbits are naturally resistant to RHDV infection. Here, we have compared naturally occurring CD4(+)Foxp3(+) regulatory T cells (Tregs) between young and adult rabbits after infection by RHDV. The number and frequency of Tregs was decreased in the spleen of adult rabbits 24h after the RHDV infection; this was in contrast with the unchanged number and frequency of splenic Tregs found in young rabbits after the same infection. Also, serum levels of IL-10 and TGF-β were enhanced in the infected adult rabbits whereas no alteration was observed in infected young rabbits. However, this increase is accompanied by a burst of pro-inflammatory cytokines, but seems not able to prevent the death of the animals with severe acute liver inflammation in few days after infection. Since Tregs downregulate inflammation, we conclude that their decrease may contribute to the natural susceptibility of adult rabbits to RHDV infection.

  17. Evidence against T-cell development in the adult human intestinal mucosa based upon lack of terminal deoxynucleotidyltransferase expression.

    PubMed Central

    Taplin, M E; Frantz, M E; Canning, C; Ritz, J; Blumberg, R S; Balk, S P

    1996-01-01

    Several lines of evidence indicate that a subset of murine intestinal intraepithelial lymphocytes (iIEL), particularly those which express the CD8 alpha alpha homodimer, mature extrathymically. This study confirms that a small fraction of adult human iIEL also express the CD8 alpha alpha homodimer and demonstrates that most of these cells in the small intestine are T cells using the alpha beta T-cell receptor (TCR). Whether these cells or other subsets of adult human iIEL mature extrathymically in the intestine was assessed by measuring the expression of terminal deoxynucleotidyltransferase (TdT), an enzyme expressed exclusively by immature lymphocytes. Very low levels of TdT message could be detected by polymerase chain reaction (PCR) amplification in some iIEL samples. The level of TdT expression was assayed by competitive PCR amplification and compared with thymocytes and peripheral blood lymphocytes. These measurements indicated that the number of immature T cells expressing TdT in the intestinal epithelium was less than one cell per 10(7) lymphocytes. This demonstrates that there are few if any TdT expressing immature T cells in the adult human intestinal mucosa and indicates, therefore, that T-cell development in the intestinal mucosa does not contribute significantly to the T-cell repertoire of the adult human intestine. Images Figure 1 Figure 2 Figure 3 PMID:8778025

  18. Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma.

    PubMed

    Fuji, S; Fujiwara, H; Nakano, N; Wake, A; Inoue, Y; Fukuda, T; Hidaka, M; Moriuchi, Y; Miyamoto, T; Uike, N; Taguchi, J; Eto, T; Tomoyose, T; Kondo, T; Yamanoha, A; Ichinohe, T; Atsuta, Y; Utsunomiya, A

    2016-02-01

    Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for aggressive adult T-cell leukemia/lymphoma (ATLL). Considering the dismal prognosis associated with conventional chemotherapies, early application of allo-HSCT might be beneficial for patients with ATLL. However, no previous study has addressed the optimal timing of allo-HSCT from related donors. Hence, to evaluate the impact of timing of allo-HSCT for patients with ATLL, we retrospectively analyzed data from patients with ATLL who received an allo-HSCT from a related donor. The median age was 52 years. Patients were grouped according to the interval from diagnosis to allo-HSCT: early transplant group, <100 days, n=72; late transplant group, ⩾100 days, n=428. The corresponding constituents of disease status were not statistically different between the two groups (P=0.11). The probability of OS in the early transplant group was significantly higher than that in the late transplant group (4-year OS, 49.3% vs 31.2%). Multivariate analysis revealed that late allo-HSCT was an unfavorable prognostic factor for OS (hazard ratio, 1.46; 95% confidence interval (CI), 1.01-2.11; P=0.04). Despite the limitations of a retrospective study, it might be acceptable to consider early application of allo-HSCT for ATLL. PMID:26524263

  19. A probable identical Epstein-Barr virus clone-positive composite lymphoma with aggressive natural killer-cell leukemia and cytotoxic T-cell lymphoma

    PubMed Central

    Sugimoto, Kei-Ji; Shimada, Asami; Wakabayashi, Mutsumi; Imai, Hidenori; Sekiguchi, Yasunobu; Nakamura, Noriko; Sawada, Tomohiro; Ota, Yasunori; Takeuchi, Kengo; Ito, Yoshinori; Kimura, Hiroshi; Komatsu, Norio; Noguchi, Masaaki

    2014-01-01

    The patient was a 52-year old woman with a history of mosquito-bite hypersensitivity since childhood. In July 2011, she developed pyrexia, headaches, and nausea, and Epstein-Barr virus (EBV)-positive aggressive natural killer leukemia (ANKL) was diagnosed on the basis of both a peripheral blood and bone marrow examination. An inguinal lymph node biopsy, on the other hand, revealed EBV-positive cytotoxic T-cell lymphoma plus the presence of a small number of EBV-positive ANKL cells, and a diagnosis of EBV-positive composite lymphoma was made. Both the cytotoxic T-cell lymphoma and ANKL exhibited EBV terminal repeat (Southern blot analysis) monoclonal patterns, and they were almost the same size, approximately 9.0 kb. If it was the identical EBV clone, it is possible that EBV infected progenitor cells common to both NK cells and T cells, that the progenitor cells then differentiated into NK cells and T cells, a chronic active Epstein-Barr virus infection developed, and neoplastic transformation occurred. If it was not the identical EBV clone, fairly similar EBVs must have infected NK cells and T cells separately, and they then underwent neoplastic transformation. Because the mechanism by which EBV infects NK cells or T cells is still unknown, we concluded that this case is also important from the standpoint of elucidating it. We are currently in the process of conducting gene analyses to determine whether the fairly similar EBVs that infected the ANKL and cytotoxic T-cell lymphoma are the identical clone. PMID:24427365

  20. Alterations in T Cell Subsets in Human Immunodeficiency Virus–Infected Adults with Co-infections in Southern Mozambique

    PubMed Central

    Naniche, Denise; Letang, Emilio; Nhampossa, Tacilta; David, Catarina; Menendez, Clara; Alonso, Pedro

    2011-01-01

    T cell activation and depletion of naive T cells are hallmarks of human immunodeficiency virus (HIV) pathogenesis. This study explored the relationships between certain co-infections (including syphilis, hepatitis B and C, human T cell lymphotrophic viruses I and II [HTLV-I/II], Kaposi sarcoma–associated herpesvirus [KSHV], Plasmodium falciparum malaria, and tuberculosis), and levels of activated CD8 and CD4 T cell subsets as well as naive and memory CD4 T cells in HIV-infected adults in a rural area of southern Mozambique. We found that syphilis infection and to a lesser extent HTLV-I/II seropositivity were independently associated with higher CD8 T cell activation (CD8+ CD38+ HLA-DR+) whereas only syphilis was associated with higher CD4 T cell activation. Furthermore, KSHV and HTLV-I/II seropositivities were independently associated with a lower percentage of naive CD4 T cells (CD4+ CD45RA+ CD62L+). These results highlight the importance of screening and prompt treatment of syphilis, and raise questions as to whether HIV-positive persons with certain chronic viral co-infections should initiate combined antiretroviral therapy at higher CD4 cell counts. PMID:21976586

  1. Suppression of IL-7-dependent Effector T-cell Expansion by Multipotent Adult Progenitor Cells and PGE2.

    PubMed

    Reading, James L; Vaes, Bart; Hull, Caroline; Sabbah, Shereen; Hayday, Thomas; Wang, Nancy S; DiPiero, Anthony; Lehman, Nicholas A; Taggart, Jen M; Carty, Fiona; English, Karen; Pinxteren, Jef; Deans, Robert; Ting, Anthony E; Tree, Timothy I M

    2015-11-01

    T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients. PMID:26216515

  2. Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia.

    PubMed

    Takahashi, Ryutaro; Yamagishi, Makoto; Nakano, Kazumi; Yamochi, Toshiko; Yamochi, Tadanori; Fujikawa, Dai; Nakashima, Makoto; Tanaka, Yuetsu; Uchimaru, Kaoru; Utsunomiya, Atae; Watanabe, Toshiki

    2014-09-01

    One of the hallmarks of cancer, global gene expression alteration, is closely associated with the development and malignant characteristics associated with adult T-cell leukemia (ATL) as well as other cancers. Here, we show that aberrant overexpression of the Ellis Van Creveld (EVC) family is responsible for cellular Hedgehog (HH) activation, which provides the pro-survival ability of ATL cells. Using microarray, quantitative RT-PCR and immunohistochemistry we have demonstrated that EVC is significantly upregulated in ATL and human T-cell leukemia virus type I (HTLV-1)-infected cells. Epigenetic marks, including histone H3 acetylation and Lys4 trimethylation, are specifically accumulated at the EVC locus in ATL samples. The HTLV-1 Tax participates in the coordination of EVC expression in an epigenetic fashion. The treatment of shRNA targeting EVC, as well as the transcription factors for HH signaling, diminishes the HH activation and leads to apoptotic death in ATL cell lines. We also showed that a HH signaling inhibitor, GANT61, induces strong apoptosis in the established ATL cell lines and patient-derived primary ATL cells. Therefore, our data indicate that HH activation is involved in the regulation of leukemic cell survival. The epigenetically deregulated EVC appears to play an important role for HH activation. The possible use of EVC as a specific cell marker and a novel drug target for HTLV-1-infected T-cells is implicated by these findings. The HH inhibitors are suggested as drug candidates for ATL therapy. Our findings also suggest chromatin rearrangement associated with active histone markers in ATL.

  3. HTLV-1 and associated adult T-cell leukemia/lymphoma.

    PubMed

    Mahieux, Renaud; Gessain, Antoine

    2003-12-01

    Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infects 15-20 millions individuals worldwide. This oncoretrovirus can be transmitted through 3 ways: horizontally, vertically (mother to child) and via blood transfusion. HTLV-1 causes 2 major diseases: adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy. Tax is a 40-kDa phosphoprotein that is encoded by the pX region of the virus. Several lines of evidence have demonstrated a central role for this protein in the immortalization or transformation of the HTLV-1 infected cells. Apart from its ability to drive transcription from the viral promoter, it also deregulates the cell cycle, inhibits apoptosis, has an effect on the maintenance of the genomic stability and induces the production of several cytokines. In addition, several arguments strongly suggest the existence of host genetic factors, that could be involved in the HTLV-1 infection as well as in the development of ATLL among HTLV-1 infected individuals. ATLL can be classified into 4 major subtypes: a smoldering type, a chronic type, a lymphoma type and a leukemic type. The demonstration by Southern blot analysis of the clonal integration of an HTLV-1 provirus in the tumoral cells represents the gold-standard to define biologically ATLL. The survival rate of ATLL patients, especially those who develop the acute leukemic or lymphomas forms, is very poor, and such clonal malignant CD4 expansion remains one of the most severe lymphoproliferations.

  4. Role for protein geranylgeranylation in adult T-cell leukemia cell survival

    SciTech Connect

    Nonaka, Mizuho; Uota, Shin; Saitoh, Yasunori; Takahashi, Mayumi; Sugimoto, Haruyo; Amet, Tohti; Arai, Ayako; Miura, Osamu; Yamamoto, Naoki; Yamaoka, Shoji

    2009-01-15

    Adult T-cell leukemia (ATL) is a fatal lymphoproliferative disease that develops in human T-cell leukemia virus type I (HTLV-I)-infected individuals. Despite the accumulating knowledge of the molecular biology of HTLV-I-infected cells, effective therapeutic strategies remain to be established. Recent reports showed that the hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitor statins have anti-proliferative and apoptotic effects on certain tumor cells through inhibition of protein prenylation. Here, we report that statins hinder the survival of ATL cells and induce apoptotic cell death. Inhibition of protein geranylgeranylation is responsible for these effects, since simultaneous treatment with isoprenoid precursors, geranylgeranyl pyrophosphate or farnesyl pyrophosphate, but not a cholesterol precursor squalene, restored the viability of ATL cells. Simvastatin inhibited geranylgeranylation of small GTPases Rab5B and Rac1 in ATL cells, and a geranylgeranyl transferase inhibitor GGTI-298 reduced ATL cell viability more efficiently than a farnesyl transferase inhibitor FTI-277. These results not only unveil an important role for protein geranylgeranylation in ATL cell survival, but also implicate therapeutic potentials of statins in the treatment of ATL.

  5. Recent advances in the treatment of adult T-cell leukemia-lymphomas

    PubMed Central

    Utsunomiya, Atae; Choi, Ilseung; Chihara, Dai; Seto, Masao

    2015-01-01

    Recent advances in treatment for adult T-cell leukemia-lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally because of advances in chemotherapy, further prolongation of survival might be difficult with conventional chemotherapy alone. Promising results have been reported for antiviral therapy using zidovudine and interferon-α, and, indeed, antiviral therapy is currently the standard treatment for patients with ATL in western countries. Remarkably, the 5-year OS rates are 100% for both the smoldering-type and chronic-type ATL. Recently, treatments for ATL have included allogeneic hematopoietic stem cell transplantation and molecular targeted therapies. Furthermore, the anti-CCR4 monoclonal antibody mogamulizumab has been shown to have marked cytotoxic effects on ATL cells, especially in the leukemic type of ATL. In the lymphoma type of ATL, the response rate may be improved by combining mogamulizumab with chemotherapy. It should be recognized that prevention of infection from carriers of human T-cell leukemia virus type-I and transfer of the virus from mother to infant are crucial issues for the eradication of ATL. PMID:25613789

  6. MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells.

    PubMed

    Wissink, Erin M; Smith, Norah L; Spektor, Roman; Rudd, Brian D; Grimson, Andrew

    2015-11-01

    Immunological memory, which protects organisms from re-infection, is a hallmark of the mammalian adaptive immune system and the underlying principle of vaccination. In early life, however, mice and other mammals are deficient at generating memory CD8+ T cells, which protect organisms from intracellular pathogens. The molecular basis that differentiates adult and neonatal CD8+ T cells is unknown. MicroRNAs (miRNAs) are both developmentally regulated and required for normal adult CD8+ T cell functions. We used next-generation sequencing to identify mouse miRNAs that are differentially regulated in adult and neonatal CD8+ T cells, which may contribute to the impaired development of neonatal memory cells. The miRNA profiles of adult and neonatal cells were surprisingly similar during infection; however, we observed large differences prior to infection. In particular, miR-29 and miR-130 have significant differential expression between adult and neonatal cells before infection. Importantly, using RNA-Seq, we detected reciprocal changes in expression of messenger RNA targets for both miR-29 and miR-130. Moreover, targets that we validated include Eomes and Tbx21, key genes that regulate the formation of memory CD8+ T cells. Notably, age-dependent changes in miR-29 and miR-130 are conserved in human CD8+ T cells, further suggesting that these developmental differences are biologically relevant. Together, these results demonstrate that miR-29 and miR-130 are likely important regulators of memory CD8+ T cell formation and suggest that neonatal cells are committed to a short-lived effector cell fate prior to infection. PMID:26416483

  7. MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells

    PubMed Central

    Wissink, Erin M.; Smith, Norah L.; Spektor, Roman; Rudd, Brian D.; Grimson, Andrew

    2015-01-01

    Immunological memory, which protects organisms from re-infection, is a hallmark of the mammalian adaptive immune system and the underlying principle of vaccination. In early life, however, mice and other mammals are deficient at generating memory CD8+ T cells, which protect organisms from intracellular pathogens. The molecular basis that differentiates adult and neonatal CD8+ T cells is unknown. MicroRNAs (miRNAs) are both developmentally regulated and required for normal adult CD8+ T cell functions. We used next-generation sequencing to identify mouse miRNAs that are differentially regulated in adult and neonatal CD8+ T cells, which may contribute to the impaired development of neonatal memory cells. The miRNA profiles of adult and neonatal cells were surprisingly similar during infection; however, we observed large differences prior to infection. In particular, miR-29 and miR-130 have significant differential expression between adult and neonatal cells before infection. Importantly, using RNA-Seq, we detected reciprocal changes in expression of messenger RNA targets for both miR-29 and miR-130. Moreover, targets that we validated include Eomes and Tbx21, key genes that regulate the formation of memory CD8+ T cells. Notably, age-dependent changes in miR-29 and miR-130 are conserved in human CD8+ T cells, further suggesting that these developmental differences are biologically relevant. Together, these results demonstrate that miR-29 and miR-130 are likely important regulators of memory CD8+ T cell formation and suggest that neonatal cells are committed to a short-lived effector cell fate prior to infection. PMID:26416483

  8. Plasma Soluble CD30 as a Possible Marker of Adult T-cell Leukemia in HTLV-1 Carriers: a Nested Case-Control Study.

    PubMed

    Takemoto, Shigeki; Iwanaga, Masako; Sagara, Yasuko; Watanabe, Toshiki

    2015-01-01

    Elevated levels of soluble CD30 (sCD30) are linked with various T-cell neoplasms. However, the relationship between sCD30 levels and the development of adult T-cell leukemia (ATL) in human T-cell leukemia virus type 1 (HTLV-1) carriers remains to be clarified. We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers. We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sCD30 concentration at baseline was significantly higher in cases than in controls (median 65.8, range 27.2-134.5 U/mL vs. median 22.2, range 8.4-63.1 U/mL, P=0.001). In the univariate logistic regression analysis, a higher sCD30 (≥30.2 U/mL) was significantly associated with ATL development (odds ratio 7.88 and the 95% confidence intervals 1.35-45.8, P = 0.02). Among cases, sCD30 concentration tended to increase at the time of diagnosis of aggressive-type ATL, but the concentration was stable in those developing the smoldering-type. This suggests that sCD30 may serve as a predictive marker for the onset of aggressive-type ATL in HTLV-1 carriers.

  9. T Cells

    MedlinePlus

    ... or turn off the immune response. Cytotoxic or “killer” T cells directly attack and destroy cells bearing ... involve selective activation of helper T cells and killer T cells, with a corresponding decrease in regulatory ...

  10. Relationship between triterpenoid anticancer drug resistance, autophagy, and caspase-1 in adult T-cell leukemia

    PubMed Central

    Nakanishi, Tsukasa; Morita, Kentaro; Tsukada, Junichi; Kanazawa, Tamotsu

    2016-01-01

    We previously reported that the inflammasome inhibitor cucurbitacin D (CuD) induces apoptosis in human leukemia cell lines. Here, we investigated the effects of CuD and a B-cell lymphoma extra-large (Bcl-xL) inhibitor on autophagy in peripheral blood lymphocytes (PBL) isolated from adult T-cell leukemia (ATL) patients. CuD induced PBL cell death in patients but not in healthy donors. This effect was not significantly inhibited by treatment with rapamycin or 3-methyladenine (3-MA). The Bcl-xL inhibitor Z36 induced death in primary cells from ATL patients including that induced by CuD treatment, effects that were partly inhibited by 3-MA. Similarly, cell death induced by the steroid prednisolone was enhanced in the presence of Z36. A western blot analysis revealed that Z36 also promoted CuD-induced poly(ADP ribose) polymerase cleavage. Interestingly, the effects of CuD and Z36 were attenuated in primary ATL patient cells obtained upon recurrence after umbilical cord blood transplantation, as compared to those obtained before chemotherapy. Furthermore, cells from this patient expressed a high level of caspase-1, and treatment with caspase-1 inhibitor-enhanced CuD-induced cell death. Taken together, these results suggest that rescue from resistance to steroid drugs can enhance chemotherapy, and that caspase-1 is a good marker for drug resistance in ATL patients. PMID:27190722

  11. A study of adult T-cell leukemia/lymphoma incidence in central Brooklyn.

    PubMed

    Levine, P H; Dosik, H; Joseph, E M; Felton, S; Bertoni, M A; Cervantes, J; Moulana, V; Miotti, A B; Goberdhan, L J; Lee, S L; Daouad, A; DaCosta, M; Jaffe, E S; Axiotis, C A; Cleghorn, F R; Kahn, A; Welles, S L

    1999-03-01

    Adult T-cell leukemia/lymphoma (ATL), a rare outcome of infection with human T-lymphotropic virus (HTLV-I), is endemic in central Brooklyn, which has a large Caribbean migrant population. Previous studies have suggested that HTLV-I prevalence in central Brooklyn may be similar to that recorded in the Caribbean islands. We established a pilot 1-year surveillance program to identify cases of ATL in 7 of 10 hospitals serving the residents of 18 zip codes of central Brooklyn with a combined population of 1,184,670. Of the 6,198 in-patient beds in the catchment area, approximately 83% were covered. Twelve incident cases of ATL were ascertained, all among persons of Afro-Caribbean descent, indicating an annual incidence in African-Americans in this community of approximately 3.2/100,000 person-years. Unexplained hypercalcemia was the most useful screening method, identifying 3 of 5 patients not referred for possible ATL by a local hematologist. The female:male ratio was 3:1. The age pattern was different from that reported in the Caribbean Basin and closer to the pattern seen in Japan. Our study supports evidence that HTLV-I infection and ATL are endemic in central Brooklyn and suggests that a more intensive surveillance program for this disease coupled with intervention efforts to reduce HTLV-I transmission are warranted.

  12. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia

    PubMed Central

    Brentjens, Renier; Davila, Marco L; Riviere, Isabelle; Park, Jae; Wang, Xiuyan; Cowell, Lindsay G; Bartido, Shirley; Stefanski, Jolanta; Taylor, Clare; Olszewska, Malgorzata; Borquez-Ojeda, Oriana; Qu, Jinrong; Wasielewska, Teresa; He, Qing; Bernal, Yvette; Rijo, Ivelise V; Hedvat, Cyrus; Kobos, Rachel; Curran, Kevin; Steinherz, Peter; Jurcic, Joseph; Rosenblat, Todd; Maslak, Peter; Frattini, Mark; Sadelain, Michel

    2013-01-01

    Adults with relapsed B-acute lymphoblastic leukemia (ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD−) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated 5 relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD-negative complete remissions as assessed by deep sequencing PCR. Therapy was well tolerated although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Significantly, cytokine elevations directly correlated to tumor burden at the time of CAR modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR modified T cell therapy, ineligible for additional allo-HSCT therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell mediated cytotoxicity suggesting potential clinical benefit of additional CAR modified T cell infusions. These results demonstrate the marked anti-tumor efficacy of 19-28z CAR modified T cells in patients with relapsed/refractory B-ALL and the reliability of this novel therapy to induce profound molecular remissions, an ideal bridge to potentially curative therapy with subsequent allo-HSCT. PMID:23515080

  13. Fathers' Trait Verbal Aggressiveness and Argumentativeness as Predictors of Adult Sons' Perceptions of Fathers' Sarcasm, Criticism, and Verbal Aggressiveness.

    ERIC Educational Resources Information Center

    Beatty, Michael J.; And Others

    1994-01-01

    Finds that approximately 40% of the variance in adult sons' reports of fathers' messages (sarcasm, criticism, and verbal aggressiveness) was attributable to fathers' self-reported argumentativeness and verbal aggression. (SR)

  14. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology.

  15. Tax unleashed: fulminant Tax-positive Adult T-cell Leukemia/Lymphoma after failed allogeneic stem cell transplantation.

    PubMed

    Ghez, David; Renand, Amédée; Lepelletier, Yves; Sibon, David; Suarez, Felipe; Rubio, Marie-Thérèse; Delarue, Richard; Buzyn, Agnès; Beljord, Kheira; Tanaka, Yuetsu; Varet, Bruno; Hermine, Olivier

    2009-12-01

    The human retrovirus HTLV-1 causes Adult T-cell Leukemia/Lymphoma (ATLL), a malignant lymphoproliferative disease of CD4+ T cells of dismal prognosis, in 3-5% of the 20 million infected individuals (Proietti et al.(1) and Bazarbachi et al.(2)). Infection with HTLV-1 represents a prototypical model of virus-mediated oncogenesis by virtue of the viral transactivator Tax, a potent oncogenic protein that exerts pleiotropic effects through its ability to deregulate the transcription of various cellular genes and signal transduction pathways and inhibit DNA repair enzymes, which are critical for T-cell homeostasis and genetic stability (Matsuoka and Jeang(3)) (et Boxus Retrovirology 2009). However, the oncogenic potential of Tax remains a conundrum. Tax protein expression is undetectable using conventional methods in freshly harvested ATLL cells and in non-malignant infected CD4+ T cells (Furukawa et al.(4)) but is up regulated after only a few hours of culture in vitro (Hanon et al.(5)). These observations strongly suggest that a host-derived mechanism is able to either actively repress the transcription of viral proteins in vivo or refrain the emergence of Tax-expressing cells, which would have a growth advantage. We report herein a unique case of CD4+ T-cell leukemia highly expressing Tax following rejection of an allogenic peripheral blood stem cell graft for an HTLV-1 associated lymphoma. PMID:19836302

  16. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. PMID:26847489

  17. Broad HIV-1 inhibition in vitro by vaccine-elicited CD8+ T cells in African adults

    PubMed Central

    Mutua, Gaudensia; Farah, Bashir; Langat, Robert; Indangasi, Jackton; Ogola, Simon; Onsembe, Brian; Kopycinski, Jakub T; Hayes, Peter; Borthwick, Nicola J; Ashraf, Ambreen; Dally, Len; Barin, Burc; Tillander, Annika; Gilmour, Jill; De Bont, Jan; Crook, Alison; Hannaman, Drew; Cox, Josephine H; Anzala, Omu; Fast, Patricia E; Reilly, Marie; Chinyenze, Kundai; Jaoko, Walter; Hanke, Tomáš; HIV-CORE 004 study group, the

    2016-01-01

    We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8+ T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy.

  18. Broad HIV-1 inhibition in vitro by vaccine-elicited CD8+ T cells in African adults

    PubMed Central

    Mutua, Gaudensia; Farah, Bashir; Langat, Robert; Indangasi, Jackton; Ogola, Simon; Onsembe, Brian; Kopycinski, Jakub T; Hayes, Peter; Borthwick, Nicola J; Ashraf, Ambreen; Dally, Len; Barin, Burc; Tillander, Annika; Gilmour, Jill; De Bont, Jan; Crook, Alison; Hannaman, Drew; Cox, Josephine H; Anzala, Omu; Fast, Patricia E; Reilly, Marie; Chinyenze, Kundai; Jaoko, Walter; Hanke, Tomáš; HIV-CORE 004 study group, the

    2016-01-01

    We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8+ T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy. PMID:27617268

  19. Broad HIV-1 inhibition in vitro by vaccine-elicited CD8(+) T cells in African adults.

    PubMed

    Mutua, Gaudensia; Farah, Bashir; Langat, Robert; Indangasi, Jackton; Ogola, Simon; Onsembe, Brian; Kopycinski, Jakub T; Hayes, Peter; Borthwick, Nicola J; Ashraf, Ambreen; Dally, Len; Barin, Burc; Tillander, Annika; Gilmour, Jill; De Bont, Jan; Crook, Alison; Hannaman, Drew; Cox, Josephine H; Anzala, Omu; Fast, Patricia E; Reilly, Marie; Chinyenze, Kundai; Jaoko, Walter; Hanke, Tomáš; Hiv-Core 004 Study Group, The

    2016-01-01

    We are developing a pan-clade HIV-1 T-cell vaccine HIVconsv, which could complement Env vaccines for prophylaxis and be a key to HIV cure. Our strategy focuses vaccine-elicited effector T-cells on functionally and structurally conserved regions (not full-length proteins and not only epitopes) of the HIV-1 proteome, which are common to most global variants and which, if mutated, cause a replicative fitness loss. Our first clinical trial in low risk HIV-1-negative adults in Oxford demonstrated the principle that naturally mostly subdominant epitopes, when taken out of the context of full-length proteins/virus and delivered by potent regimens involving combinations of simian adenovirus and poxvirus modified vaccinia virus Ankara, can induce robust CD8(+) T cells of broad specificities and functions capable of inhibiting in vitro HIV-1 replication. Here and for the first time, we tested this strategy in low risk HIV-1-negative adults in Africa. We showed that the vaccines were well tolerated and induced high frequencies of broadly HIVconsv-specific plurifunctional T cells, which inhibited in vitro viruses from four major clades A, B, C, and D. Because sub-Saharan Africa is globally the region most affected by HIV-1/AIDS, trial HIV-CORE 004 represents an important stage in the path toward efficacy evaluation of this highly rational and promising vaccine strategy. PMID:27617268

  20. The relation between clinical features of adult T-cell leukemia/lymphoma and the serum levels of soluble CD25 and CD30.

    PubMed

    Takemoto, Shigeki; Pornkuna, Ratiorn; Hidaka, Michihiro; Kawano, Fumio

    2016-07-01

    Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T cells. We aimed to ascertain the relationships between soluble CD25 (sIL-2R) and CD30 (sCD30) levels and nodal or extra-nodal involvement of ATL. Our study subjects were ATL patients whose sIL-2R and sCD30 levels were measured before initial therapy (n=32). Their sCD30 levels correlated significantly with the number of ATL cells in peripheral blood (PB) (ρ=0.456; P=0.009), while sIL-2R levels correlated significantly with the number of nodal lesions (ρ=0.660; P=0.001). We then also assessed the relationships of pulmonary lesions with the number of ATL cells in PB, lactate dehydrogenase levels, sIL-2R levels, and sCD30 levels in 24 patients whose pleural effusions and hilar lymphadenopathy were investigated before initial therapy. The results suggested that a high number of ATL cells in PB may be associated with pulmonary lesions. It is known that metalloproteinases shed and cleave cytokine receptors such as CD25 and CD30 from the cell surface as well as E-cadherin and extracellular matrix. It seems that serum levels of sIL-2R and sCD30 indicate the activation of metalloproteinases associated with ATL involvement in vivo.

  1. Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model.

    PubMed

    Yu, P; Petrus, M N; Ju, W; Zhang, M; Conlon, K C; Nakagawa, M; Maeda, M; Bamford, R N; Waldmann, T A

    2015-03-01

    Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus-1. There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the nuclear factor-κB pathway. Physical and functional interaction between these two pathways provides the rationale to combine the γ-secretase inhibitor compound E with the proteasome inhibitor bortezomib. Moreover, romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and the combination of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P<0.05), and prolonged survival of leukemia-bearing mice (P<0.05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human soluble interleukin-2 receptor-α and β2-microglobulin) and survival of the MT-1 tumor-bearing mice, compared with all other treatment groups (P<0.05). Improved therapeutic efficacy obtained by combining compound E, bortezomib and romidepsin supports a clinical trial of this combination in the treatment of ATL.

  2. Structure-activity relationship of 9-methylstreptimidone, a compound that induces apoptosis selectively in adult T-cell leukemia cells.

    PubMed

    Takeiri, Masatoshi; Ota, Eisuke; Nishiyama, Shigeru; Kiyota, Hiromasa; Umezawa, Kazuo

    2012-01-01

    We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells.

  3. Long-term exposure to decabrominated diphenyl ether impairs CD8 T-cell function in adult mice

    PubMed Central

    Zeng, Weihong; Wang, Ying; Liu, Zhicui; Khanniche, Asma; Hu, Qingliang; Feng, Yan; Ye, Weiyi; Yang, Jianglong; Wang, Shujun; Zhou, Lin; Shen, Hao; Wang, Yan

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) at doses of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine (IFN-γ, IL-2 and TNF-α) production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenes expressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice. PMID:24705197

  4. Quantitative evaluation of T-cell response after specific antigen stimulation in active and latent tuberculosis infection in adults and children.

    PubMed

    Latorre, Irene; De Souza-Galvão, Malú; Ruiz-Manzano, Juan; Lacoma, Alicia; Prat, Cristina; Fuenzalida, Loreto; Altet, Neus; Ausina, Vicente; Domínguez, Jose

    2009-11-01

    We have evaluated the quantitative T-cell response after specific Mycobacterium tuberculosis antigen stimulation in active tuberculosis (TB) and latent TB infection (LTBI) patients. In adults, the median number of T cells after RD1 antigen stimulation was significantly higher in active TB patients than in LTBI patients. In children, the number of responder T cells against the specific antigens was higher in active TB than in LTBI patients, although the differences were not significant. In summary, in patients with suspected clinical TB, although there is overlapping in the number of responder T cells between both groups, a T-cell count above the described threshold could suggest active TB, especially in patients with a high probability of having active TB and low probability of having LTBI. In addition, the results are consistent with the current evidence that T-cell response may indicate mycobacterial burden and disease activity.

  5. Symptom Severity Predicts Degree of T Cell Activation In Adult Women Following Childhood Maltreatment

    PubMed Central

    Lemieux, Andrine; Coe, Christopher L.; Carnes, Molly

    2008-01-01

    Although depression is often associated with a reduction in cellular immune responses, other types of emotional disturbance and psychopathology can activate certain aspects of immunity. Activation markers on T cells, in particular, have been found to be elevated in post-traumatic stress states. However, little is known about the relationship between the severity of PTSD symptoms and the degree of change in T cell phenotypes, or about the potential role of neuroendocrine factors in mediating the association. Twenty-four women with a history of sexual trauma during childhood, including 11 who met diagnostic criteria for PTSD, were compared to 12 age-matched, healthy women without a history of maltreatment. The women provided fasted blood samples for enumeration of cell subsets by immunofluorescence and 24-hour urine samples for analysis of catecholamine and cortisol levels. The percent of T cells expressing CD45RA, an early activation marker, was higher in the PTSD diagnosed women, and the levels correlated positively with intrusive symptoms and negatively with avoidant symptoms. These alterations in cell surface markers did not appear to be mediated by norepinephrine (NE) or cortisol, making them a distinctive and independent biomarker of arousal and disturbance in PTSD. PMID:18396007

  6. Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional.

    PubMed

    Sun, Wenji; Wang, Yi; East, James E; Kimball, Amy S; Tkaczuk, Katherine; Kesmodel, Susan; Strome, Scott E; Webb, Tonya J

    2015-03-01

    Invariant natural killer T (iNKT) cells constitute an important subset of T cells that can both directly and indirectly mediate anti-tumor immunity. However, cancer patients have a reduction in both iNKT cell number and function, and these deficits limit the potential clinical application of iNKT cells for cancer therapy. To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from bone marrow-derived adult hematopoietic stem-progenitor cells (HSPC). Our data demonstrate that co-culture of HSPC with OP9-DL1 stromal cells, results in a functional CD3(+) T cell population. These T cells can be further differentiated into iNKT cells by secondary culture with CD1d-Ig-based artificial antigen-presenting cells (aAPC). Importantly, these in vitro-generated iNKT cells are functional, as demonstrated by their ability to proliferate and secrete IFN-γ and GM-CSF following stimulation. PMID:25569376

  7. Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional

    PubMed Central

    Sun, Wenji; Wang, Yi; East, James E.; Kimball, Amy S.; Tkaczuk, Katherine; Kesmodel, Susan; Strome, Scott E.; Webb, Tonya J.

    2014-01-01

    Invariant natural killer T (iNKT) cells constitute an important subset of T cells that can both directly and indirectly mediate anti-tumor immunity. However, cancer patients have a reduction in both iNKT cell number and function, and these deficits limit the potential clinical application of iNKT cells for cancer therapy. To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from bone marrow-derived adult hematopoietic stem-progenitor cells (HSPC). Our data demonstrate that co-culture of HSPC with OP9-DL1 stromal cells, results in a functional CD3+ T cell population. These T cells can be further differentiated into iNKT cells by secondary culture with CD1d-Ig-based artificial antigen-presenting cells (aAPC). Importantly, these in vitro-generated iNKT cells are functional, as demonstrated by their ability to proliferate and secrete IFN-γ and GM-CSF following stimulation. PMID:25569376

  8. Inhibition of proliferation by agricultural plant extracts in seven human adult T-cell leukaemia (ATL)-related cell lines.

    PubMed

    Kai, Hisahiro; Akamatsu, Ena; Torii, Eri; Kodama, Hiroko; Yukizaki, Chizuko; Sakakibara, Yoichi; Suiko, Masahito; Morishita, Kazuhiro; Kataoka, Hiroaki; Matsuno, Koji

    2011-07-01

    Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I) infection and is resistant to conventional chemotherapy. We evaluated the inhibitory effects of agricultural plants on the proliferation of seven ATL-related human leukaemia cells, using three ATL cell lines (ED, Su9T01 and S1T), two human T-cell lines transformed by HTLV-I infection (HUT-102 and MT-2) and two HTLV-I-negative human T-cell acute lymphoblastic leukaemia cell lines (Jurkat and MOLT-4). A total of 52 samples of 80% ethanol extracts obtained from 30 types of agricultural plants were examined. On the basis of IC(50) values, we selected samples with greater activity than genistein, which was used as a positive control. The highest inhibitory effect was observed with extracts from leaves of Vaccinium virgatum Aiton (blueberry) on four cell lines (ED, Su9T01, HUT-102 and Jurkat); seeds of Momordica charantia L. (bitter gourd) exhibited the second highest activity. The bitter gourd seeds suppressed the proliferation of three cell lines (Su9T01, HUT-102 and Jurkat). The extracts from edible parts of Ipomea batatas LAM. (sweet potato), edible parts of Colocasia esculenta (L.) Schott (taro), skin of taro and seeds of Prunus mume Sieb. et Zucc. (mume) showed markedly greater inhibitory effects on Su9T01 than genistein. These findings suggest that ATL-preventative bioactive compounds may exist in these agricultural plants, which are considered to be functional foods. PMID:21293936

  9. Incidence of antibody to adult T-cell leukemia-virus-associated antigen among T-cell malignancies in the Kyoto District, with a report of two unusual cases.

    PubMed

    Kita, K; Nasu, K; Kamesaki, H; Fukuhara, S; Nishikori, M; Uchino, H; Hanaoka, M

    1983-01-01

    Titration of antibody to adult T-cell leukemia (ATL)-virus-associated antigen (ATLA) is of much help for diagnosing ATL, because almost all patients with ATL are seropositive even in an ATL-nonendemic area such as Kyoto. In T-cell lymphoma, anti-ATLA antibody was thought to be related to the birthplace of the patients and the epidermotropism of their skin lesions, but it was not confirmative because the number of cases was so small. We present here two curious cases of anti-ATLA-negative T-cell leukemia/lymphoma. A 53-yr-old man, born in a nonendemic area, had manifestations similar to those of ATL except for the lack of skin involvement, but the morphology of his leukemic cells was less like that of ATL cells than that of prolymphocytic leukemia cells. Therefore, his leukemia was not diagnosed as ATL. A 52-yr-old woman, whose parents' hometown was in an endemic area, showed typical manifestations of nonleukemic T-cell lymphoma, and her biopsied lymph node was compatible with diffuse, pleomorphic lymphoma histologically. In the latter patient, the negative anti-ATLA finding might be due to titration sensitivity. Therefore, the clinical and hematologic features are still informative for distinguishing ATL from other T-cell malignancies.

  10. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

    PubMed Central

    Giam, Chou-Zen; Semmes, Oliver John

    2016-01-01

    HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10–20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%–5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling—the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)—to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided. PMID:27322308

  11. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ.

    PubMed

    Giam, Chou-Zen; Semmes, Oliver John

    2016-01-01

    HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10-20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%-5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling-the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)-to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided. PMID:27322308

  12. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ.

    PubMed

    Giam, Chou-Zen; Semmes, Oliver John

    2016-06-16

    HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10-20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%-5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling-the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)-to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided.

  13. Few Foxp3⁺ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity.

    PubMed

    Mayer, Christian T; Ghorbani, Peyman; Kühl, Anja A; Stüve, Philipp; Hegemann, Maike; Berod, Luciana; Gershwin, M Eric; Sparwasser, Tim

    2014-10-01

    Foxp3 specifies the Treg cell lineage and is indispensable for immune tolerance. Accordingly, rare Foxp3 mutations cause lethal autoimmunity. The mechanisms precipitating more prevalent human autoimmune diseases are poorly understood, but involve a combination of genetic and environmental factors. Many autoimmune diseases associate with a partial Treg-cell dysfunction, yet mouse models reflecting such complex pathophysiological processes are rare. Around 95% of Foxp3(+) Treg cells can be specifically depleted in bacterial artifical chromosome (BAC)-transgenic Depletion of REGulatory T cells (DEREG) mice through diphtheria toxin (DT) treatment. However, Treg-cell depletion fails to cause autoimmunity in adult DEREG mice for unclear reasons. By crossing Foxp3(GFP) knock-in mice to DEREG mice, we introduced additional genetic susceptibility that does not affect untreated mice. Strikingly, DT treatment of DEREG × Foxp3(GFP) mice rapidly causes autoimmunity characterized by blepharitis, tissue damage, and autoantibody production. This inflammatory disease is associated with augmented T-cell activation, increased Th2 cytokine production and myeloproliferation, and is caused by defective Treg-cell homeostasis, preventing few DT-insensitive Treg cells from repopulating the niche after Treg-cell depletion. Our study provides important insights into self-tolerance. We further highlight DEREG × Foxp3(GFP) mice as a model to investigate the role of environmental factors in precipitating autoimmunity. This may help to better understand and treat human autoimmunity. PMID:25042334

  14. Effects of Violent-Video-Game Exposure on Aggressive Behavior, Aggressive-Thought Accessibility, and Aggressive Affect Among Adults With and Without Autism Spectrum Disorder.

    PubMed

    Engelhardt, Christopher R; Mazurek, Micah O; Hilgard, Joseph; Rouder, Jeffrey N; Bartholow, Bruce D

    2015-08-01

    Recent mass shootings have prompted the idea among some members of the public that exposure to violent video games can have a pronounced effect on individuals with autism spectrum disorder (ASD). Empirical evidence for or against this claim has been missing, however. To address this issue, we assigned adults with and without ASD to play a violent or nonviolent version of a customized first-person shooter video game. After they played the game, we assessed three aggression-related outcome variables (aggressive behavior, aggressive-thought accessibility, and aggressive affect). Results showed strong evidence that adults with ASD, compared with typically developing adults, are not differentially affected by acute exposure to violent video games. Moreover, model comparisons provided modest evidence against any effect of violent game content whatsoever. Findings from this experiment suggest that societal concerns that exposure to violent games may have a unique effect on adults with autism are not supported by evidence. PMID:26113064

  15. Effects of Violent-Video-Game Exposure on Aggressive Behavior, Aggressive-Thought Accessibility, and Aggressive Affect Among Adults With and Without Autism Spectrum Disorder.

    PubMed

    Engelhardt, Christopher R; Mazurek, Micah O; Hilgard, Joseph; Rouder, Jeffrey N; Bartholow, Bruce D

    2015-08-01

    Recent mass shootings have prompted the idea among some members of the public that exposure to violent video games can have a pronounced effect on individuals with autism spectrum disorder (ASD). Empirical evidence for or against this claim has been missing, however. To address this issue, we assigned adults with and without ASD to play a violent or nonviolent version of a customized first-person shooter video game. After they played the game, we assessed three aggression-related outcome variables (aggressive behavior, aggressive-thought accessibility, and aggressive affect). Results showed strong evidence that adults with ASD, compared with typically developing adults, are not differentially affected by acute exposure to violent video games. Moreover, model comparisons provided modest evidence against any effect of violent game content whatsoever. Findings from this experiment suggest that societal concerns that exposure to violent games may have a unique effect on adults with autism are not supported by evidence.

  16. Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

    PubMed Central

    Tomita, Mariko; Semenza, Gregg L.; Michiels, Canine; Matsuda, Takehiro; Uchihara, Jun-Nosuke; Okudaira, Taeko; Tanaka, Yuetsu; Taira, Naoya; Ohshiro, Kazuiku; Mori, Naoki

    2007-01-01

    HTLV-1 (human T-cell leukaemia virus type 1) is the causative agent for ATL (adult T-cell leukaemia). HTLV-1 Tax can activate the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway, which is responsible for survival of HTLV-1-infected T-cells. HIFs (hypoxia-inducible factors) are transcriptional regulators that play a central role in the response to hypoxia. Overexpression of HIF-1α in many cancers is associated with a poor response to treatment and increased patient mortality. Our objectives in the present study were to investigate whether HIF-1 was activated in HTLV-1-infected T-cells and to elucidate the molecular mechanisms of HIF-1 activation by focusing on the PI3K/Akt signalling pathway. We detected a potent pathway that activated HIF-1 in the HTLV-1-infected T-cells under a normal oxygen concentration. Enhanced HIF-1α protein expression and HIF-1 DNA-binding activity were exhibited in HTLV-1-infected T-cell lines. Knockdown of HIF-1α by siRNA (small interfering RNA) suppressed the growth and VEGF (vascular endothelial growth factor) expression of the HTLV-1-infected T-cell line. HIF-1 protein accumulation and transcriptional activity were enhanced by Tax, which was inhibited by dominant-negative Akt. Importantly, mutant forms of Tax that are defective in activation of the PI3K/Akt pathway failed to induce HIF-1 transcriptional activity. The PI3K inhibitor LY294002 suppressed HIF-1α protein expression, HIF-1 DNA-binding and HIF-1 transcriptional activity in HTLV-1-infected T-cell lines. In primary ATL cells, HIF-1α protein levels were strongly correlated with levels of phosphorylated Akt. The results of the present study suggest that PI3K/Akt activation induced by Tax leads to activation of HIF-1. As HIF-1 plays a major role in tumour progression, it may represent a molecular target for the development of novel ATL therapeutics. PMID:17576198

  17. IRF1 and NF-kB restore MHC class I-restricted tumor antigen processing and presentation to cytotoxic T cells in aggressive neuroblastoma.

    PubMed

    Lorenzi, Silvia; Forloni, Matteo; Cifaldi, Loredana; Antonucci, Chiara; Citti, Arianna; Boldrini, Renata; Pezzullo, Marco; Castellano, Aurora; Russo, Vincenzo; van der Bruggen, Pierre; Giacomini, Patrizio; Locatelli, Franco; Fruci, Doriana

    2012-01-01

    Neuroblastoma (NB), the most common solid extracranial cancer of childhood, displays a remarkable low expression of Major Histocompatibility Complex class I (MHC-I) and Antigen Processing Machinery (APM) molecules, including Endoplasmic Reticulum (ER) Aminopeptidases, and poorly presents tumor antigens to Cytotoxic T Lymphocytes (CTL). We have previously shown that this is due to low expression of the transcription factor NF-kB p65. Herein, we show that not only NF-kB p65, but also the Interferon Regulatory Factor 1 (IRF1) and certain APM components are low in a subset of NB cell lines with aggressive features. Whereas single transfection with either IRF1, or NF-kB p65 is ineffective, co-transfection results in strong synergy and substantial reversion of the MHC-I/APM-low phenotype in all NB cell lines tested. Accordingly, linked immunohistochemistry expression patterns between nuclear IRF1 and p65 on the one hand, and MHC-I on the other hand, were observed in vivo. Absence and presence of the three molecules neatly segregated between high-grade and low-grade NB, respectively. Finally, APM reconstitution by double IRF1/p65 transfection rendered a NB cell line susceptible to killing by anti MAGE-A3 CTLs, lytic efficiency comparable to those seen upon IFN-γ treatment. This is the first demonstration that a complex immune escape phenotype can be rescued by reconstitution of a limited number of master regulatory genes. These findings provide molecular insight into defective MHC-I expression in NB cells and provide the rational for T cell-based immunotherapy in NB variants refractory to conventional therapy.

  18. Effects of Developmental Activation of the AhR on CD4+ T-Cell Responses to Influenza Virus Infection in Adult Mice

    PubMed Central

    Boule, Lisbeth A.; Winans, Bethany

    2014-01-01

    Background: Epidemiological and animal studies indicate that maternal exposure to pollutants that bind the aryl hydrocarbon receptor (AhR) correlates with poorer ability to combat respiratory infection and lower antibody levels in the offspring. These observations point to an impact on CD4+ T cells. Yet, the consequence of developmental exposure to AhR ligands on the activation and differentiation of CD4+ T cells has not been directly examined. Objectives: Our goal was to determine whether maternal exposure to an AhR ligand directly alters CD4+ T cell differentiation and function later in life. Methods: C57BL/6 mice were exposed to a prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in utero and via suckling. We then measured CD4+ T-cell activation and differentiation into distinct effector populations in adult offspring that were infected with influenza A virus (IAV). Reciprocal adoptive transfers were used to define whether modifications in CD4+ T-cell responses resulted from direct effects of developmental TCDD exposure on CD4+ T cells. Results: Developmental exposure skewed CD4+ T-cell responses to IAV infection. We observed fewer virus-specific, activated CD4+ T cells and a reduced frequency of conventional CD4+ effector-cell subsets. However, there was an increase in regulatory CD4+ T cells. Direct effects of AhR activation on CD4+ T cells resulted in impaired differentiation into conventional effector subsets; this defect was transferred to mice that had not been developmentally exposed to TCDD. Conclusions: Maternal exposure to TCDD resulted in durable changes in the responsive capacity and differentiation of CD4+ T cells in adult C57BL/6 mice. Citation: Boule LA, Winans B, Lawrence BP. 2014. Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice. Environ Health Perspect 122:1201–1208; http://dx.doi.org/10.1289/ehp.1408110 PMID:25051576

  19. Identifying protective Streptococcus pyogenes vaccine antigens recognized by both B and T cells in human adults and children

    PubMed Central

    Mortensen, Rasmus; Nissen, Thomas Nørrelykke; Fredslund, Sine; Rosenkrands, Ida; Christensen, Jan Pravsgaard; Andersen, Peter; Dietrich, Jes

    2016-01-01

    No commercial vaccine exists against Group A streptococci (GAS; Streptococcus pyogenes) and only little is known about anti-GAS protective immunity. In our effort to discover new protective vaccine candidates, we selected 21 antigens based on an in silico evaluation. These were all well-conserved among different GAS strains, upregulated in host-pathogen interaction studies, and predicted to be extracellular or associated with the surface of the bacteria. The antigens were tested for both antibody recognition and T cell responses in human adults and children. The antigenicity of a selected group of antigens was further validated using a high-density peptide array technology that also identified the linear epitopes. Based on immunological recognition, four targets were selected and tested for protective capabilities in an experimental GAS infection model in mice. Shown for the first time, three of these targets (spy0469, spy1228 and spy1801) conferred significant protection whereas one (spy1643) did not. PMID:26911649

  20. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia.

    PubMed

    Simon, Camille; Chagraoui, Jalila; Krosl, Jana; Gendron, Patrick; Wilhelm, Brian; Lemieux, Sébastien; Boucher, Geneviève; Chagnon, Pierre; Drouin, Simon; Lambert, Raphaëlle; Rondeau, Claude; Bilodeau, Annie; Lavallée, Sylvie; Sauvageau, Martin; Hébert, Josée; Sauvageau, Guy

    2012-04-01

    In this study, we show the high frequency of spontaneous γδ T-cell leukemia (T-ALL) occurrence in mice with biallelic deletion of enhancer of zeste homolog 2 (Ezh2). Tumor cells show little residual H3K27 trimethylation marks compared with controls. EZH2 is a component of the PRC2 Polycomb group protein complex, which is associated with DNA methyltransferases. Using next-generation sequencing, we identify alteration in gene expression levels of EZH2 and acquired mutations in PRC2-associated genes (DNMT3A and JARID2) in human adult T-ALL. Together, these studies document that deregulation of EZH2 and associated genes leads to the development of mouse, and likely human, T-ALL.

  1. Co-existence of PHF6 and NOTCH1 mutations in adult T-cell acute lymphoblastic leukemia

    PubMed Central

    LI, MIN; XIAO, LICHAN; XU, JINGYAN; ZHANG, RUN; GUO, JINGJING; OLSON, JUSTIN; WU, YUJIE; LI, JIANYONG; SONG, CHUNHUA; GE, ZHENG

    2016-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) results from the collaboration of multiple genetic abnormalities in the transformation of T-cell progenitors. Plant homeodomain finger protein 6 (PHF6) has recently been established as a key tumor suppressor, which is mutated in T-ALL; however, the clinical significance of PHF6 mutations has not been fully determined in adult T-ALL. In the present study, amplification of the PHF6 exons was performed, followed by DNA sequencing to identify the genomic mutations and examine the expression of PHF6 in adult patients with T-ALL. The correlation between PHF6 mutations and clinical features was also analyzed using a χ2 test, and between PHF6 mutations and survival curve using the Kaplan-Meier methods. PHF6 mutations were detected in 27.1% of the Chinese adults with T-ALL (16/59), 10 of which were found to be novel mutations. A significantly lower expression level of PHF6 was observed in T-ALL patients with PHF6 mutations compared with those without mutations. Of the observed mutations in PHF6, 6/16 were frame-shift mutations, indicating a PHF6 dysfunction in those patients. Of note, PHF6 mutations were found to be significantly associated with older age, lower hemoglobin levels, higher frequency of CD13 positivity and higher incidence of splenomegaly or lymphadenopathy. Furthermore, PHF6 mutations were found to be significantly correlated with Notch homolog 1, translocation-associated (Drosophila) (NOTCH1) mutations. The patients with T-ALL with co-existence of the two mutations had a significantly shorter event-free survival and a poor prognosis. The present results indicated that PHF6 is inactivated in adult T-ALL, due to its low expression and mutations. The present data indicated the synergistic effect of PHF6 and NOTCH1 mutations, as well as their co-existence, on the oncogenesis of adult T-ALL, and their potential as a prognostic marker for the disease. PMID:27347093

  2. Maturation and Mip-1β Production of Cytomegalovirus-Specific T Cell Responses in Tanzanian Children, Adolescents and Adults: Impact by HIV and Mycobacterium tuberculosis Co-Infections.

    PubMed

    Portevin, Damien; Moukambi, Félicien; Mpina, Maxmillian; Bauer, Asli; Haraka, Frederick; Chachage, Mkunde; Metzger, Philipp; Saathoff, Elmar; Clowes, Petra; Ntinginya, Nyanda E; Rachow, Andrea; Hoelscher, Michael; Reither, Klaus; Daubenberger, Claudia A; Geldmacher, Christof

    2015-01-01

    It is well accepted that aging and HIV infection are associated with quantitative and functional changes of CMV-specific T cell responses. We studied here the expression of Mip-1β and the T cell maturation marker CD27 within CMVpp65-specific CD4(+) and CD8(+) T cells in relation to age, HIV and active Tuberculosis (TB) co-infection in a cohort of Tanzanian volunteers (≤ 16 years of age, n = 108 and ≥ 18 years, n = 79). Independent of HIV co-infection, IFNγ(+) CMVpp65-specific CD4(+) T cell frequencies increased with age. In adults, HIV co-infection further increased the frequencies of these cells. A high capacity for Mip-1β production together with a CD27(low) phenotype was characteristic for these cells in children and adults. Interestingly, in addition to HIV co-infection active TB disease was linked to further down regulation of CD27 and increased capacity of Mip-1β production in CMVpp65-specific CD4+ T cells. These phenotypic and functional changes of CMVpp65-specific CD4 T cells observed during HIV infection and active TB could be associated with increased CMV reactivation rates.

  3. CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL).

    PubMed

    Tasian, Sarah K; Gardner, Rebecca A

    2015-10-01

    Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults. Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major preclinical and clinical priority. Adoptive cellular therapy with patient-derived human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CD19 CAR T cells) is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with multiply relapsed B-ALL. Investigative teams at several major cancer centers are currently conducting phase I clinical trials in children and/or adults with relapsed/refractory B-ALL to assess the safety and to identify the maximally tolerated dose of each group's CD19 CAR T-cell product. All groups have reported major clinical toxicities associated with CD19 CAR T-cell treatment, including cytokine release syndrome (CRS) and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19 CAR T cells persist in vivo. Toxicities have generally been transient or manageable with supportive care measures. Some patients with life-threatening CD19 CAR T-cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T-cell proliferation. Remarkably, 67-90% of children and adults with B-ALL treated with CD19 CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission. The duration of CD19 CAR T cell persistence in vivo has varied appreciably among treated patients and likely reflects differences in the CD19 CAR constructs utilized at each institution. CD19-positive and CD19-negative B-ALL relapses after CD19 CAR T-cell treatment have occurred in some patients. Phase II trials to assess the efficacy of

  4. CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL)

    PubMed Central

    Gardner, Rebecca A.

    2015-01-01

    Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults. Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major preclinical and clinical priority. Adoptive cellular therapy with patient-derived human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CD19 CAR T cells) is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with multiply relapsed B-ALL. Investigative teams at several major cancer centers are currently conducting phase I clinical trials in children and/or adults with relapsed/refractory B-ALL to assess the safety and to identify the maximally tolerated dose of each group’s CD19 CAR T-cell product. All groups have reported major clinical toxicities associated with CD19 CAR T-cell treatment, including cytokine release syndrome (CRS) and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19 CAR T cells persist in vivo. Toxicities have generally been transient or manageable with supportive care measures. Some patients with life-threatening CD19 CAR T-cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T-cell proliferation. Remarkably, 67–90% of children and adults with B-ALL treated with CD19 CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission. The duration of CD19 CAR T cell persistence in vivo has varied appreciably among treated patients and likely reflects differences in the CD19 CAR constructs utilized at each institution. CD19-positive and CD19-negative B-ALL relapses after CD19 CAR T-cell treatment have occurred in some patients. Phase II trials to assess the efficacy

  5. Transformed aggressive γδ-variant T-cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11.2q25.3 and additional aberrations.

    PubMed

    Zhang, Ling; Ramchandren, Radhakrishnan; Papenhausen, Peter; Loughran, Thomas P; Sokol, Lubomir

    2014-09-01

    T-cell large granular lymphocytic leukemia (T-LGLL) is a rare indolent lymphoproliferative disorder characterized by cytopenias, splenomegaly, and various degrees of T-cell lymphocytosis, due to a clonal expansion of CD8-positive cytotoxic T-cells. Phenotypic variants of T-LGLL include CD4(+) /CD8(-) T-cells, with dual CD4(-) /CD8(-) /γδ(+) T-cells being even rarer. Cytogenetic abnormalities in T-LGLL have rarely been reported, and there is scientific debate regarding the existence of aggressive or transformed variants of T-LGLL. We report a patient with T-LGLL, γδ variant, with nearly 20-year-long duration of cytopenias before transformation to an unusual clinical scenario, manifesting with marked lymphocytosis >100 × 10(9) /L and infiltration of lymph nodes, tonsils, and subcutaneous tissue. Single-nucleotide polymorphism assays revealed acquired copy neutral loss of heterozygosity at 17q and deletion of 3p21.31, in addition to trisomy 5, monosomy X, and monosomy 21. These genetic abnormalities provided a better understanding of the molecular nature and the potentiality of disease transformation. PMID:24635703

  6. Interleukin-15 enhances the expansion and function of natural killer T cells from adult peripheral and umbilical cord blood.

    PubMed

    Lin, Syh-Jae; Huang, Ying-Cheng; Cheng, Po-Jen; Lee, Pei-Tzu; Hsiao, Hsiu-Shan; Kuo, Ming-Ling

    2015-12-01

    Invariant natural killer T cells (iNKT cells) are innate-like non-conventional T cells restricted by the CD1d molecule that are unique in their ability to play a pivotal role in immune regulation. Deficient iNKT function has been reported in patients receiving umbilical cord blood (UCB) transplantation. We sought to determine the effect of interleukin (IL)-15 on α-galactosylceramide (α-GalCer)-expanded iNKT cell function from UCB and adult peripheral blood (APB) mononuclear cells (MNCs). Fresh APB and UCB MNCs were cultured with IL-15 (50 ng/ml) in the presence or absence of α-GalCer (100 ng/ml) for 10 days. Cells were harvested for examination of cell yield, apoptosis, cytokine production and cytotoxic function of Vα24(+)/Vβ11(+) iNKT cells. We observed that α-GalCer-expanded APB and UCB iNKT cells and such expansion was further enhanced with IL-15. The percentage of CD3(+)CD56(+) NKT-like cells in both APB and UCB MNCs was increased with IL-15 but not with α-GalCer. Apoptosis of UCB iNKT cells was ameliorated by IL-15. Although APB and UCB iNKT cells secreted lower IFN-γ, it could be enhanced with IL-15. The expression of perforin in APB iNKT cells can also be enhanced with IL-15. UCB Vα24(+)Vβ11(+) iNKT cells further augmented K562 cytotoxicity mediated by IL-15. Taken together, these results demonstrated the relative functional deficiencies of α-GalCer induced UCB iNKT cells, which can be ameliorated by IL-15. Our findings suggest a therapeutic benefit of IL-15 immunotherapy during the post-UCB transplant period when iNKT function remains poor.

  7. Development of the Adult Scale of Hostility and Aggression: Reactive-Proactive (A-SHARP)

    ERIC Educational Resources Information Center

    Matlock, Scott Thomas; Aman, Michael G.

    2011-01-01

    In this study, the authors developed the Adult Scale of Hostility and Aggression Reactive-Proactive (A-SHARP). Sixty-one caregivers rated 512 individuals with intellectual and developmental disabilities on the A-SHARP. Exploratory factor analysis revealed 5 factors on the Problem Scale: (a) Verbal Aggression, (b) Physical Aggression, (c) Hostile…

  8. Nivolumab in Treating Patients With HTLV-Associated T-Cell Leukemia/Lymphoma

    ClinicalTrials.gov

    2016-10-17

    Acute Adult T-Cell Leukemia/Lymphoma; Adult T-Cell Leukemia/Lymphoma; Chronic Adult T-Cell Leukemia/Lymphoma; HTLV-1 Infection; Lymphomatous Adult T-Cell Leukemia/Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Smoldering Adult T-Cell Leukemia/Lymphoma

  9. Gamma-delta t-cell lymphomas.

    PubMed

    Foppoli, Marco; Ferreri, Andrés J M

    2015-03-01

    Gamma-delta T-cell lymphomas are aggressive and rare diseases originating from gamma-delta lymphocytes. These cells, which naturally play a role in the innate, non-specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for <1% of all primary cutaneous lymphomas, occurring in adults with relevant comorbidities. Cutaneous lesions may vary, but its clinical behaviour is usually aggressive and long-term survival is anecdotal. Available literature on gamma-delta T-cell lymphomas is fractioned, mostly consisting of case reports or small cumulative series. Therefore, clinical suspicion and diagnosis are usually delayed, and therapeutic management remains to be established. This review critically analyses available evidence on diagnosis, staging and behaviour of gamma-delta T-cell lymphomas, provides recommendations for therapeutic management in routine practice and discusses relevant unmet clinical needs for future studies.

  10. The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL.

    PubMed

    Grossmann, Vera; Haferlach, Claudia; Weissmann, Sandra; Roller, Andreas; Schindela, Sonja; Poetzinger, Franziska; Stadler, Kathrin; Bellos, Frauke; Kern, Wolfgang; Haferlach, Torsten; Schnittger, Susanne; Kohlmann, Alexander

    2013-04-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous disease. The diagnosis is predominantly based on immunophenotyping. In addition to known cytogenetic abnormalities molecular mutations were recently identified. Here, 90 adult T-ALL cases were investigated for mutations in NOTCH1, FBXW7, PHF6, CDKN2A, DNMT3A, FLT3, PTEN, and RUNX1 using 454 next-generation amplicon sequencing and melting curve analyses. These data were further complemented by FISH, chromosome banding, array CGH, and CDKN2B promoter methylation analyses. NOTCH1 was the most frequently mutated gene with a 71.1% frequency followed by FBXW7 (18.9%), PHF6 (39.5%), DNMT3A (17.8%), RUNX1 (15.5%), PTEN (10.0%), CDKN2A (4.4%), FLT3-ITD (2.2%), and FLT3-TKD (1.1%). In total, 84/90 (93.3%) cases harbored at least one mutation. Combining these data with CDKN2A/B deletions and CDKN2B methylation status, we detected minimum one aberration in 89/90 (98.9%) patients. Survival analyses revealed the subtype as defined by the immunophenotype as the strongest independent prognostic factor. When restricting the survival analysis to the early T-ALL subtype, a strong association of RUNX1 (P = 0.027) and DNMT3A (P = 0.005) mutations with shorter overall survival was observed. In conclusion, RUNX1 and DNMT3A are frequently mutated in T-ALL and are associated with poor prognosis in early T-ALL.

  11. In Vitro T-Cell Generation From Adult, Embryonic, and Induced Pluripotent Stem Cells: Many Roads to One Destination.

    PubMed

    Smith, Michelle J; Webber, Beau R; Mohtashami, Mahmood; Stefanski, Heather E; Zúñiga-Pflücker, Juan Carlos; Blazar, Bruce R

    2015-11-01

    T lymphocytes are critical mediators of the adaptive immune system and have the capacity to serve as therapeutic agents in the areas of transplant and cancer immunotherapy. While T cells can be isolated and expanded from patients, T cells derived in vitro from both hematopoietic stem/progenitor cells (HSPCs) and human pluripotent stem cells (hPSCs) offer great potential advantages in generating a self-renewing source of T cells that can be readily genetically modified. T-cell differentiation in vivo is a complex process requiring tightly regulated signals; providing the correct signals in vitro to induce T-cell lineage commitment followed by their development into mature, functional, single positive T cells, is similarly complex. In this review, we discuss current methods for the in vitro derivation of T cells from murine and human HSPCs and hPSCs that use feeder-cell and feeder-cell-free systems. Furthermore, we explore their potential for adoption for use in T-cell-based therapies.

  12. Unrelated cord blood transplantation for patients with adult T-cell leukemia/lymphoma: experience at a single institute.

    PubMed

    Nakamura, Takayuki; Oku, Eijiro; Nomura, Kei; Morishige, Satoshi; Takata, Yuka; Seki, Ritsuko; Imamura, Rie; Osaki, Koichi; Hashiguchi, Michitoshi; Yakushiji, Kazuaki; Mouri, Fumihiko; Mizuno, Shinichi; Yoshimoto, Koji; Ohshima, Koichi; Nagafuji, Koji; Okamura, Takashi

    2012-11-01

    We report the results of unrelated cord blood transplantation (UCBT) for patients with adult T-cell leukemia/lymphoma (ATLL) conducted in our single institute. Ten patients with ATLL (nine acute and one lymphoma-type) received UCBT during the period from August 2003 to July 2011. The median age at the time of diagnosis of ATLL was 51 years (range 37-64). The median period from diagnosis of ATLL to UCBT was 130 days (range 94-344). Conditioning regimens were myeloablative for six and reduced intensity for four. The median number of infused nucleated cells and CD34 positive cells were 2.52 × 10(7)/kg and 1.04 × 10(5)/kg, respectively. There was no engraftment failure. Three patients developed grade II acute graft versus host disease, and four developed grade III. The estimated 2-year overall survival was 40 % (95 % CI 12-67 %). Four of six chemosensitive patients prior to UCBT survived for 1035, 793, 712, and 531 days post-UCBT, respectively. There were no survivors among the four chemorefractory patients prior to UCBT. Our data indicates that UCBT is feasible and provides long-term survival in patients with chemosensitive ATLL. PMID:22976114

  13. Thymic hyperplasia after chemotherapy in adults with mature B cell lymphoma and its influence on thymic output and CD4(+) T cells repopulation.

    PubMed

    Sun, Dao-Ping; Jin, Hui; Ding, Chong-Yang; Liang, Jin-Hua; Wang, Li; Fan, Lei; Wu, Yu-Jie; Xu, Wei; Li, Jian-Yong

    2016-05-01

    To investigate the thymic regenerative potential in adults accepting chemotherapy for lymphoma. The dynamics of thymic activity in 54 adults from baseline to 12 mo post-chemotherapy was analyzed by assessing thymic structural changes with serial computed tomography (CT) scans, and correlating these with measurements of thymic output by concurrent analysis of single-joint (sj) T-cell receptor excision circles (sjTREC) and CD31(+) recent thymic emigrants (RTE) in peripheral blood. Furthermore, the consequence of thymic renewal on peripheral CD4(+) T cell recovery after chemotherapy was evaluated. Time-dependent changes of thymic size and thymic output assessed by both sjTREC levels and CD31(+) RTE counts in peripheral blood were observed during and after chemotherapy. Enlargement of thymus over baseline following chemotherapy regarded as rebound thymic hyperplasia (TH) was identified in 20 patients aged 18-53 y (median 33 y). By general linear models repeated measure analysis, it was found that, patients with TH (n = 20) had a faster recovery of sjTREC levels and CD31(+) RTE counts after chemotherapy than patients with comparable age, gender, diagnosis, disease stage, thymic volume and output function at baseline but without TH (n = 18) (p = 0.035, 0.047); besides, patients with TH had a faster repopulation of both naïve CD4(+) T cell and natural regulatory CD4(+) T cell subsets than those without TH (p = 0.042, 0.038). These data suggested that adult thymus retains the capacity of regeneration after chemotherapy, especially in young adults. The presence of TH could contribute to the renewal of thymopoiesis and the replenishment of peripheral CD4(+) T cell pool following chemotherapy in adults. PMID:27467956

  14. A Case of Pneumonia Caused by Pneumocystis Jirovecii and Cryptococcus Neoformans in a Patient with HTLV-1 Associated Adult T- Cell Leukemia/Lymphoma: Occam's Razor Blunted.

    PubMed

    Desai, Anish; Fe, Alexander; Desai, Amishi; Ilowite, Jonathan; Cunha, Burke A; Mathew, Joseph P

    2016-02-01

    Adult T-cell leukemia/lymphoma (ATLL) is usually preceded by infection with human T-cell lymphotropic virus I (HTLV-I). Patients with ATLL frequently get opportunistic infections of the lungs, intestines, and central nervous system. Pneumocystis pneumonia is commonly known as an AIDS defining illness. Grocott's methenamine silver stain of bronchoalveolar lavage (BAL) samples obtained via bronchoscopy remain the gold standard for diagnosis. Pulmonary cryptococcosis is seen in patients with T-cell deficiencies and a diagnosis is made by culture of sputum, BAL, or occasionally of pleural fluid. We present the second case of coinfection with these two organisms in a patient with ATLL who was successfully treated with trimethoprim-sulfamethoxazole, corticosteroids, and fluconazole. We illustrate the need for high clinical vigilance for seeking out an additional diagnosis, especially in immunocompromised patients if they are not improving despite receiving appropriate treatment. PMID:27024978

  15. T-cell-replete haploidentical transplantation versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis.

    PubMed

    Gorin, Norbert-Claude; Labopin, Myriam; Piemontese, Simona; Arcese, William; Santarone, Stella; Huang, He; Meloni, Giovanna; Ferrara, Felicetto; Beelen, Dietrich; Sanz, Miguel; Bacigalupo, Andrea; Ciceri, Fabio; Mailhol, Audrey; Nagler, Arnon; Mohty, Mohamad

    2015-04-01

    Adult patients with acute leukemia in need of a transplant but without a genoidentical donor are usually considered upfront for transplantation with stem cells from any other allogeneic source, rather than autologous stem cell transplantation. We used data from the European Society for Blood and Marrow Transplantation and performed a matched pair analysis on 188 T-cell-replete haploidentical and 356 autologous transplants done from January 2007 to December 2012, using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. "Haploidentical expert" centers were defined as having reported more than five haploidentical transplants for acute leukemia (median value for the study period). The median follow-up was 28 months. Multivariate analyses, including type of transplant categorized into three classes ("haploidentical regular", "haploidentical expert" and autologous), conditioning intensity (reduced intensity versus myeloablative conditioning) and the random effect taking into account associations related to matching, showed that non-relapse mortality was higher following haploidentical transplants in expert (HR: 4.7; P=0.00004) and regular (HR: 8.98; P<10(-5)) centers. Relapse incidence for haploidentical transplants was lower in expert centers (HR:0.39; P=0.0003) but in regular centers was similar to that for autologous transplants. Leukemia-free survival and overall survival rates were higher following autologous transplantation than haploidentical transplants in regular centers (HR: 1.63; P=0.008 and HR: 2.31; P=0.0002 respectively) but similar to those following haploidentical transplants in expert centers. We conclude that autologous stem cell transplantation should presently be considered as a possible alternative to haploidentical transplantation in regular centers that have not developed a specific expert program. PMID:25637051

  16. T-cell-replete haploidentical transplantation versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis.

    PubMed

    Gorin, Norbert-Claude; Labopin, Myriam; Piemontese, Simona; Arcese, William; Santarone, Stella; Huang, He; Meloni, Giovanna; Ferrara, Felicetto; Beelen, Dietrich; Sanz, Miguel; Bacigalupo, Andrea; Ciceri, Fabio; Mailhol, Audrey; Nagler, Arnon; Mohty, Mohamad

    2015-04-01

    Adult patients with acute leukemia in need of a transplant but without a genoidentical donor are usually considered upfront for transplantation with stem cells from any other allogeneic source, rather than autologous stem cell transplantation. We used data from the European Society for Blood and Marrow Transplantation and performed a matched pair analysis on 188 T-cell-replete haploidentical and 356 autologous transplants done from January 2007 to December 2012, using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. "Haploidentical expert" centers were defined as having reported more than five haploidentical transplants for acute leukemia (median value for the study period). The median follow-up was 28 months. Multivariate analyses, including type of transplant categorized into three classes ("haploidentical regular", "haploidentical expert" and autologous), conditioning intensity (reduced intensity versus myeloablative conditioning) and the random effect taking into account associations related to matching, showed that non-relapse mortality was higher following haploidentical transplants in expert (HR: 4.7; P=0.00004) and regular (HR: 8.98; P<10(-5)) centers. Relapse incidence for haploidentical transplants was lower in expert centers (HR:0.39; P=0.0003) but in regular centers was similar to that for autologous transplants. Leukemia-free survival and overall survival rates were higher following autologous transplantation than haploidentical transplants in regular centers (HR: 1.63; P=0.008 and HR: 2.31; P=0.0002 respectively) but similar to those following haploidentical transplants in expert centers. We conclude that autologous stem cell transplantation should presently be considered as a possible alternative to haploidentical transplantation in regular centers that have not developed a specific expert program.

  17. Alterations in Activation, Cytotoxic Capacity and Trafficking Profile of Peripheral CD8 T Cells in Young Adult Binge Drinkers

    PubMed Central

    Zaldivar Fujigaki, José Luis; Arroyo Valerio, América Guadalupe; López Alvarenga, Juan Carlos; Gutiérrez Reyes, Esperanza Gabriela; Kershenobich, David; Hernández Ruiz, Joselin

    2015-01-01

    Background Excess of alcohol consumption is a public health problem and has documented effects on the immune system of humans and animals. Animal and in vitro studies suggest that alcohol abuse changes CD8 T cell (CD8) characteristics, however it remains unknown if the CD8 profile of binge drinkers is different in terms of activation, trafficking and cytotoxic capacity. Aim To analyze the peripheral CD8 cytotoxic capacity, activation and trafficking phenotypic profile of Mexican young adults with regard to alcohol consumption pattern. Methods 55 Mexican young adults were stratified as Light (20), Intermediate (18) or Binge drinkers (17) according to their reported alcohol consumption pattern. Blood samples were obtained and hematic biometry and liver enzyme analysis were performed. Peripheral CD8 profile was established by expression of Granzyme B (GB), CD137, CD127, CD69, TLR4, PD1, CCR2, CCR4, CCR5 and CXCR4 by FACS. Data was analyzed by ANOVA, posthoc DMS and Tamhane, and principal component analysis (PCA) with varimax rotation, p<0.05. Results The Binge drinking group showed increased γGT together with increased expression of CD69 and reduced expression of TLR4, PD1, CCR2 and CXCR4 in peripheral CD8 cells. Other parameters were also specific to Binge drinkers. PCA established 3 factors associated with alcohol consumption: “Early Activation” represented by CD69 and TLR4 expression in the CD8 population; “Effector Activation” by CD69 expression in CD8 CD127+CD137+ and CD8 CD25+ CD137+; and Trafficking by CXCR4 expression on total CD8 and CD8 GB+CXCR4+, and CCR2 expression on total CD8. Binge drinking pattern showed low expression of Early Activation and Trafficking factors while Light drinking pattern exhibited high expression of Effector Activation factor. Conclusions Alcohol consumption affects the immune phenotype of CD8 cells since binge drinking pattern was found to be associated with high CD69 and low TLR4, CXCR4 and CCR2 expression, which suggest

  18. Risky and aggressive driving in young adults: Personality matters.

    PubMed

    Constantinou, Elena; Panayiotou, Georgia; Konstantinou, Nikos; Loutsiou-Ladd, Anthi; Kapardis, Andreas

    2011-07-01

    Young, novice drivers constitute a disproportionate percentage of fatalities and injuries in road traffic accidents around the world. This study, attempts to identify motivational factors behind risky driving behavior, and examines the role of personality, especially sensation seeking, impulsivity and sensitivity to punishment/reward in predicting negative driving outcomes (accident involvement and traffic offences) among young drivers. Gender and driver's age are additional factors examined in relation to driving outcomes and personality. Adopting the contextual mediated model of traffic accident involvement (Sümer, 2003), the study is based on the theory that personality, age and gender represent distal factors that predict accident involvement indirectly through their relationship with stable tendencies towards aberrant driving behavior. Results from correlations and Structural Equation Modeling using AMOS 6 indicated that direct personality effects on driving outcomes were few, whereas personality had significant correlations with aberrant driving behavior, showing that personality is a distal but important predictor of negative driving outcomes. These high risk traits appear to be at a peak among young male drivers. Thus, personality is important in understanding aggressive and risky driving by young adults and needs to be taken into consideration in designing targeted accident prevention policies.

  19. The relationship between young adults' beliefs about anonymity and subsequent cyber aggression.

    PubMed

    Wright, Michelle F

    2013-12-01

    Anonymity is considered a key motivator for cyber aggression, but few investigations have focused on the connection between anonymity and the subsequent engagement in aggression through the cyber context. The present longitudinal study utilized structural equation modeling to reveal indirect associations between two types of anonymity (i.e., punishment by authority figures and retaliation from the target) and later cyber aggression among 130 young adults. These relationships were examined through the influence of beliefs about not getting caught and not believing in the permanency of online content. Findings indicated that both forms of anonymity were related to cyber aggression 6 months later through two explanatory mechanisms (i.e., confidence with not getting caught and believing online content is not permanent), after controlling for gender and cyber aggression at Time 1. The implications of these findings are discussed, and an appeal for additional research investigating cyber aggression among young adults is given.

  20. The relationship between young adults' beliefs about anonymity and subsequent cyber aggression.

    PubMed

    Wright, Michelle F

    2013-12-01

    Anonymity is considered a key motivator for cyber aggression, but few investigations have focused on the connection between anonymity and the subsequent engagement in aggression through the cyber context. The present longitudinal study utilized structural equation modeling to reveal indirect associations between two types of anonymity (i.e., punishment by authority figures and retaliation from the target) and later cyber aggression among 130 young adults. These relationships were examined through the influence of beliefs about not getting caught and not believing in the permanency of online content. Findings indicated that both forms of anonymity were related to cyber aggression 6 months later through two explanatory mechanisms (i.e., confidence with not getting caught and believing online content is not permanent), after controlling for gender and cyber aggression at Time 1. The implications of these findings are discussed, and an appeal for additional research investigating cyber aggression among young adults is given. PMID:23849002

  1. Effects of oxytocin on aggressive responding in healthy adult men.

    PubMed

    Alcorn, Joseph L; Green, Charles E; Schmitz, Joy; Lane, Scott D

    2015-12-01

    This study investigated the acute effects of oxytocin (OT) on human aggression using a well-established laboratory measure of state (reactive) aggression to test the hypothesis that OT would decrease the frequency of aggressive responding. In a within-subject design, 17 healthy male volunteers received placebo or 24 IU of intranasal OT. Aggression was measured using the Point Subtraction Aggression Paradigm at 30 min before and 30, 60, and 90 min after dose. Acute OT did not produce a significant main effect on aggressive behavior. OT attenuated the expected rise in diastolic blood pressure from morning to early afternoon observed under placebo, providing a possible indication of biological activity. Examination of individual differences showed that aggressive responding following OT dosing (but not placebo) was positively correlated with psychometric measures of interpersonal manipulation and anger (Pearson's r=0.57), indicating that higher scores on these antisocial personality traits were related to increased aggressive behavior following OT administration. These preliminary results stand in contrast to previous work on the prosocial effects of OT and highlight the need for further understanding of individual differences in aggression following OT administration. Such individual differences may have implications for the therapeutic use of OT in individuals with psychiatric disorders and dysfunctional social behavior. PMID:26241153

  2. Immune competence of cancer-reactive T cells generated de novo in adult tumor-bearing mice.

    PubMed

    May, Kenneth F; Lute, Kenneth; Kocak, Ergun; Abdessalam, Shahab; Yin, Lijie; Li, Ou; Guan, Zhen; Philips, Gary; Zheng, Pan; Liu, Yang

    2007-01-01

    The impact of timing of antigen introduction into fetus and neonates leads to the suggestion that pre-existing antigens are tolerogenic to immunocompetent cells generated thereafter. This hypothesis predicts that in patients with cancer who are undergoing bone marrow transplantation, newly produced T cells with specificity for pre-existing tumor cells will be inactivated by the tumor antigens in the host. Because the effect of tumor cells on developing cancer-reactive T cells has not been investigated, we set out to systematically analyze the impact of tumor cells in the periphery on the development of tumor-reactive T cells in the thymus and their immunocompetence in the periphery. Our data demonstrate that in the host in which a tumor is established in the periphery, the cancer-reactive T cells develop normally, remain fully immunocompetent, become activated in the periphery, and cause regression of large established tumors. The immunocompetence of T cells generated in an antigen-bearing host is also confirmed in a skin graft transplantation model.

  3. Markers for Aggression in Inpatient Treatment Facilities for Adults with Mild to Borderline Intellectual Disability

    ERIC Educational Resources Information Center

    Tenneij, Nienke H.; Didden, Robert; Stolker, Joost Jan; Koot, Hans M.

    2009-01-01

    In high care settings for persons with intellectual disability (ID) aggressive incidents often occur. Still little is known about factors that are associated with an increased risk for aggressive behavior in clients who are admitted to an inpatient treatment facility. In four inpatient facilities, 108 adults with mild and borderline ID and…

  4. Aggressive Challenging Behaviour in Adults with Intellectual Disability Following Community Resettlement

    ERIC Educational Resources Information Center

    Bhaumik, S.; Watson, J. M.; Devapriam, J.; Raju, L. B.; Tin, N. N.; Kiani, R.; Talbott, L.; Parker, R.; Moore, L.; Majumdar, S. K.; Ganghadaran, S. K.; Dixon, K.; Gupta, A. Das; Barrett, M.; Tyrer, F.

    2009-01-01

    Background: Aggressive challenging behaviour is common in adults with intellectual disability (ID) in long-term care facilities. The government's commitment to the closure of all facilities in England has led to concerns over how to manage this behaviour in the community. The aim of this study was to assess changes in aggressive challenging…

  5. Physical Aggression towards Others in Adults with Learning Disabilities: Prevalence and Associated Factors

    ERIC Educational Resources Information Center

    Tyrer, F.; McGrother, C. W.; Thorp, C. F.; Donaldson, M.; Bhaumik, S.; Watson, J. M.; Hollin, C.

    2006-01-01

    Background: Many people with learning disabilities (LD) show aggressive behaviour, but the extent of the problem and its associated factors and effects are unclear. Methods: A cross-sectional analysis was carried out using interview data from 3065 adults with LD on the Leicestershire LD Register. Physical aggression towards others was defined as…

  6. Detection of an early adult T-cell leukemia-lymphoma clone in lymph nodes with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma involvement.

    PubMed

    Tokunaga, Masahito; Yoshida, Noriaki; Nakano, Nobuaki; Kubota, Ayumu; Takeuchi, Shogo; Takatsuka, Yoshifusa; Seto, Masao; Utsunomiya, Atae

    2016-04-01

    A 58-year-old man was admitted to our hospital with systemic lymphadenopathy and was diagnosed with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL) by lymph node biopsy. Although he was a human T-cell leukemia virus type I (HTLV-1) carrier, Southern blot analysis of the lymph node did not show monoclonal integration of HTLV-1 provirus deoxyribonucleic acid (DNA). He achieved complete remission after chemotherapy and subsequently, autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed. Fifteen months after the auto-PBSCT, abnormal lymphocytes in the peripheral blood gradually increased. Southern blot analysis revealed monoclonal integration of HTLV-1 provirus DNA and monoclonal rearrangement of TRB. He was diagnosed with chronic type adult T-cell leukemia-lymphoma (ATL), which immediately progressed to the acute type. He died of tumor progression despite intensive chemotherapy. We analyzed genomic alterations of the ALCL and ATL cells using array comparative genomic hybridization. We found that the genomic alteration pattern differed between the two diseases. T-cell receptor clonality analysis using polymerase chain reaction (PCR) showed that the T-cell clone of the ATL was present in the lymph nodes with ALCL involvement, but not in peripheral blood. This finding suggests that lymph nodes can serve as a niche for ATL development.

  7. Are tattooed adults really more aggressive and rebellious than those without tattoos?

    PubMed

    Swami, Viren; Gaughan, Helen; Tran, Ulrich S; Kuhlmann, Tim; Stieger, Stefan; Voracek, Martin

    2015-09-01

    One stereotype of people with tattoos is that they are more aggressive and rebellious than people without tattoos. However, studies examining differences in these traits between tattooed and non-tattooed individuals are dated and have returned equivocal results. To re-examine this issue, we asked 378 adults from London, UK, to complete self-report measures of aggression and rebelliousness, and to report the number of tattoos they possessed. Of this sample, 25.7% possessed at least one tattoo, with no sex difference in the distribution of tattoo status. We found that tattooed adults had significantly higher reactive rebelliousness, anger, and verbal aggression than non-tattooed adults. However, effect sizes were small and there were also no significant between-group differences in terms of proactive rebelliousness, physical aggression, and hostility. These results suggest that, while stereotypes may contain a kernel of truth, they likely present an outmoded picture of tattooed adults. PMID:26439666

  8. Are tattooed adults really more aggressive and rebellious than those without tattoos?

    PubMed

    Swami, Viren; Gaughan, Helen; Tran, Ulrich S; Kuhlmann, Tim; Stieger, Stefan; Voracek, Martin

    2015-09-01

    One stereotype of people with tattoos is that they are more aggressive and rebellious than people without tattoos. However, studies examining differences in these traits between tattooed and non-tattooed individuals are dated and have returned equivocal results. To re-examine this issue, we asked 378 adults from London, UK, to complete self-report measures of aggression and rebelliousness, and to report the number of tattoos they possessed. Of this sample, 25.7% possessed at least one tattoo, with no sex difference in the distribution of tattoo status. We found that tattooed adults had significantly higher reactive rebelliousness, anger, and verbal aggression than non-tattooed adults. However, effect sizes were small and there were also no significant between-group differences in terms of proactive rebelliousness, physical aggression, and hostility. These results suggest that, while stereotypes may contain a kernel of truth, they likely present an outmoded picture of tattooed adults.

  9. Kicking the digital dog: a longitudinal investigation of young adults' victimization and cyber-displaced aggression.

    PubMed

    Wright, Michelle F; Li, Yan

    2012-09-01

    Using the general strain theory as a theoretical framework, the present longitudinal study investigated both face-to-face and cyber victimization in relation to cyber-displaced aggression. Longitudinal data were collected from 130 (70 women) young adults who completed measures assessing their victimization (face-to-face and cyber), cyber aggression, and both face-to-face and cyber-displaced aggression. Findings indicated that victimization in both social contexts (face-to-face and cyber) contributed to cyber-displaced aggression 6 months later (Time 2), after controlling for gender, cyber aggression, face-to-face displaced aggression, and cyber-displaced aggression at Time 1. A significant two-way interaction revealed that Time 1 cyber victimization was more strongly related to Time 2 cyber-displaced aggression when young adults had higher levels of face-to-face victimization at Time 1. Implications of these findings are discussed as well as a call for more research investigating displaced aggression in the cyber context.

  10. Rabbit antithymocyte globulin (Thymoglobulin®) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients

    PubMed Central

    Na, Il-Kang; Wittenbecher, Friedrich; Dziubianau, Mikalai; Herholz, Anne; Mensen, Angela; Kunkel, Désirée; Blau, Olga; Blau, Igor; Thiel, Eckhard; Uharek, Lutz; Scheibenbogen, Carmen; Rieger, Kathrin; Thiel, Andreas

    2013-01-01

    Rabbit antithymocyte globulin-Genzyme™ is used to prevent graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Common disadvantages of treatment are infectious complications. The effects of rabbit antithymocyte globulin-Genzyme™ on thymic function have not been well-studied. Multicolor flow cytometry was used to analyze the kinetics of conventional and regulatory T cells in adult patients treated (n=12) or not treated (n=8) with rabbit antithymocyte globulin-Genzyme™ during the first 6 months after allogeneic hematopoietic stem cell transplantation. Patients treated with rabbit antithymocyte globulin-Genzyme™ had almost undetectable levels of recent thymic emigrants (CD45RA+CD31+) of both conventional and regulatory CD4T cells throughout the 6 months after allogeneic hematopoietic stem cell transplantation whereas CD4+CD45RA-memory T cells were less affected, but their levels were also significantly lower than in patients not treated with rabbit antithymocyte globulin-Genzyme™. In vitro, rabbit antithymocyte globulin-Genzyme™ induced apoptosis and cytolysis of human thymocytes, and its cytotoxic effects were greater than those of rabbit antithymocyte globulin-Fresenius™. Rabbit antithymocyte globulin-Genzyme™ in combination with a conditioning regimen strongly impairs thymic recovery of both conventional and regulatory CD4+ T cells. The sustained depletion of conventional and regulatory CD4+T cells carries a high risk of both infections and graft-versus-host disease. Our data indicate that patients treated with rabbit antithymocyte globulin-Genzyme™ could benefit from thymus-protective therapies and that trials comparing this product with other rabbit antithymocyte globulin preparations or lymphocyte-depleting compounds would be informative. PMID:22801968

  11. Mediators of Aggression Among Young Adult Offspring of Depressed Mothers

    PubMed Central

    Keenan-Miller, Danielle; Hammen, Constance; Brennan, Patricia A.

    2010-01-01

    The current paper explores the connection between maternal depression and offspring aggression during the transition to adulthood, expanding the scope of prior research on this topic. Both family-level factors (including parent-child relationship quality and maternal relationship quality) and youth factors (including depression history and social functioning in mid-adolescence) were tested as potential mediators in a longitudinal community sample of 710 youth at ages 15 and 20. The results suggest that maternal depression confers a risk for higher levels of aggressive behavior by offspring at age 20. Structural Equation Models suggested that the association between maternal depression and youth aggression is fully mediated by youth history of depression by mid-adolescence, even when accounting for the stability of aggression between ages 15 and 20. Parent-child relationship quality, youth social functioning, and maternal relationship quality were not unique mediators of this association. Limitations and implications are discussed. PMID:20919790

  12. Human T-cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T-cells.

    PubMed

    Takachi, Takayuki; Takahashi, Masahiko; Takahashi-Yoshita, Manami; Higuchi, Masaya; Obata, Miki; Mishima, Yukio; Okuda, Shujiro; Tanaka, Yuetsu; Matsuoka, Masao; Saitoh, Akihiko; Green, Patrick L; Fujii, Masahiro

    2015-04-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.

  13. T-cell count

    MedlinePlus

    Thymus derived lymphocyte count; T-lymphocyte count; T cell count ... T cells are a type of lymphocyte. Lymphocytes are white blood cells. They make up part of the immune system. T cells help the body fight diseases or harmful ...

  14. Early Entries into Adult Roles: Associations with Aggressive Behavior from Early Adolescence into Young Adulthood

    ERIC Educational Resources Information Center

    Roche, Kathleen M.; Ensminger, Margaret E.; Ialongo, Nicholas; Poduska, Jeanne M.; Kellam, Sheppard G.

    2006-01-01

    This study examines how early entries into adult roles are associated with aggressive and violent behavior occurring from early adolescence to young adulthood among 499 males and 578 females living in low-income, central-city neighborhoods. Among males, engagement in adult roles accounted for the relationship between higher levels of aggressive…

  15. Adults with Intellectual Disabilities: Prevalence, Incidence and Remission of Aggressive Behaviour and Related Factors

    ERIC Educational Resources Information Center

    Cooper, S.-A.; Smiley, E.; Jackson, A.; Finlayson, J.; Allan, L.; Mantry, D.; Morrison, J.

    2009-01-01

    Introduction: Aggressive behaviours can be disabling for adults with intellectual disabilities (ID), with negative consequences for the adult, their family and paid carers. It is surprising how little research has been conducted into the epidemiology of these needs, given the impact they can have. This study investigates point prevalence, 2-year…

  16. Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.

    PubMed

    Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun

    2015-05-01

    Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL. PMID:25612920

  17. Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.

    PubMed

    Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun

    2015-05-01

    Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL.

  18. Parental Physical and Psychological Aggression: Psychological Symptoms in Young Adults

    ERIC Educational Resources Information Center

    Miller-Perrin, Cindy L.; Perrin, Robin D.; Kocur, Jodie L.

    2009-01-01

    Objective: The purpose of the present study was to evaluate the relationship between various levels of parent-child physical violence and psychological symptoms reported by college students, while controlling for demographic variables, severity and frequency of violence, and co-occurrence of parental psychological aggression. Method: Participants…

  19. Early Language Impairment and Young Adult Delinquent and Aggressive Behavior

    ERIC Educational Resources Information Center

    Brownlie, E.B.; Beitchman, Joseph H.; Escobar, Michael; Young, Arlene; Atkinson, Leslie; Johnson, Carla; Wilson, Beth; Douglas, Lori

    2004-01-01

    Clinic and forensic studies have reported high rates of language impairments in conduct- disordered and incarcerated youth. In community samples followed to early adolescence, speech and language impairments have been linked to attention deficits and internalizing problems, rather than conduct problems, delinquency, or aggression. This study…

  20. Giant Septic Lymphadenitis with Marked Gas Formation Caused by Bacteroides fragilis in a Patient with Adult T-cell Leukemia/lymphoma.

    PubMed

    Tomoyose, Takeaki; Nakachi, Sawako; Nishi, Yukiko; Morichika, Kazuho; Tedokon, Iori; Tamaki, Keita; Shimabukuro, Natsuki; Hanashiro, Taeko; Samura, Hironori; Fukushima, Takuya; Masuzaki, Hiroaki

    2015-01-01

    Adult T-cell leukemia/lymphoma (ATL) sometimes causes opportunistic infections. A 53-year-old woman with systemic lymphadenopathies was diagnosed with ATL by inguinal lymph node biopsies and underwent oral chemotherapy. Two months later, high grade fever, lower abdominal pain and lymphadenopathy recurred. Computed tomography revealed the presence of lymphadenopathy with marked gas formation in the pelvic lesion. Blood cultures were suggestive of septic lymphadenitis by Bacteroides fragilis (BF). This represents the first demonstration of giant lymphadenitis with gas formation caused by BF in a patient with ATL. Notably, septic lymphadenitis is pivotal in the differential diagnosis of systemic lymphadenopathy in ATL.

  1. Vaccine adjuvant systems containing monophosphoryl lipid A and QS21 induce strong and persistent humoral and T cell responses against hepatitis B surface antigen in healthy adult volunteers.

    PubMed

    Vandepapelière, Pierre; Horsmans, Yves; Moris, Philippe; Van Mechelen, Marcelle; Janssens, Michel; Koutsoukos, Marguerite; Van Belle, Pascale; Clement, Frédéric; Hanon, Emmanuel; Wettendorff, Martine; Garçon, Nathalie; Leroux-Roels, Geert

    2008-03-01

    A randomised, double-blind study assessing the potential of four adjuvants in combination with recombinant hepatitis B surface antigen has been conducted to evaluate humoral and cell-mediated immune responses in healthy adults after three vaccine doses at months 0, 1 and 10. Three Adjuvant Systems (AS) contained 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and QS21, formulated either with an oil-in-water emulsion (AS02B and AS02V) or with liposomes (AS01B). The fourth adjuvant was CpG oligonucleotide. High levels of antibodies were induced by all adjuvants, whereas cell-mediated immune responses, including cytolytic T cells and strong and persistent CD4(+) T cell response were mainly observed with the three MPL/QS21-containing Adjuvant Systems. The CD4(+) T cell response was characterised in vitro by vigorous lymphoproliferation, high IFN-gamma and moderate IL-5 production. Antigen-specific T cell immune response was further confirmed ex vivo by detection of IL-2- and IFN-gamma-producing CD4(+) T cells, and in vivo by measuring increased levels of IFN-gamma in the serum and delayed-type hypersensitivity (DTH) responses. The CpG adjuvanted vaccine induced consistently lower immune responses for all parameters. All vaccine adjuvants were shown to be safe with acceptable reactogenicity profiles. The majority of subjects reported local reactions at the injection site after vaccination while general reactions were recorded less frequently. No vaccine-related serious adverse event was reported. Importantly, no increase in markers of auto-immunity and allergy was detected over the whole study course. In conclusion, the Adjuvant Systems containing MPL/QS21, in combination with hepatitis B surface antigen, induced very strong humoral and cellular immune responses in healthy adults. The AS01B-adjuvanted vaccine induced the strongest and most durable specific cellular immune responses after two doses. These Adjuvant Systems, when added to recombinant protein antigens, can be

  2. TCR variable gene involvement in chromosome inversion between 14q11 and 14q24 in adult T-cell leukemia.

    PubMed

    Haider, Shawkat; Hayakawa, Kousuke; Itoyama, Takahiro; Sadamori, Naoki; Kurosawa, Nobuyuki; Isobe, Masaharu

    2006-01-01

    Chromosomal translocations in T-cell malignancies frequently involve the T-cell receptor (TCR)alpha/delta locus at chromosome 14q11. Although 14q11 abnormalities are found in about 10% of adult T-cell leukemia (ATL) cases, until now there has been no direct evidence showing involvement of the TCR locus in ATL-a malignancy closely associated with HTLV-1 infection. The breakpoints of T-cell malignancies most commonly occur within the Jalpha or Jdelta region of the TCR locus. In ATL, however, despite extensive searching no breakpoint has yet been found in that region. Using fluorescence in situ hybridization with a panel of cosmid and bacterial artificial chromosome probes derived from chromosome 14, including the variable region of the TCRalpha locus, comprehensive analysis of an ATL patient carrying inv(14)(q11q32) revealed that the TCR locus was indeed involved in this inversion. Molecular cloning of the breakpoint revealed the juxtaposition of TCR Valpha to the 14q24 region as a result of two consecutive inversions: inv(14)(q11q32) and inv(14)(q11q24). We also found a gene near the breakpoint at the 14q24 region that is downregulated in this ATL patient and is assigned in the database as a pseudogene of ADAM21 (a disintegrin and metalloproteinase domain 21). Our expression analysis, however, showed that this pseudogene was actually expressed and was capable of encoding a protein similar to ADAM21; thus we have named this gene ADAM21-like (ADAM21-L).

  3. Adolescent social defeat disturbs adult aggression-related impulsivity in wild-type rats.

    PubMed

    Coppens, Caroline M; Coolen, Alex; de Boer, Sietse F; Koolhaas, Jaap M

    2014-10-01

    Adolescence is generally considered as a developmental period during which adverse social experiences may have lasting consequences in terms of an increased vulnerability to affective disorders. This study aimed at determining the individual susceptibility to adolescent social stress using a rat model. We used rats of the Wild-type Groningen strain, which are characterized by a broad variation in adult levels of aggression and impulsivity. We hypothesized that experience of social defeat in adolescence results in heightened aggression and impulsivity levels in adulthood. In contrast to our expectation, adolescent social defeat did not lead to a difference in the average adult level of aggression and impulsivity, but the significant correlation between offensive aggression and impulsivity found in control animals was not present in animals defeated during adolescence.

  4. A Phase II Study of Single Agent Brentuximab Vedotin in Relapsed/Refractory CD30 Low (<10%) Mature T Cell Lymphoma (TCL)

    ClinicalTrials.gov

    2016-06-24

    T-cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepato-splenic T-cell Lymphoma; Adult T-cell Leukemia/Lymphoma; Enteropathy Associated T-cell Lymphoma; NK T-cell Lymphoma; Transformed Mycosis Fungoides

  5. Methotrexate-Loaded Four-Arm Star Amphiphilic Block Copolymer Elicits CD8+ T Cell Response against a Highly Aggressive and Metastatic Experimental Lymphoma.

    PubMed

    Hira, Sumit Kumar; Ramesh, Kalyan; Gupta, Uttam; Mitra, Kheyanath; Misra, Nira; Ray, Biswajit; Manna, Partha Pratim

    2015-09-16

    We have synthesized a well-defined four-arm star amphiphilic block copolymer [poly(DLLA)-b-poly(NVP)]4 [star-(PDLLA-b-PNVP)4] that consists of D,L-lactide (DLLA) and N-vinylpyrrolidone (NVP) via the combination of ring-opening polymerization (ROP) and xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthesis of the polymer was verified by 1H NMR spectroscopy and gel permeation chromatography (GPC). The amphiphilic four-arm star block copolymer forms spherical micelles in water as demonstrated by transmission electron microscopy (TEM) and 1H NMR spectroscopy. Pyrene acts as a probe to ascertain the critical micellar concentration (cmc) by using fluorescence spectroscopy. Methotrexate (MTX)-loaded polymeric micelles of star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer were prepared and characterized by fluorescence and TEM studies. Star-(PDLLA15-b-PNVP10)4 copolymer was found to be significantly effective with respect to inhibition of proliferation and lysis of human and murine lymphoma cells. The amphiphilic block copolymer causes cell death in parental and MTX-resistant Dalton lymphoma (DL) and Raji cells. The formulation does not cause hemolysis in red blood cells and is tolerant to lymphocytes compared to free MTX. Therapy with MTX-loaded star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer micelles prolongs the life span of animals with neoplasia by reducing the tumor load, preventing metastasis and augmenting CD8+ T cell-mediated adaptive immune responses.

  6. Evidence for aggressive mimicry in an adult brood parasitic bird, and generalized defences in its host.

    PubMed

    Feeney, W E; Troscianko, J; Langmore, N E; Spottiswoode, C N

    2015-07-01

    Mimicry of a harmless model (aggressive mimicry) is used by egg, chick and fledgling brood parasites that resemble the host's own eggs, chicks and fledglings. However, aggressive mimicry may also evolve in adult brood parasites, to avoid attack from hosts and/or manipulate their perception of parasitism risk. We tested the hypothesis that female cuckoo finches (Anomalospiza imberbis) are aggressive mimics of female Euplectes weavers, such as the harmless, abundant and sympatric southern red bishop (Euplectes orix). We show that female cuckoo finch plumage colour and pattern more closely resembled those of Euplectes weavers (putative models) than Vidua finches (closest relatives); that their tawny-flanked prinia (Prinia subflava) hosts were equally aggressive towards female cuckoo finches and southern red bishops, and more aggressive to both than to their male counterparts; and that prinias were equally likely to reject an egg after seeing a female cuckoo finch or bishop, and more likely to do so than after seeing a male bishop near their nest. This is, to our knowledge, the first quantitative evidence for aggressive mimicry in an adult bird, and suggests that host-parasite coevolution can select for aggressive mimicry by avian brood parasites, and counter-defences by hosts, at all stages of the reproductive cycle. PMID:26063850

  7. Evidence for aggressive mimicry in an adult brood parasitic bird, and generalized defences in its host

    PubMed Central

    Feeney, W. E.; Troscianko, J.; Langmore, N. E.; Spottiswoode, C. N.

    2015-01-01

    Mimicry of a harmless model (aggressive mimicry) is used by egg, chick and fledgling brood parasites that resemble the host's own eggs, chicks and fledglings. However, aggressive mimicry may also evolve in adult brood parasites, to avoid attack from hosts and/or manipulate their perception of parasitism risk. We tested the hypothesis that female cuckoo finches (Anomalospiza imberbis) are aggressive mimics of female Euplectes weavers, such as the harmless, abundant and sympatric southern red bishop (Euplectes orix). We show that female cuckoo finch plumage colour and pattern more closely resembled those of Euplectes weavers (putative models) than Vidua finches (closest relatives); that their tawny-flanked prinia (Prinia subflava) hosts were equally aggressive towards female cuckoo finches and southern red bishops, and more aggressive to both than to their male counterparts; and that prinias were equally likely to reject an egg after seeing a female cuckoo finch or bishop, and more likely to do so than after seeing a male bishop near their nest. This is, to our knowledge, the first quantitative evidence for aggressive mimicry in an adult bird, and suggests that host–parasite coevolution can select for aggressive mimicry by avian brood parasites, and counter-defences by hosts, at all stages of the reproductive cycle. PMID:26063850

  8. Evidence for aggressive mimicry in an adult brood parasitic bird, and generalized defences in its host.

    PubMed

    Feeney, W E; Troscianko, J; Langmore, N E; Spottiswoode, C N

    2015-07-01

    Mimicry of a harmless model (aggressive mimicry) is used by egg, chick and fledgling brood parasites that resemble the host's own eggs, chicks and fledglings. However, aggressive mimicry may also evolve in adult brood parasites, to avoid attack from hosts and/or manipulate their perception of parasitism risk. We tested the hypothesis that female cuckoo finches (Anomalospiza imberbis) are aggressive mimics of female Euplectes weavers, such as the harmless, abundant and sympatric southern red bishop (Euplectes orix). We show that female cuckoo finch plumage colour and pattern more closely resembled those of Euplectes weavers (putative models) than Vidua finches (closest relatives); that their tawny-flanked prinia (Prinia subflava) hosts were equally aggressive towards female cuckoo finches and southern red bishops, and more aggressive to both than to their male counterparts; and that prinias were equally likely to reject an egg after seeing a female cuckoo finch or bishop, and more likely to do so than after seeing a male bishop near their nest. This is, to our knowledge, the first quantitative evidence for aggressive mimicry in an adult bird, and suggests that host-parasite coevolution can select for aggressive mimicry by avian brood parasites, and counter-defences by hosts, at all stages of the reproductive cycle.

  9. Lenalidomide Therapy for Patients With Relapsed and/or Refractory, Peripheral T-Cell Lymphomas

    ClinicalTrials.gov

    2012-04-18

    Peripheral T-cell Lymphomas; Adult T-cell Leukemia; Adult T-cell Lymphoma; Peripheral T-cell Lymphoma Unspecified; Angioimmunoblastic T-cell Lymphoma; Anaplastic Large Cell Lymphoma; T/Null Cell Systemic Type; Cutaneous t-Cell Lymphoma With Nodal/Visceral Disease

  10. Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL).

    PubMed

    Kchour, Ghada; Tarhini, Mahdi; Kooshyar, Mohamad-Mehdi; El Hajj, Hiba; Wattel, Eric; Mahmoudi, Mahmoud; Hatoum, Hassan; Rahimi, Hossein; Maleki, Masoud; Rafatpanah, Houshang; Rezaee, S A Rahim; Yazdi, Mojtaba Tabatabaei; Shirdel, Abbas; de Thé, Hugues; Hermine, Olivier; Farid, Reza; Bazarbachi, Ali

    2009-06-25

    Adult T-cell leukemia/lymphoma (ATL) is resistant to chemotherapy and carries a dismal prognosis particularly for the acute and lymphoma subtypes. Promising results were obtained with the combination of zidovudine and interferon-alpha. Chronic ATL has a relatively better outcome, but poor long-term survival is noted when patients are managed with a watchful-waiting policy or with chemotherapy. In ATL cell lines, arsenic trioxide shuts off constitutive NF-kappaB activation and potentiates interferon-alpha apoptotic effects through proteasomal degradation of Tax. Clinically, arsenic/interferon therapy exhibits some efficacy in refractory aggressive ATL patients. These results prompted us to investigate the efficacy and safety of the combination of arsenic, interferon-alpha, and zidovudine in 10 newly diagnosed chronic ATL patients. An impressive 100% response rate was observed including 7 complete remissions, 2 complete remissions but with more than 5% circulating atypical lymphocytes, and 1 partial response. Responses were rapid and no relapse was noted. Side effects were moderate and mostly hematologic. In conclusion, treatment of chronic ATL with arsenic, interferon-alpha, and zidovudine is feasible and exhibits an impressive response rate with moderate toxicity. Long-term follow up will clarify whether this will translate to disease cure. Overall, these clinical results strengthen the concept of oncogene-targeted cancer therapy.

  11. Suppression of adult T cell leukemia-derived factor/human thioredoxin induction by FK506 and cyclosporin A: a new mechanism of immune modulation via redox control.

    PubMed

    Furuke, K; Nakamura, H; Hori, T; Iwata, S; Maekawa, N; Inamoto, T; Yamaoka, Y; Yodoi, J

    1995-06-01

    Adult T cell leukemia-derived factor (ADF), which is identical to a disulfide reducing enzyme human thioredoxin (TRX), is produced and released by activated or virus-infected lymphocytes. Here we report that, in peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin (PHA), ADF/TRX mRNA was induced within 8 h after stimulation as detected by in situ hybridization study. To analyze the mechanism of ADF/TRX induction during T cell activation, the effects of immunosuppressants including FK506, rapamycin (Rap) and cyclosporin A (CsA) on ADF/TRX expression were investigated by immunoblot analysis. ADF/TRX induction in PBMC by PHA, Con A or OKT3 mAb was almost completely suppressed by FK506. Whereas CsA also inhibited ADF/TRX expression in OKT3 mAb-stimulated PBMC, Rap failed to affect it in spite of exhibiting growth inhibition. In addition, exogenous IL-2 could not increase ADF/TRX production in FK506-treated PBMC or in PHA blasts. These results indicate that ADF/TRX induction in T cell activation depends on calcineurin-dependent events in the early phase and that IL-2 production is not directly involved in ADF/TRX induction. Furthermore, when recombinant ADF (rADF) was added to a culture of PBMC 1 h before the addition of PHA and FK506, the action of FK506 was partially reversed as determined by [3H]thymidine incorporation and viable cell counts. These results suggest that ADF/TRX produced and released from PBMC may be a crucial event in lymphocyte activation, and that FK506 and CsA may exert the immune suppression partly through inhibiting the induction of the endogenous reducing factor ADF/TRX. PMID:7577807

  12. Alisertib in Treating Patients With Relapsed or Refractory Peripheral T-Cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-02-09

    Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Hepatosplenic T-Cell Lymphoma; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma

  13. Antibody to the central region of human T-lymphotropic virus type 1 gp46 is associated with the progression of adult T-cell leukemia.

    PubMed

    Sagara, Yasuko; Inoue, Yukiko; Ohshima, Koichi; Kojima, Eijiro; Utsunomiya, Atae; Tsujimura, Mitsushi; Shiraki, Hiroshi; Kashiwagi, Seizaburo

    2007-02-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 is spread by cell-to-cell transmission via the gp46-197 region, Asp197 to Leu216, on the envelope protein gp46. In the present study, we revealed a positive correlation between the appearance of an antibody recognizing the gp46-197 region (anti-gp46-197 antibody) and the severity of ATL. The prevalence and titer of the anti-gp46-197 antibody were found to be elevated along with the progression of ATL. In serial samples obtained from a single patient, the anti-gp46-197 antibody was detected before treatment in acute phase, then diminished after allogeneic bone marrow transplantation, to which the patient had a complete response. However, the antibody appeared again before a relapse, along with an increase of the serum-soluble interleukin-2 receptor level and proviral load. The results from the other six patients also indicate that seroconversion of this antibody was synchronized with the deterioration of ATL. Taken together, the findings indicate that the anti-gp46-197 antibody may be a novel beacon for gauging the efficacy of therapeutic approaches to ATL, and a survey of this antibody would be useful for identifying asymptomatic carriers infected with HTLV-1 who are at high risk of developing ATL.

  14. Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma

    PubMed Central

    Berkowitz, Jonathan L.; Janik, John E.; Stewart, Donn M.; Jaffe, Elaine S.; Stetler-Stevenson, Maryalice; Shih, Joanna H.; Fleisher, Thomas A.; Turner, Maria; Urquhart, Nicole E.; Wharfe, Gilian H.; Figg, William D.; Peer, Cody J.; Goldman, Carolyn K.; Waldmann, Thomas A.; Morris, John C.

    2014-01-01

    Interleukin-2 receptor α chain (CD25) is overexpressed in human T-cell leukemia virus 1 associated adult T-cell leukemia/lymphoma (ATL). Daclizumab a humanized monoclonal antibody blocks IL-2 binding by recognizing the interleukin-2 receptor α chain (CD25). We conducted a phase I/II trial of daclizumab in 34 patients with ATL. Saturation of surface CD25 on circulating ATL cells was achieved at all doses; however saturation on ATL cells in lymph nodes required 8 mg/kg. Up to 8 mg/kg of daclizumab administered every 3 weeks was well tolerated. No responses were observed in 18 patients with acute or lymphoma ATL; however, 6 partial responses were observed in 16 chronic and smoldering ATL patients. The pharmacokinetics / pharmacodynamics of daclizumab suggest that high-dose daclizumab would be more effective than low-dose daclizumab in treatment of lymphoid malignancies and autoimmune diseases (e.g., multiple sclerosis) since high-dose daclizumab is required to saturate IL-2R alpha in extravascular sites. PMID:25267440

  15. Langerhans cell histiocytosis in Chinese adults: absence of BRAF mutations and increased FOXP3+ regulatory T cells

    PubMed Central

    Tong, Chunguang; Jia, Xingyuan; Jia, Yanjun; He, Yanling

    2014-01-01

    Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of abnormal Langerhans cells. Previous studies mainly focused on children with LCH. However, there is limited information on the clinical and pathological aspects of LCH in adults. Therefore, this study aimed to investigate the clinical and pathological aspects of LCH in Chinese adults. The results showed that the average age of 18 LCH patients was 35.22 ± 16.57 years old. The ratio of male to female was 3.5:1.14 patients (77.8%) had single-system involvement and 4 patients (22.2%) had multi-system diseases. The skin (38.9%) and lungs (44.4%) were the mainly affected organs. No BRAF mutations were detected in the lesions of 18 cases. The number of FOXP3+ Tregs was significantly increased in LCH. In conclusion, clinical features of LCH in adults are distinct from those in children. Adult LCH has a relatively good prognosis and presents as a benign disease. Immune regulation plays an important role in the pathogenesis of adult LCH. PMID:25031736

  16. [Companion diagnostics "POTELIGEO TEST IHC/FCM" used with "POTELIGEO" (mogamulizumab) for adult T-cell leukemia-lymphoma (ATL) treatment].

    PubMed

    Goami, Takeshi

    2014-05-01

    Personalized medicine offers the best treatment for individual patients, it is important for an IVD manufacturer to develop companion diagnostics in parallel with the development of new drugs through close cooperation with drug companies, and supply diagnostics companies with new drugs for physicians and patients. We received approval for a premarket approval application (PMA) for two in vitro diagnostic ("IVD") reagents, POTELIGEO TEST IHC and POTELIGEO TEST FCM ("POTELIGEO TEST"), in March 2012, and subsequently launched POTELIGEO TEST in May 2012. POTELIGEO TEST is a companion diagnostic used with POTELIGEO for which Kyowa Hakko Kirin has a new drug application (NDA) that was approved in March 2012, and is designed to help physicians identify appropriate subpopulations of adult T-cell leukemia-lymphoma(ATL) patients who are most likely to respond to POTELIGEO 20 mg (mogamulizumab) Injection ("POTELIGEO"). PMID:25051659

  17. Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal Nk/T-cell lymphoma, nasal type.

    PubMed

    Nakashima, Yasuhiro; Tagawa, Hiroyuki; Suzuki, Ritsuro; Karnan, Sivasundaram; Karube, Kennosuke; Ohshima, Koichi; Muta, Koichiro; Nawata, Hajime; Morishima, Yasuo; Nakamura, Shigeo; Seto, Masao

    2005-11-01

    Natural killer (NK) cell lymphomas/leukemias are highly aggressive lymphoid malignancies, but little is known about their genomic alterations, and thus there is an urgent need for identification and analysis of NK cell lymphomas/leukemias. Recently, we developed our own array-based comparative genomic hybridization (array CGH) with an average resolution of 1.3 Mb. We performed an array CGH analysis for 27 NK-cell lymphoma/leukemia cases that were classified into two disease groups based on the World Health Organization Classification (10 aggressive NK-cell leukemia cases and 17 extranodal NK/T-cell [NK/T] lymphomas, nasal type). We identified the differences in the genomic alteration patterns of the two groups. The recurrent regions characteristic of the aggressive NK-cell leukemia group compared with those of the extranodal NK/T lymphoma, nasal-type group, were gain of 1q and loss of 7p15.1-p22.3 and 17p13.1. In particular, gain of 1q23.1-24.2 (P = 0.041) and 1q31.3-q44 (P = 0.003-0.047), and loss of 7p15.1-p22.3 (P = 0.012-0.041) and 17p13.1 (P = 0.012) occurred significantly more frequently in the former than in the latter group. Recurrent regions characteristic of the extranodal NK/T lymphoma, nasal-type group, compared with those of the other group were gain of 2q, and loss of 6q16.1-q27, 11q22.3-q23.3, 5p14.1-p14.3, 5q34-q35.3, 1p36.23-p36.33, 2p16.1-p16.3, 4q12, and 4q31.3-q32.1. Our results can be expected to provide further insights into the genetic basis of lymphomagenesis and the clinicopathologic features of NK-cell lymphomas/leukemias.

  18. DexaBEAM versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T cell lymphoma: a retrospective evaluation of parallel patient cohorts of one center.

    PubMed

    Mikesch, Jan-Henrik; Kuhlmann, Mareike; Demant, Angela; Krug, Utz; Thoennissen, Gabriela B; Schmidt, Eva; Kessler, Torsten; Schliemann, Christoph; Pohlen, Michele; Mohr, Michael; Evers, Georg; Köhler, Gabriele; Wessling, Johannes; Mesters, Rolf; Müller-Tidow, Carsten; Berdel, Wolfgang E; Thoennissen, Nils H

    2013-08-01

    High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline-based first-line chemotherapy who received either DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan; n = 16) or ICE (ifosfamide, carboplatin, and etoposide; n = 15) regimen as first salvage chemotherapy followed by HDT/ASCT. The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69 %; 95 % confidence interval 46.0-91.5 %) as compared to the ICE group (20 %; 95 % confidence interval -0.2-40.2 %; P = 0.01), with higher complete response (CR; 38 %; 95 % confidence interval 13.8-61.2 %; vs. 7 %; 95 % confidence interval -6.0-19.6 %) as well as partial response (PR; 31 vs. 13 %) rate. Changing regimen due to failure of first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58 % (33 % CR, 25 % PR) with DexaBEAM as second salvage therapy, whereas in three patients receiving ICE after DexaBEAM failure, only one achieved an OR (1 PR). Median progression-free survival was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P = 0.01). Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. For all patients proceeding to HDT/ASCT, a 3-year overall survival was 50 %. Together, considering the limitations of the retrospective design of the evaluation and the small sample size, our data suggest that DexaBEAM salvage chemotherapy is superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher

  19. Risk factors for aggressive recurrent respiratory papillomatosis in adults and juveniles.

    PubMed

    Omland, Turid; Akre, Harriet; Lie, Kathrine A; Jebsen, Peter; Sandvik, Leiv; Brøndbo, Kjell

    2014-01-01

    In this cohort study we examined whether gender, age at onset, observation time or human papillomavirus (HPV) genotype are risk factors for an aggressive clinical course in Recurrent Respiratory Papillomatosis (RRP). Clinical data from patient records comprised gender, age at onset, date of first endolaryngeal procedure with biopsy, date of last follow-up, total number of endolaryngeal procedures, and complications during the observation period. Disease was defined as juvenile (JoRRP) or adult onset (AoRRP) according to whether the disease was acquired before or after the age of 18. Aggressive disease was defined as distal spread, tracheostomy, four surgical operations annually or >10 surgeries in total. DNA was extracted from formalin-fixed paraffin-embedded tissue. HPV genotyping was performed by quantitative PCR assay identifying 15 HPV genotypes. The study included 224 patients. The majority were males (141/174 in AoRRPs and 31/50 in JoRRPs; p = 0.005). The median follow-up from initial diagnosis was 12.0 years (IQR 3.7-32.9) for JoRRPs and 4.0 years (IQR 0.8-11.7) for AoRRPs. The disease was more aggressive in juveniles than adults (p<0.001), a difference that disappeared after 10 years' observation. JoRRPs with aggressive disease were younger at onset (mean difference 4.6 years, 95%CI [2.4, 6.8], p = 0.009). HPV6 or -11 was present in all HPV-positive papillomas. HPV11 was more prevalent in aggressive disease, and HPV6 in non-aggressive disease (p<0.001). Multiple logistic regression revealed that only age at onset (OR = 0.69, 95% CI [0.53, 0.88], p = 0.003) was associated with aggressive disease in juveniles, while HPV11 (OR = 3.74, 95% CI [1.40, 9.97], p = 0.008) and observation time >10 years (OR = 13.41, 95% CI [5.46, 32.99[, p<001) were risk factors in adults. In conclusion, the only significant risk factor for developing aggressive disease in JoRRPs was age at onset, but both HPV11 and observation time >10 years were risk factors for an aggressive

  20. Adult-Directed and Peer-Directed Respect for Authority: Relationships With Aggressive and Manipulative Behavior.

    PubMed

    Clemans, Katherine H; Graber, Julia A; Bettencourt, Amie F

    2012-09-01

    This study investigated whether respect for adult and peer authority are separate attitudes which have distinct relationships with aggressive and manipulative behavior. Items assessing admiration for and obedience toward parents, teachers, popular students, and friend group leaders were administered to 286 middle school students (M age = 12.6 yrs). Factor analysis revealed two primary factors which corresponded to adult-directed and peer-directed respect orientations. Results suggested that adult-directed respect was associated with lower levels of aggression and social manipulation, whereas peer-directed respect was associated with higher levels of these behaviors. The role of peer-directed respect as a risk factor for negative social behavior in adolescence is discussed.

  1. Adult-Directed and Peer-Directed Respect for Authority: Relationships With Aggressive and Manipulative Behavior

    PubMed Central

    Clemans, Katherine H.; Graber, Julia A.; Bettencourt, Amie F.

    2012-01-01

    This study investigated whether respect for adult and peer authority are separate attitudes which have distinct relationships with aggressive and manipulative behavior. Items assessing admiration for and obedience toward parents, teachers, popular students, and friend group leaders were administered to 286 middle school students (M age = 12.6 yrs). Factor analysis revealed two primary factors which corresponded to adult-directed and peer-directed respect orientations. Results suggested that adult-directed respect was associated with lower levels of aggression and social manipulation, whereas peer-directed respect was associated with higher levels of these behaviors. The role of peer-directed respect as a risk factor for negative social behavior in adolescence is discussed. PMID:23329877

  2. Development of T cell lymphoma in HTLV-1 bZIP factor and Tax double transgenic mice.

    PubMed

    Zhao, Tiejun; Satou, Yorifumi; Matsuoka, Masao

    2014-07-01

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection.

  3. Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice

    PubMed Central

    Yu, Qinghui; Teixeira, Cátia M.; Mahadevia, Darshini; Huang, Yung-Yu; Balsam, Daniel; Mann, J John; Gingrich, Jay A; Ansorge, Mark S.

    2014-01-01

    Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypo-activity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (> P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction. PMID:24589889

  4. Emotional effect of physical aggression among adults in the general population in a Canadian province.

    PubMed

    Wells, Samantha; Graham, Kathryn

    2003-02-01

    The emotional effect of personal involvement in physical aggression was examined in a random sample of 1,753 adults from Ontario, Canada, using Computer Assisted Telephone Interviewing (response rate of 67%). Respondents reported a range of emotional responses from feeling good or justified to feeling angry, upset, terrified, disgusted, hurt, and embarrassed. Open-ended responses regarding emotional response were rated by the authors for 149 incidents of aggression, which yielded five categories: (1) positive impact 4%, (2) no feeling or no effect 31%, (3) mildly negative 20%, (4) moderately negative 28%, and (5) severely negative 17% (Kappa statistic of interrater agreement=.77). The substantial proportion of incidents involving positive or no emotional response suggests that a greater understanding of aggression among individuals can be gained by the development and application of a quantitative measure of emotional response that reflects the full range of emotions (positive and negative), using dimensions identified in this study such as feeling upset, fear, and anger.

  5. CD8 T-Cell Responses before and after Structured Treatment Interruption in Ugandan Adults Who Initiated ART with CD4 T Cells <200 Cell/μL: The DART Trial STI Substudy.

    PubMed

    Serwanga, Jennifer; Mugaba, Susan; Betty, Auma; Pimego, Edward; Walker, Sarah; Munderi, Paula; Gilks, Charles; Gotch, Frances; Grosskurth, Heiner; Kaleebu, Pontiano

    2011-01-01

    Objective. To better understand attributes of ART-associated HIV-induced T-cell responses that might be therapeutically harnessed. Methods. CD8(+) T-cell responses were evaluated in some HIV-1 chronically infected participants of the fixed duration STI substudy of the DART trial. Magnitudes, breadths, and functionality of IFN-γ and Perforin responses were compared in STI (n = 42) and continuous treatment (CT) (n = 46) before and after a single STI cycle when the DART STI trial was stopped early due to inferior clinical outcome in STI participants. Results. STI and CT had comparable magnitudes and breadths of monofunctional CD8(+)IFNγ(+) and CD8(+)Perforin(+) responses. However, STI was associated with significant decline in breadth of bi-functional (CD8(+)IFNγ(+)Perforin(+)) responses; P = .02, Mann-Whitney test. Conclusions. STI in individuals initiated onto ART at <200 CD4(+) T-cell counts/μl significantly reduced occurrence of bifunctional CD8(+)IFNγ(+)/Perforin(+) responses. These data add to others that found no evidence to support STI as a strategy to improve HIV-specific immunity during ART.

  6. Bortezomib and Azacitidine in Treating Patients With Relapsed or Refractory T-Cell Lymphoma

    ClinicalTrials.gov

    2013-12-02

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Small Intestine Lymphoma; T-cell Large Granular Lymphocyte Leukemia

  7. T Cell Immune Reconstitution Following Lymphodepletion

    PubMed Central

    Williams, Kirsten; Hakim, Frances T.; Gress, Ronald E.

    2007-01-01

    T cell reconstitution following lymphopenia from chemotherapy or stem cell transplant is often slow and incompetent, contributing to the development of infectious diseases, relapse, and graft-versus-host disease. This is due to the fact that de novo T cell production is impaired following cytoreductive regimens. T cells can be generated from two pathways: 1) thymus derived through active thymopoiesis and 2) peripherally expanded clones through homeostatic proliferation. In the development of lymphopenia, the thymic pathway is commonly compromised in adults and T cells rely upon peripheral expansion to recover T cell numbers. This homeostatic proliferation exploits the high cytokine levels following lymphopenia to rapidly generate T cells in the periphery. Moreover, this early peripheral expansion of T cells can also be driven by exogenous antigen. This results in loss of T cell repertoire diversity and may predispose to auto- or alloimmunity. Alternatively, the high homeostatic proliferation following lymphopenia may facilitate expansion of anti-tumor immunity. Murine and human studies have provided insight into the cytokine and cellular regulators of these two pathways of T cell generation and the disparate portraits of T cell immunity created through robust thymopoiesis or peripheral expansion following lymphopenia. This insight has permitted the manipulation of the immune system to maximize anti-tumor immunity through lymphopenia and led to an appreciation of mechanisms that underlie graft vs. host disease. PMID:18023361

  8. KLRG1 and PD-1 expression are increased on T-cells following tuberculosis-treatment and identify cells with different proliferative capacities in BCG-vaccinated adults.

    PubMed

    Boer, Mardi C; van Meijgaarden, Krista E; Goletti, Delia; Vanini, Valentina; Prins, Corine; Ottenhoff, Tom H M; Joosten, Simone A

    2016-03-01

    In cancer and chronic infectious diseases, immune checkpoint-blockade of inhibitory receptors can enhance T-cell immunity. In tuberculosis (TB), a chronic infectious disease, prolonged antigen exposure can potentially drive terminal T-cell differentiation towards functional 'exhaustion': in human TB T-cells express PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein-4). However, in murine TB not PD-1 but rather killer cell lectin-like receptor subfamily-G1 (KLRG1) was a superior indicator of terminal T-cell differentiation. We therefore compared expression of KLRG1, PD-1 and CTLA-4 on T-cells in different stages of human TB, and also analysed their induction following BCG-vaccination. KLRG1, PD-1 and CTLA-4-expression were highest on in vitro BCG-stimulated CD4(+) T-cells following recent TB-treatment; KLRG1 and PD-1-expression on CD4(+) T-cells in active--but not latent--TB were only slightly increased compared to healthy donors. BCG-vaccination induced KLRG1-expression on BCG-stimulated CD8(+) but not CD4(+) T-cells, while neither PD-1 nor CTLA-4-expression increased. KLRG1-expressing CD8(+) T-cells exhibited markedly decreased proliferation, whereas PD-1(+) T-cells proliferated after in vitro BCG-stimulation. Thus, we demonstrate the presence of increased KLRG1-expressing T-cells in TB-treated individuals, and present KLRG1 as a marker of decreased human T-cell proliferation following BCG-vaccination. These results expand our understanding of cell-mediated immune control of mycobacterial infections.

  9. Exposure to Client Aggression and Burnout among Community Staff Who Support Adults with Intellectual Disabilities in Ontario, Canada

    ERIC Educational Resources Information Center

    Hensel, J. M.; Lunsky, Y.; Dewa, C. S.

    2012-01-01

    Background: Studies have shown that staff who support adults with intellectual disabilities (ID) are exposed to challenging behaviour in their work including client aggression. Exposure to aggressive behaviour has been associated with staff stress and burnout. Study samples have been small however, and there has been very little data exploring…

  10. The effect of adult aggression on habitat selection by settlers of two coral-dwelling damselfishes.

    PubMed

    Ben-Tzvi, Ofer; Kiflawi, Moshe; Polak, Omer; Abelson, Avigdor

    2009-01-01

    Coral-reef fishes experience a major challenge when facing settlement in a multi-threat environment, within which, using settlement cues, they need to select a suitable site. Studies in laboratories and artificial setups have shown that the presence of conspecific adults often serves as a positive settlement cue, whose value is explained by the increased survival of juveniles in an already proven fit environment. However, settlement in already inhabited corals may expose the recruits to adult aggression. Daily observations and manipulation experiments were used in the present study, which was conducted in the natural reef. We revealed differential strategies of settlers, which do not necessarily join conspecific adults. Dascyllus aruanus prefer to settle near (not with) their aggressive adults, and to join them only after gaining in size; whereas Dascyllus marginatus settlers in densely populated reefs settle independently of their adult distribution. Our results present different solutions to the challenges faced by fish recruits while selecting their microhabitat, and emphasize the complexity of habitat selection by the naïve settlers. Although laboratory experiments are important to the understanding of fish habitat selection, further studies in natural habitats are essential in order to elucidate the actual patterns of settlement and habitat selection, which are crucial for the survival of coral-reef fish populations. PMID:19436725

  11. SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma.

    PubMed

    Higuchi, Tomonori; Nakayama, Takashi; Arao, Tokuzo; Nishio, Kazuto; Yoshie, Osamu

    2013-05-01

    Previously, we have shown that an AP-1 family member, FRA-2, is constitutively expressed in adult T-cell leukemia/lymphoma (ATL) and, together with JUND, upregulates CCR4 and promotes ATL cell growth. Among the identified potential target genes of FRA-2/JUND was SOX4. Here, we examine the expression and function of SOX4 in ATL. SOX4 was indeed consistently expressed in primary ATL cells. FRA-2/JUND efficiently activated the SOX4 promoter via an AP-1 site. Knockdown of SOX4 expression by small interfering RNA (siRNA) strongly suppressed cell growth of ATL cell lines. Microarray analyses revealed that SOX4 knockdown reduced the expression of genes such as germinal center kinase related (GCKR), NAK-associated protein 1 (NAP1), and histone deacetylase 8 (HDAC8). We confirmed consistent expression of GCKR, NAP1, and HDAC8 in primary ATL cells. We also showed direct activation of the HDAC8 promoter by SOX4. Furthermore, siRNA knockdown of GCKR, NAP1, and HDAC8 each significantly suppressed cell growth of ATL cell lines. Taken together, we have revealed an important oncogenic cascade involving FRA-2/JUND and SOX4 in ATL, which leads to the expression of genes such as GCKR, NAP1, and HDAC8. PMID:23482931

  12. Concomitant use of radiotherapy and two topoisomerase inhibitors to treat adult T-cell leukemia with a radiotherapy-resistant bulky disease: a case series.

    PubMed

    Obama, Kosuke

    2014-01-01

    Concomitant chemoradiotherapy is established as the standard treatment to improve the prognosis of several types of solid tumor, but has not been the general practice for hematological malignancies. Here, I report two cases of adult T-cell leukemia (ATL) with a radiotherapy-resistant bulky disease treated with concomitant radiotherapy and two topoisomerase inhibitors: etoposide (VP-16) and irinotecan (CPT-11). Patient 1 was a 78-year-old man with chemotherapy-resistant inguinal bulky mass. Radiotherapy (total 40 Gy) for this inguinal lesion was started; however, the bulky disease was found to be resistant to radiotherapy and progressed. VP-16 and CPT-11 were administered in addition to radiotherapy (after a total of 20 Gy of radiotherapy). Patient 2 was a 71-year-old man with a solitary bulky mass in left cervical lesion. Various previous chemotherapy and radiotherapy approaches had not been able to control the disease. Six months after first radiotherapy, the bulky disease rapidly progressed with the occurrence of pain. Second radiotherapy (30 Gy) was started with simultaneous administration of CPT-11 and VP-16. In both cases, the bulky disease gradually regressed and completely disappeared by the end of radiotherapy. Thus, flexible adaptation of concomitant chemoradiotherapy including two topoisomerase inhibitors may offer a potential therapeutic option for radiotherapy-resistant bulky diseases, even in hematological malignancies.

  13. T Cells in Fish

    PubMed Central

    Nakanishi, Teruyuki; Shibasaki, Yasuhiro; Matsuura, Yuta

    2015-01-01

    Cartilaginous and bony fish are the most primitive vertebrates with a thymus, and possess T cells equivalent to those in mammals. There are a number of studies in fish demonstrating that the thymus is the essential organ for development of T lymphocytes from early thymocyte progenitors to functionally competent T cells. A high number of T cells in the intestine and gills has been reported in several fish species. Involvement of CD4+ and CD8α+ T cells in allograft rejection and graft-versus-host reaction (GVHR) has been demonstrated using monoclonal antibodies. Conservation of CD4+ helper T cell functions among teleost fishes has been suggested in a number studies employing mixed leukocyte culture (MLC) and hapten/carrier effect. Alloantigen- and virus-specific cytotoxicity has also been demonstrated in ginbuna and rainbow trout. Furthermore, the important role of cell-mediated immunity rather than humoral immunity has been reported in the protection against intracellular bacterial infection. Recently, the direct antibacterial activity of CD8α+, CD4+ T-cells and sIgM+ cells in fish has been reported. In this review, we summarize the recent progress in T cell research focusing on the tissue distribution and function of fish T cells. PMID:26426066

  14. The relationship between adult reactive and proactive aggression, hostile interpretation bias, and antisocial personality disorder.

    PubMed

    Lobbestael, Jill; Cima, Maaike; Arntz, Arnoud

    2013-02-01

    Reactive aggression (RA) refers to angry responses to provocation or frustration, while proactive aggression (PA) denotes nonemotional, instrumental, and unprovoked aggression. The current study examined personality-related and cognitive correlates of both aggressive types. Respectively, the predictive values of antisocial personality disorder (ASPD), and of hostile interpretation bias, which is the tendency to interpret ambiguous stimuli in a hostile manner, were studied. The sample consisted of n = 37 male adult patients with mixed diagnoses and n = 29 male nonpatients that responded to vignettes and pictures of ambiguous situations, using both open and closed answer formats. ASPD was assessed by means of the Structured Clinical Interview for DSM-IV Axis II disorders (SCID-II), and the Reactive Proactive Questionnaire (RPQ) measured RA and PA. Results showed that although both RA and PA types were predicted by ASPD traits, RA was additionally predicted by a hostile interpretation bias. These findings suggest that reducing hostile bias is a promising avenue for clinical treatment of ASPD-patients high in RA.

  15. Development of Ultra-Super Sensitive Immunohistochemistry and Its Application to the Etiological Study of Adult T-Cell Leukemia/Lymphoma

    PubMed Central

    Hasui, Kazuhisa; Wang, Jia; Tanaka, Yuetsu; Izumo, Shuji; Eizuru, Yoshito; Matsuyama, Takami

    2012-01-01

    Antigen retrieval (AR) and ultra-super sensitive immunohistochemistry (ultra-IHC) have been established for application to archival human pathology specimens. The original ultra-IHC was the ImmunoMax method or the catalyzed signal amplification system (ImmunoMax/CSA method), comprising the streptavidin-biotin complex (sABC) method and catalyzed reporter deposition (CARD) reaction with visualization of its deposition. By introducing procedures to diminish non-specific staining in the original ultra-IHC method, we developed the modified ImmunoMax/CSA method with AR heating sections in an AR solution (heating-AR). The heating-AR and modified ImmunoMax/CSA method visualized expression of the predominantly simple present form of HTLV-1 proviral DNA pX region p40Tax protein (Tax) in adult T-cell leukemia/lymphoma (ATLL) cells in archival pathology specimens in approximately 75% of cases. The simple present form of Tax detected exhibited a close relation with ATLL cell proliferation. We also established a new simplified CSA (nsCSA) system by replacing the sABC method with the secondary antibody- and horse radish peroxidase-labeled polymer reagent method, introducing the pretreatments blocking non-specific binding of secondary antibody reagent, and diminishing the diffusion of deposition in the CARD reaction. Combined with AR treating sections with proteinase K solution (enzymatic-AR), the nsCSA system visualized granular immunostaining of the complex present form of Tax in a small number of ATLL cells in most cases, presenting the possibility of etiological pathological diagnosis of ATLL and suggesting that the complex present form of Tax-positive ATLL cells were young cells derived from ATLL stem cells. The heating-AR and ultra-IHC detected physiological expression of the p53 protein and its probable phosphorylation by Tax in peripheral blood mononuclear cells of peripheral blood tissue specimens from HTLV-1 carriers, as well as physiological and pathological expression

  16. Development of ultra-super sensitive immunohistochemistry and its application to the etiological study of adult T-cell leukemia/lymphoma.

    PubMed

    Hasui, Kazuhisa; Wang, Jia; Tanaka, Yuetsu; Izumo, Shuji; Eizuru, Yoshito; Matsuyama, Takami

    2012-04-26

    Antigen retrieval (AR) and ultra-super sensitive immunohistochemistry (ultra-IHC) have been established for application to archival human pathology specimens. The original ultra-IHC was the ImmunoMax method or the catalyzed signal amplification system (ImmunoMax/CSA method), comprising the streptavidin-biotin complex (sABC) method and catalyzed reporter deposition (CARD) reaction with visualization of its deposition. By introducing procedures to diminish non-specific staining in the original ultra-IHC method, we developed the modified ImmunoMax/CSA method with AR heating sections in an AR solution (heating-AR). The heating-AR and modified ImmunoMax/CSA method visualized expression of the predominantly simple present form of HTLV-1 proviral DNA pX region p40Tax protein (Tax) in adult T-cell leukemia/lymphoma (ATLL) cells in archival pathology specimens in approximately 75% of cases. The simple present form of Tax detected exhibited a close relation with ATLL cell proliferation. We also established a new simplified CSA (nsCSA) system by replacing the sABC method with the secondary antibody- and horse radish peroxidase-labeled polymer reagent method, introducing the pretreatments blocking non-specific binding of secondary antibody reagent, and diminishing the diffusion of deposition in the CARD reaction. Combined with AR treating sections with proteinase K solution (enzymatic-AR), the nsCSA system visualized granular immunostaining of the complex present form of Tax in a small number of ATLL cells in most cases, presenting the possibility of etiological pathological diagnosis of ATLL and suggesting that the complex present form of Tax-positive ATLL cells were young cells derived from ATLL stem cells. The heating-AR and ultra-IHC detected physiological expression of the p53 protein and its probable phosphorylation by Tax in peripheral blood mononuclear cells of peripheral blood tissue specimens from HTLV-1 carriers, as well as physiological and pathological expression

  17. The role of serotonin in impulsive aggression, suicide, and homicide in adolescents and adults: a literature review.

    PubMed

    Glick, Amy R

    2015-05-01

    This is a literature review discussing previous studies on the associations between impulsive aggression and the serotonergic system in adults, adolescents, and children. The review demonstrates that there is a clear association between low cerebrospinal fluid serotonin and impulsive aggression. However, studies on neurotransmitter receptor profiles, functional imaging, genetics, and epigenetics reviewed in this article suggest a more complicated picture that includes consideration of gene vs. environment in the evaluation of risk. Serotonin supplementation studies suggest that selective serotonin reuptake inhibitors may reduce impulsive aggression in some adults but are less effective in adults with pathological aggression and also in children and adolescents. Child and adolescent studies are less conclusive, in part due to the heterogeneous physiologic and psychosocial changes occurring over the course of development. The author thus concludes that psychiatrists can reduce risk in these special patient populations by creating safer environments in the form of changes in policy and increased support services. PMID:25924230

  18. The role of serotonin in impulsive aggression, suicide, and homicide in adolescents and adults: a literature review.

    PubMed

    Glick, Amy R

    2015-05-01

    This is a literature review discussing previous studies on the associations between impulsive aggression and the serotonergic system in adults, adolescents, and children. The review demonstrates that there is a clear association between low cerebrospinal fluid serotonin and impulsive aggression. However, studies on neurotransmitter receptor profiles, functional imaging, genetics, and epigenetics reviewed in this article suggest a more complicated picture that includes consideration of gene vs. environment in the evaluation of risk. Serotonin supplementation studies suggest that selective serotonin reuptake inhibitors may reduce impulsive aggression in some adults but are less effective in adults with pathological aggression and also in children and adolescents. Child and adolescent studies are less conclusive, in part due to the heterogeneous physiologic and psychosocial changes occurring over the course of development. The author thus concludes that psychiatrists can reduce risk in these special patient populations by creating safer environments in the form of changes in policy and increased support services.

  19. Synchronous presentation of Epstein-Barr virus-associated Hodgkin's disease and adult T-cell leukemia/lymphoma (ATLL) in a patient from an endemic area of ATLL.

    PubMed

    Hayashi, T; Yamabe, H; Haga, H; Akasaka, T; Kadowaki, N; Ohno, H; Okuma, M; Fukuhara, S

    1995-06-01

    We report a patient from an endemic area of adult T-cell leukemia/lymphoma (ATLL), who developed lymphoma with features characteristic of Hodgkin's disease (HD). Large atypical Reed-Sternberg/Hodgkin's cells (RS/H cells) had a CD3-CD15+CD20-CD30+CD45RO- immunophenotype. Epstein-Barr virus (EBV) latent membrane protein and EBV-encoded small RNA were detected in the RS/H cells. The patient received C-MOPP/ABVD chemotherapy for the HD resulting in a partial response. However, relapse occurred and he died of disease progression associated with serious bacterial infection. Although serial lymph node biopsies revealed consistent presence of the EBV-positive RS/H cells, the background small lymphocytes showed progressive increase in pleomorphism and nuclear irregularity. The lymphocytes had the T-cell phenotype, CD3+CD4+CD7-CD8-. Southern blot analysis using DNA probes for the human T-cell lymphotrophic virus-I (HTLV-I) and the T-cell receptor beta-chain gene demonstrated expansion of the HTLV-I infected monoclonal T-cells with the disease progression. We concluded that the patient synchronously presented two independent lymphoproliferative disorders; EBV-associated HD and ATLL resulting from HTLV-I infection.

  20. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    PubMed

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.

  1. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    PubMed

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs. PMID:26526988

  2. Impaired expression of DICER and some microRNAs in HBZ expressing cells from acute adult T-cell leukemia patients.

    PubMed

    Gazon, Hélène; Belrose, Gildas; Terol, Marie; Meniane, Jean-Come; Mesnard, Jean-Michel; Césaire, Raymond; Peloponese, Jean-Marie

    2016-05-24

    Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previously described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as well as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL. PMID:26849145

  3. Study of Alisertib (MLN8237) in Adults With Aggressive Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2013-11-15

    Diffuse Large B-cell Lymphoma; Mantle Cell Lymphoma; Burkitt's Lymphoma; Precursor B-lymphoblastic Leukemia/Lymphoma; T-cell Lymphoma, Excluding Primary Cutaneous T-cell Lymphoma; Transformed Follicular Lymphoma With ≥ 50% Diffuse Large Cell Component

  4. Oral Cyclosporin A Inhibits CD4 T cell P-glycoprotein Activity in HIV-Infected Adults Initiating Treatment with Nucleoside Reverse Transcriptase Inhibitors

    PubMed Central

    Hulgan, Todd; Donahue, John P.; Smeaton, Laura; Pu, Minya; Wang, Hongying; Lederman, Michael M.; Smith, Kimberly; Valdez, Hernan; Pilcher, Christopher; Haas, David W.

    2010-01-01

    Purpose P-glycoprotein limits tissue penetration of many antiretroviral drugs. We characterized effects of the P-glycoprotein substrate cyclosporin A on T cell P-glycoprotein activity in HIV-infected AIDS Clinical Trials Group study A5138 participants. Methods We studied P-glycoprotein activity on CD4 and CD8 T cells in 16 participants randomized to receive oral cyclosporin A (n=9) or not (n=7) during initiation antiretroviral therapy (ART) that did not include protease or non-nucleoside reverse transcriptase inhibitors. Results CD4 T cell P-glycoprotein activity decreased by a median of 8 percentage points with cyclosporin A/ART (difference between cyclosporin A/ART versus ART only P=0.001). Plasma trough cyclosporin A concentrations correlated with change in P-glycoprotein activity in several T cell subsets. Conclusions Oral cyclosporin A can inhibit peripheral blood CD4 T cell P-glycoprotein activity. Targeted P-glycoprotein inhibition might enhance delivery of ART to T cells. PMID:19779705

  5. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

    PubMed Central

    Bond, Jonathan; Marchand, Tony; Touzart, Aurore; Cieslak, Agata; Trinquand, Amélie; Sutton, Laurent; Radford-Weiss, Isabelle; Lhermitte, Ludovic; Spicuglia, Salvatore; Dombret, Hervé; Macintyre, Elizabeth; Ifrah, Norbert; Hamel, Jean-François; Asnafi, Vahid

    2016-01-01

    Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently

  6. Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults.

    PubMed

    Riddell, Natalie E; Griffiths, Stephen J; Rivino, Laura; King, David C B; Teo, Guo H; Henson, Sian M; Cantisan, Sara; Solana, Rafael; Kemeny, David M; MacAry, Paul A; Larbi, Anis; Akbar, Arne N

    2015-04-01

    Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8(+) T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8(+) T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8(+)  CD45RA(+)  CD27(-) T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8(+) T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8(+) T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8(+) T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.

  7. Multifunctional cytomegalovirus (CMV)-specific CD8+ T cells are not restricted by telomere-related senescence in young or old adults

    PubMed Central

    Riddell, Natalie E; Griffiths, Stephen J; Rivino, Laura; King, David C B; Teo, Guo H; Henson, Sian M; Cantisan, Sara; Solana, Rafael; Kemeny, David M; MacAry, Paul A; Larbi, Anis; Akbar, Arne N

    2015-01-01

    Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8+ T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8+ T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8+ CD45RA+ CD27− T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8+ T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8+ T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8+ T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion. PMID:25314332

  8. Impulsive-aggressive traits and suicidal adolescents and young adults with alcoholism.

    PubMed

    Carballo, Juan J; Oquendo, Maria A; Giner, Lucas; Zalsman, Gil; Roche, Ansley M; Sher, Leo

    2006-01-01

    Suicidal behavior and alcohol use disorders among adolescents and young adults are serious public health problems. In the study of suicidal behavior among young people with alcoholism, it has been shown that aggression and impulsivity are higher among those who attempted suicide. Impulsivity has been related to suicidal and self-destructive behaviors within different psychiatric conditions, i.e. alcohol and substance use disorders, mood disorders, conduct disorder, impulse control disorders, antisocial personality disorder, and borderline personality disorder. The term impulsivity has been used to define different constructs such as (1) personality trait or cognitive style in which disinhibition is the core characteristic, (2) a tendency to act immediately in response to external or internal stimuli, and (3) a group of psychiatric disorders with behavioral dyscontrol. Among adolescents suicidal behavior is transmitted in families independently of psychiatric conditions, but not independently of impulsivity/aggression. Two causal links between impulsiveness and alcoholism have been proposed: (1) adolescents who develop alcoholism possess higher premorbid levels of impulsiveness than those who do not develop alcoholism, and (2) levels of impulsiveness differentiate both populations only after the development of alcoholism, with higher levels of impulsiveness among those adolescents who developed alcoholism. Cognitive behavioral techniques have shown promising results in the treatment of adolescents with alcohol and substance use disorder and suicidality. The relative frequency of suicidal behavior among adolescents and young adults suffering from alcoholism and its subsequent devastating effects on individuals, families and society merits further research and development of prevention strategies.

  9. Abundance and specificity of influenza reactive circulating memory follicular helper and non-follicular helper CD4 T cells in healthy adults.

    PubMed

    Leddon, Scott A; Richards, Katherine A; Treanor, John J; Sant, Andrea J

    2015-09-01

    CD4 T-cell responses are functionally complex and regulate many aspects of innate and adaptive immunity. Follicular helper (Tfh) cells are CD4 T cells specialized to support B-cell production of isotype-switched, high-affinity antibody. So far, studies of Tfh cells in humans have focused on their differentiation requirements, with little research devoted to their antigen specificity. Here, after separating circulating human memory CD4 T cells based on expression of CXCR5, a signature marker of Tfh, we have quantified and assayed the influenza protein antigen specificity of blood Tfh cells and CD4 T cells lacking this marker. Through the use of peptide pools derived from nucleoprotein (NP) or haemagglutinin (HA) and a panel of human donors, we have discovered that circulating Tfh cells preferentially recognize peptide epitopes from HA while cells lacking CXCR5 are enriched for specificity toward NP. These studies suggest that reactive CD4 T cells specific for distinct viral antigens may have generalized differences in their functional potential due to their previous stimulation history. PMID:26094691

  10. Engineered T cell therapies.

    PubMed

    Field, Anne-Christine; Qasim, Waseem

    2015-11-04

    Alongside advancements in gene therapy for inherited immune disorders, the need for effective alternative therapeutic options for other conditions has resulted in an expansion in the field of research for T cell gene therapy. T cells are easily obtained and can be induced to divide robustly ex vivo, a characteristic that allows them to be highly permissible to viral vector-mediated introduction of transgenes. Pioneering clinical trials targeting cancers and infectious diseases have provided safety and feasibility data and important information about persistence of engineered cells in vivo. Here, we review clinical experiences with γ-retroviral and lentiviral vectors and consider the potential of integrating transposon-based vectors as well as specific genome editing with designer nucleases in engineered T cell therapies.

  11. Treatment of both native and deamidated gluten peptides with an endo-peptidase from Aspergillus niger prevents stimulation of gut-derived gluten-reactive T cells from either children or adults with celiac disease.

    PubMed

    Toft-Hansen, Henrik; Rasmussen, Karina S; Staal, Anne; Roggen, Erwin L; Sollid, Ludvig M; Lillevang, Søren T; Barington, Torben; Husby, Steffen

    2014-08-01

    Celiac disease (CD) is characterized by an inappropriate immunological reaction against gluten driven by gluten-specific CD4+ T cells. We screened 25 proteases and tested 10 for their potential to degrade gluten in vitro. Five proteases were further tested for their ability to prevent the proliferative response by a gluten-specific CD4+ T cell clone and seven gluten-reactive T cell lines to protease-digested gluten peptides. A proline-specific endo-peptidase from Aspergillus niger (AnP2) was particularly efficient at diminishing proliferation after stimulation with cleaved antigen, and could completely block the response against both native and deamidated gluten peptides. We found that AnP2 was efficient down to a 1:64 protease:substrate ratio (w:w). When AnP2 was tested in assays using seven gluten-reactive T cell lines from individual CD patients (three adults and four children), the response to gluten was diminished in all cases. Our study indicates a therapeutic benefit of AnP2 to CD patients.

  12. PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma.

    PubMed

    Miyoshi, Hiroaki; Kiyasu, Junichi; Kato, Takeharu; Yoshida, Noriaki; Shimono, Joji; Yokoyama, Shintaro; Taniguchi, Hiroaki; Sasaki, Yuya; Kurita, Daisuke; Kawamoto, Keisuke; Kato, Koji; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-09-01

    Programmed cell death ligand 1 (PD-L1) is expressed on both tumor and tumor-infiltrating nonmalignant cells in lymphoid malignancies. The programmed cell death 1 (PD-1)/PD-L1 pathway suppresses host antitumor responses, although little is known about the significance of PD-1/PD-L1 expression in the tumor microenvironment. To investigate the clinicopathological impact of PD-L1 expression in adult T-cell leukemia/lymphoma (ATLL), we performed PD-L1 immunostaining in 135 ATLL biopsy samples. We observed 2 main groups: 1 had clear PD-L1 expression in lymphoma cells (nPD-L1(+), 7.4% of patients), and the other showed minimal expression in lymphoma cells (nPD-L1(-), 92.6%). Within the nPD-L1(-) group, 2 subsets emerged: the first displayed abundant PD-L1 expression in nonmalignant stromal cells of the tumor microenvironment (miPD-L1(+), 58.5%) and the second group did not express PD-L1 in any cell (PD-L1(-), 34.1%). nPD-L1(+) ATLL (median survival time [MST] 7.5 months, 95% CI [0.4-22.3]) had inferior overall survival (OS) compared with nPD-L1(-) ATLL (MST 14.5 months, 95% CI [10.1-20.0]) (P = .0085). Among nPD-L1(-) ATLL, miPD-L1(+) ATLL (MST 18.6 months, 95% CI [11.0-38.5]) showed superior OS compared with PD-L1(-) ATLL (MST 10.2 months, 95% CI [8.0-14.7]) (P = .0029). The expression of nPD-L1 and miPD-L1 maintained prognostic value for OS in multivariate analysis (P = .0322 and P = .0014, respectively). This is the first report describing the clinicopathological features and outcomes of PD-L1 expression in ATLL. More detailed studies will disclose clinical and biological significance of PD-L1 expression in ATLL. PMID:27418641

  13. CPI-613 and Bendamustine Hydrochloride in Treating Patients With Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma or Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-07-26

    Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Large Granular Lymphocyte Leukemia

  14. PHF6 mutations in T-cell acute lymphoblastic leukemia.

    PubMed

    Van Vlierberghe, Pieter; Palomero, Teresa; Khiabanian, Hossein; Van der Meulen, Joni; Castillo, Mireia; Van Roy, Nadine; De Moerloose, Barbara; Philippé, Jan; González-García, Sara; Toribio, María L; Taghon, Tom; Zuurbier, Linda; Cauwelier, Barbara; Harrison, Christine J; Schwab, Claire; Pisecker, Markus; Strehl, Sabine; Langerak, Anton W; Gecz, Jozef; Sonneveld, Edwin; Pieters, Rob; Paietta, Elisabeth; Rowe, Jacob M; Wiernik, Peter H; Benoit, Yves; Soulier, Jean; Poppe, Bruce; Yao, Xiaopan; Cordon-Cardo, Carlos; Meijerink, Jules; Rabadan, Raul; Speleman, Frank; Ferrando, Adolfo

    2010-04-01

    Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.

  15. Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

    PubMed Central

    Castro-Manrreza, Marta E.; Mayani, Hector; Monroy-García, Alberto; Flores-Figueroa, Eugenia; Chávez-Rueda, Karina; Legorreta-Haquet, Victoria; Santiago-Osorio, Edelmiro

    2014-01-01

    Bone marrow-mesenchymal stromal cells (BM-MSCs) have immunosuppressive properties and have been used in cell therapies as immune regulators for the treatment of graft-versus-host disease. We have previously characterized several biological properties of MSCs from placenta (PL) and umbilical cord blood (UCB), and compared them to those of BM—the gold standard. In the present study, we have compared MSCs from BM, UCB, and PL in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells. Our results confirm the immunosuppressive potential of BM-MSCs, and demonstrate that MSCs from UCB and, to a lesser extent PL, also have immunosuppressive potential. In contrast to PL-MSCs, BM-MSCs and UCB-MSCs significantly inhibited the proliferation of both CD4+ and CD8+ activated T cells in a cell–cell contact-dependent manner. Such a reduced proliferation in cell cocultures correlated with upregulation of programmed death ligand 1 on MSCs and cytotoxic T lymphocyte-associated Ag-4 (CTLA-4) on T cells, and increased production of interferon-γ, interleukin-10, and prostaglandin E2. Importantly, and in contrast to PL-MSCs, both BM-MSCs and UCB-MSCs favored the generation of T-cell subsets displaying a regulatory phenotype CD4+CD25+CTLA-4+. Our results indicate that, besides BM-MSCs, UCB-MSCs might be a potent and reliable candidate for future therapeutic applications. PMID:24428376

  16. Novel biological insights in T-cell acute lymphoblastic leukemia.

    PubMed

    Durinck, Kaat; Goossens, Steven; Peirs, Sofie; Wallaert, Annelynn; Van Loocke, Wouter; Matthijssens, Filip; Pieters, Tim; Milani, Gloria; Lammens, Tim; Rondou, Pieter; Van Roy, Nadine; De Moerloose, Barbara; Benoit, Yves; Haigh, Jody; Speleman, Frank; Poppe, Bruce; Van Vlierberghe, Pieter

    2015-08-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. It is considered as a paradigm for the multistep nature of cancer initiation and progression. Genetic and epigenetic reprogramming events, which transform T-cell precursors into malignant T-ALL lymphoblasts, have been extensively characterized over the past decade. Despite our comprehensive understanding of the genomic landscape of human T-ALL, leukemia patients are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable acute and long-term side effects, about 15% of pediatric and 40% of adult T-ALL patients still relapse, owing to acquired therapy resistance, and present with very dismal survival perspectives. Unfortunately, the molecular mechanisms by which residual T-ALL tumor cells survive chemotherapy and act as a reservoir for leukemic progression and hematologic relapse remain poorly understood. Nevertheless, it is expected that enhanced molecular understanding of T-ALL disease biology will ultimately facilitate a targeted therapy driven approach that can reduce chemotherapy-associated toxicities and improve survival of refractory T-ALL patients through personalized salvage therapy. In this review, we summarize recent biological insights into the molecular pathogenesis of T-ALL and speculate how the genetic landscape of T-ALL could trigger the development of novel therapeutic strategies for the treatment of human T-ALL. PMID:26123366

  17. Sacral chordoma in an adult showing an aggressive clinical course: A case report

    PubMed Central

    ENDO, KOJI; YAMASHITA, HIDEKI; NAGASHIMA, HIDEKI; TESHIMA, RYOTA

    2014-01-01

    The current report presents a case of a 78-year-old male with sacral chordoma, showing an aggressive clinical course. The patient underwent sacral resection, however, nine months later, multiple metastases were detected by magnetic resonance imaging. The metastases progressed rapidly and 15 months following surgery the patient succumbed to respiratory dysfunction. An autopsy revealed multiple metastases of the lung, liver, heart, kidneys and vertebrae. Pathologically, the tumors did not show proliferation of anaplastic cells or dedifferentiation; however, the metastatic tumor cells were smaller than the primary tumor cells. The Ki-67 labeling indices were <5% in all of the patient’s tumors, therefore, the capacity for cellular proliferation of the tumors was considered to be low. Chordoma in adults are generally slow-growing tumors and are associated with a relatively prolonged course and frequent local recurrences. Therefore, it must be recognized that chordoma may grow rapidly and show an aggressive clinical course, even when the Ki-67 labeling index is low. PMID:24765153

  18. High Fetal Estrogen Concentrations: Correlation with Increased Adult Sexual Activity and Decreased Aggression in Male Mice

    NASA Astrophysics Data System (ADS)

    Vom Saal, Frederick S.; Grant, William M.; McMullen, Carol W.; Laves, Kurt S.

    1983-06-01

    In the house mouse (Mus musculus), fetuses may develop in utero next to siblings of the same or opposite sex. The amniotic fluid of the female fetuses contains higher concentrations of estradiol than that of male fetuses. Male fetuses that developed in utero between female fetuses had higher concentrations of estradiol in their amniotic fluid than males that were located between other male fetusesw during intrauterine development. They were also more sexually active as adults, less aggressive, and had smaller seminal vesicles than males that had developed between other male fetuses in utero. These findings raise the possibility that during fetal life circulating estrogens may interact with circulating androgens both in regulating the development of sex differences between males and females and in producing variation in phenotype among males and among females.

  19. Differentiating Forms and Functions of Aggression in Emerging Adults: Associations with Hostile Attribution Biases and Normative Beliefs

    ERIC Educational Resources Information Center

    Bailey, Christopher A.; Ostrov, Jamie M.

    2008-01-01

    The purpose of this study was to extend the current literature on forms (i.e., physical and relational) and functions (i.e., proactive and reactive) of participants' cognitions and beliefs about aggressive behavior. Participants included an ethnically diverse group of emerging adults (N = 165; M = 19.05 years; SD = 1.55) and completed a battery of…

  20. Trajectories of Adolescent Hostile-Aggressive Behavior and Family Climate: Longitudinal Implications for Young Adult Romantic Relationship Competence

    ERIC Educational Resources Information Center

    Fosco, Gregory M.; Van Ryzin, Mark J.; Xia, Mengya; Feinberg, Mark E.

    2016-01-01

    The formation and maintenance of young adult romantic relationships that are free from violence and are characterized by love, connection, and effective problem-solving have important implications for later well-being and family functioning. In this study, we examined adolescent hostile-aggressive behavior (HAB) and family relationship quality as…

  1. Designer T cells by T cell receptor replacement.

    PubMed

    Sommermeyer, Daniel; Neudorfer, Julia; Weinhold, Monika; Leisegang, Matthias; Engels, Boris; Noessner, Elfriede; Heemskerk, Mirjam H M; Charo, Jehad; Schendel, Dolores J; Blankenstein, Thomas; Bernhard, Helga; Uckert, Wolfgang

    2006-11-01

    T cell receptor (TCR) gene transfer is a convenient method to produce antigen-specific T cells for adoptive therapy. However, the expression of two TCR in T cells could impair their function or cause unwanted effects by mixed TCR heterodimers. With five different TCR and four different T cells, either mouse or human, we show that some TCR are strong--in terms of cell surface expression--and replace weak TCR on the cell surface, resulting in exchange of antigen specificity. Two strong TCR are co-expressed. A mouse TCR replaces human TCR on human T cells. Even though it is still poorly understood why some TCRalpha/beta combinations are preferentially expressed on T cells, our data suggest that, in the future, designer T cells with exclusive tumor reactivity can be generated by T cell engineering. PMID:17051621

  2. Investigating human T cell lymphotropic retrovirus (HTLV) Tax function with molecular and immunophenotypic techniques.

    PubMed

    Forlani, Greta; Accolla, Roberto S; Tosi, Giovanna

    2014-01-01

    Human T cell Lymphotropic Viruses 1 and 2 (HTLV-1 and HTLV-2) are the first described human retroviruses. HTLV-1 is the causative agent of an aggressive malignancy of CD4+ T lymphocytes named adult T-cell leukemia/lymphoma (ATLL) and of a chronic neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 shares many similarities with HTLV-1, but displays lower or absent association to diseases. Among the proteins encoded by HTLVs, the viral transactivator Tax exerts an essential role in viral transcription as well as in cell transformation. Different experimental methods to study Tax activity on HTLV-LTR promoter and Tax subcellular distribution are described. Emphasis is given to the functional and physical interaction between Tax-1/Tax-2 and cellular cofactors which may have an impact on the infectivity process of the HTLVs and on the capacity of cell transformation.

  3. Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting: Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4{sup +} T cells compared

    SciTech Connect

    Ford, A.L.; Goodsall, A.L.; Sedgwick, J.D.

    1995-05-01

    Ramified microglia in the adult central nervous system (CNS) are the principal glial element up-regulating MHC class I and II expression in response to inflammatory events or neuronal damage. A proportion of these cells also express MHC class II constitutively in the normal CNS. The role of microglia as APCs for CD4{sup +} cells extravasating into the CNS remains undefined. In this study, using irradiation bone marrow chimeras in CD45-congenic rats, the phenotype CD45{sup low}CD11b/c{sup +} is shown to identify microglial cells specifically within the CNS. Highly purified populations of microglia and nonmicroglial but CNS-associated macrophages (CD45{sup high}CD11b/c{sup +}) have been obtained directly from the adult CNS, by using flow cytometric sorting. Morphologically, freshly isolated microglia vs other CNS macrophages are quite distinct. Of the two populations recovered from the normal CNS, it is the minority CD45{sup high}CD11 b/c{sup +} transitional macrophage population, and not microglia, that is the effective APC for experimental autoimmune encephalomyelitis-inducing CD4{sup +} myelin basic protein (MBP)-reactive T cells. CD45{sup high}CD11b/c{sup +} CNS macrophages also stimulate MBP-reactive T cells without addition of MBP to culture suggesting presentation of endogenous Ag. This is the first study in which microglia vs other CNS macrophages have been analyzed for APC ability directly from the CNS, with substantial cross-contamination between the two populations eliminated. The heterogeneity of these populations in terms of APC function is clearly demonstrated. Evidence is still lacking that adult CNS microglia have the capacity to interact with and stimulate CD4{sup +} T cells to proliferate or secrete IL-2. 60 refs., 6 figs., 1 tab.

  4. Olanzapine vs. Risperidone in Treating Aggressive Behaviours in Adults with Intellectual Disability: A Single Blind Study

    ERIC Educational Resources Information Center

    Amore, M.; Bertelli, M.; Villani, D.; Tamborini, S.; Rossi, M.

    2011-01-01

    Background: Aggressive behaviour represents a frequent symptom in people with intellectual disability (PWID). Despite uncertain evidence of effectiveness, the use of antipsychotics (APs) drugs to treat aggressive behaviour is very common. Antipsychotic medication of aggressivity in PWID has recently become one of the most debated issues in mental…

  5. I spy alloreactive T cells.

    PubMed

    Alegre, Maria-Luisa

    2015-01-28

    High-throughput sequencing of the T cell receptor Vβ CDR3 region allowed longitudinal tracking of alloreactive T cells in kidney transplant patients, revealing clonal deletion as a mechanism of transplantation tolerance (Morris et al., this issue). PMID:25632032

  6. Peripheral T-cell lymphoma.

    PubMed

    Foss, Francine M; Zinzani, Pier Luigi; Vose, Julie M; Gascoyne, Randy D; Rosen, Steven T; Tobinai, Kensei

    2011-06-23

    Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive diseases associated with poor outcome. Studies that focus specifically on PTCL are emerging, with the ultimate goal of improved understanding of disease biology and the development of more effective therapies. However, one of the difficulties in classifying and studying treatment options in clinical trials is the rarity of these subtypes. Various groups have developed lymphoma classifications over the years, including the World Health Organization, which updated its classification in 2008. This article briefly reviews the major lymphoma classification schema, highlights contributions made by the collaborative International PTCL Project, discusses prognostic issues and gene expression profiling, and outlines therapeutic approaches to PTCL. These include the standard chemotherapeutic regimens and other modalities incorporating antifolates, conjugates, histone deacetylase inhibitors, monoclonal antibodies, nucleoside analogs, proteasome inhibitors, and signaling inhibitors. As this review emphasizes, the problem has now evolved into an abundance of drugs and too few patients available to test them. Collaborative groups will aid in future efforts to find the best treatment strategies to improve the outcome for patients with PTCL.

  7. An overview of cutaneous T cell lymphomas

    PubMed Central

    Bagherani, Nooshin; Smoller, Bruce R.

    2016-01-01

    Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas that are characterized by a cutaneous infiltration of malignant monoclonal T lymphocytes. They typically afflict adults with a median age of 55 to 60 years, and the annual incidence is about 0.5 per 100,000. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T cell lymphomas not otherwise specified are the most important subtypes of CTCL. CTCL is a complicated concept in terms of etiopathogenesis, diagnosis, therapy, and prognosis. Herein, we summarize advances which have been achieved in these fields. PMID:27540476

  8. Treatment of T cell lymphoma in dogs.

    PubMed

    Moore, Antony S

    2016-09-17

    Overall, canine lymphoma remains one of the most chemotherapy-responsive cancers in the dog. In addition to the stage and the substage of disease, T cell phenotype is the most consistently important prognostic factor. T cell lymphoma (TCL) in dogs is a heterogeneous disease; dogs with a separate entity of indolent TCL can have a considerably better prognosis than dogs with other forms of lymphoma, and indolent TCL may not always require immediate treatment. In contrast, high-grade TCL is an aggressive disease, and when treated with CHOP-based protocols, dogs with this high-grade TCL have a complete remission rate as low as 40 per cent, relapse earlier and have shorter survival time than dogs with a comparable stage, high-grade B cell lymphoma. This review describes the different disease entities that comprise canine TCL, discusses prognosis for each and treatment options that appear to give the best outcomes. PMID:27634860

  9. Treatment of T cell lymphoma in dogs.

    PubMed

    Moore, Antony S

    2016-09-17

    Overall, canine lymphoma remains one of the most chemotherapy-responsive cancers in the dog. In addition to the stage and the substage of disease, T cell phenotype is the most consistently important prognostic factor. T cell lymphoma (TCL) in dogs is a heterogeneous disease; dogs with a separate entity of indolent TCL can have a considerably better prognosis than dogs with other forms of lymphoma, and indolent TCL may not always require immediate treatment. In contrast, high-grade TCL is an aggressive disease, and when treated with CHOP-based protocols, dogs with this high-grade TCL have a complete remission rate as low as 40 per cent, relapse earlier and have shorter survival time than dogs with a comparable stage, high-grade B cell lymphoma. This review describes the different disease entities that comprise canine TCL, discusses prognosis for each and treatment options that appear to give the best outcomes.

  10. Role of memory T cell subsets for adoptive immunotherapy.

    PubMed

    Busch, Dirk H; Fräßle, Simon P; Sommermeyer, Daniel; Buchholz, Veit R; Riddell, Stanley R

    2016-02-01

    Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. Besides the definition of optimal targets and antigen receptors, the differentiation status of transferred T cells is emerging as a crucial parameter for generating cell products with optimal efficacy and safety profiles. Long-living memory T cells subdivide into phenotypically as well as functionally different subsets (e.g. central memory, effector memory, tissue-resident memory T cells). This diversification process is crucial for effective immune protection, with probably distinct dependencies on the presence of individual subsets dependent on the disease to which the immune response is directed as well as its organ location. Adoptive T cell therapy intends to therapeutically transfer defined T cell immunity into patients. Efficacy of this approach often requires long-term maintenance of transferred cells, which depends on the presence and persistence of memory T cells. However, engraftment and survival of highly differentiated memory T cell subsets upon adoptive transfer is still difficult to achieve. Therefore, the recent observation that a distinct subset of weakly differentiated memory T cells shows all characteristics of adult tissue stem cells and can reconstitute all types of effector and memory T cell subsets, became highly relevant. We here review our current understanding of memory subset formation and T cell subset purification, and its implications for adoptive immunotherapy.

  11. Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia

    SciTech Connect

    Rajasingh, Johnson; Raikwar, Himanshu P.; Muthian, Gladson; Johnson, Caroline; Bright, John J. . E-mail: jbright1@clarian.org

    2006-02-10

    Adult T cell leukemia is an aggressive and frequently fatal malignancy that expressess constitutively activated growth-signaling pathways in association with deregulated growth and resistance to apoptosis. Curcumin (diferuloylmethane) is a naturally occurring yellow pigment, isolated from the rhizomes of the plant Curcuma longa that has traditionally been used in the treatment of injury and inflammation. But the effect and mechanism of action of curcumin on T cell leukemia is not known. To investigate the antitumor activity of curcumin in T cell leukemia, we examined its effect on constitutive phosphorylation of JAK and STAT proteins, proliferation, and apoptosis in HTLV-I-transformed T cell lines. HTLV-I-transformed T cell leukemia lines, MT-2, HuT-102, and SLB-1, express constitutively phosphorylated JAK3, TYK2, STAT3, and STAT5 signaling proteins. In vitro treatment with curcumin induced a dose-dependent decrease in JAK and STAT phosphorylation resulting in the induction of growth-arrest and apoptosis in T cell leukemia. The induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by which curcumin induces antitumor activity in T cell leukemia.

  12. Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma

    ClinicalTrials.gov

    2016-11-02

    Adult T Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Stage II Adult T-Cell Leukemia/Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-Cell Leukemia/Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-Cell Leukemia/Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  13. Prenatal testosterone supplementation alters puberty onset, aggressive behavior, and partner preference in adult male rats.

    PubMed

    Dela Cruz, Cynthia; Pereira, Oduvaldo C M

    2012-03-01

    The objective of this study was to investigate whether prenatal exposure to testosterone (T) could change the body weight (BW), anogenital distance (AGD), anogenital distance index (AGDI), puberty onset, social behavior, fertility, sexual behavior, sexual preference, and T level of male rats in adulthood. To test this hypothesis, pregnant rats received either 1 mg/animal of T propionate diluted in 0.1 ml peanut oil or 0.1 ml peanut oil, as control, on the 17th, 18th and 19th gestational days. No alterations in BW, AGD, AGDI, fertility, and sexual behavior were observed (p > 0.05). Delayed onset of puberty (p < 0.0001), increased aggressive behavior (p > 0.05), altered pattern of sexual preference (p < 0.05), and reduced T plasma level (p < 0.05) were observed for adult male rats exposed prenatally to T. In conclusion, the results showed that prenatal exposure to T was able to alter important aspects of sexual and social behavior although these animals were efficient at producing descendants. In this sense more studies should be carried to evaluated the real impact of this hormonal alteration on critical period of sexual differentiation on humans, because pregnant women exposed to hyperandrogenemia and then potentially exposing their unborn children to elevated androgen levels in the uterus can undergo alteration of normal levels of T during the sexual differentiation period, and, as a consequence, affect the reproductive and behavior patterns of their children in adulthood.

  14. [Molecular pathogenesis of peripheral T-cell lymphoma (1): angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified and anaplastic large cell lymphoma].

    PubMed

    Couronné, Lucile; Bastard, Christian; Gaulard, Philippe; Hermine, Olivier; Bernard, Olivier

    2015-10-01

    Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T/NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of the histological subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. It will be published in two parts : the first is focused on the three more frequent entities, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second (which will appear in the november issue) will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma. T or NK cell lymphoproliferative disorders with leukemic presentation, primary cutaneous T-cell lymphoma and very rare subtypes of PTCL whose prevalence is less than 5% (hepatosplenic T-cell lymphoma and subcutaneous panniculitis-like T cell lymphoma) will not be discussed herein. PMID:26481023

  15. Engineering antitumor immunity by T-cell adoptive immunotherapy.

    PubMed

    Riddell, Stanley R

    2007-01-01

    The adoptive transfer of antigen-specific T cells has been used successfully to treat experimental tumors in animal models and viral infections in humans, but harnessing the exquisite specificity and potency of T cells to treat human malignancy has proven challenging. The efforts to use T cells to treat patients with cancer have often been informative in identifying limitations that must be overcome to improve therapeutic efficacy, and a clearer picture of the requirements for successful adoptive T-cell transfer is gradually emerging. Indolent and a subset of aggressive B-cell lymphomas in humans have been shown to be susceptible to eradication by T cells in clinical settings where highly immunogenic minor histocompatibility or viral antigens are presented by tumor cells. In this article, we will review how recent advances in our understanding of the properties of antigen-specific T cells that facilitate their long-term persistence in vivo and reversion to the memory pool after in vitro culture, combined with approaches to molecularly engineer T cells with receptors that target molecules expressed by B-cell lymphoma, are providing opportunities to broaden the application of T-cell therapy and improve its efficacy for this disease.

  16. Childhood Psychological Abuse and Adult Aggression: The Mediating Role of Self-Capacities

    ERIC Educational Resources Information Center

    Allen, Brian

    2011-01-01

    The current study examines the utility of self-trauma theory for explaining the long-term impact of childhood psychological abuse on aggression. Specifically, the self-capacities of interpersonal relatedness, identity, and affect regulation are tested as mediators of the impact of psychological abuse on various types of aggression in adulthood.…

  17. Effective treatment of a murine model of adult T-cell leukemia using 211At-7G7/B6 and its combination with unmodified anti-Tac (daclizumab) directed toward CD25.

    PubMed

    Zhang, Zhuo; Zhang, Meili; Garmestani, Kayhan; Talanov, Vladimir S; Plascjak, Paul S; Beck, Barbara; Goldman, Carolyn; Brechbiel, Martin W; Waldmann, Thomas A

    2006-08-01

    Adult T-cell leukemia (ATL) consists of an overabundance of T cells, which express CD25. Therapeutic efficacy of astatine-211 ((211)At)-labeled murine monoclonal antibody 7G7/B6 alone and in combination with daclizumab was evaluated in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice given injections of MET-1 human T-cell leukemia cells. Daclizumab and 7G7/B6 are directed toward different epitopes of CD25. Either a single dose of 12 microCi (0.444 MBq) (211)At-7G7/B6 per mouse given intravenously or receptor-saturating doses of daclizumab given at 100 microg weekly for 4 weeks intravenously inhibited tumor growth as monitored by serum levels of human beta-2 microglobulin (beta(2)mu) and by prolonged survival of leukemia-bearing mice compared with the control groups (P < .001). The combination of 2 agents enhanced the antitumor effect when compared with groups treated with 12 microCi (0.444 MBq) of (211)At-7G7/B6 (P < .05) or daclizumab alone (P < .05). The median survival duration of the PBS group was 62.6 days and 61.5 days in the radiolabeled nonspecific antibody (211)At-11F11-treated group. In contrast, 91% of mice in the combination group survived through day 94. These results that demonstrate a significantly improved therapeutic efficacy by combining (211)At-7G7/B6 with daclizumab support a clinical trial of this regimen in patients with ATL. PMID:16569769

  18. Adolescent social instability stress increases aggression in a food competition task in adult male Long-Evans rats.

    PubMed

    Cumming, Mark J; Thompson, Madison A; McCormick, Cheryl M

    2014-11-01

    Adolescent social instability stress (SS; daily 1 hr isolation + new cage partners postnatal days 30-45; thereafter with original cage partner, also in the SS condition) and control (CTL) rats competed for access to a preferred food in five sessions against their cage partner. In the first session, SS pairs displayed more aggression (face whacks, p = .02; rear attacks, p = .03), were less likely to relinquish access to the food voluntarily (p = .03), spent more time at the feeder than CTL pairs (p = .06), but did not differ in latency to access the feeder (p = .41). Pairs were considered in dominant-submissive relationships (DSR) if one rat spent significantly more time at the feeder than the other; 8 of 12 SS and 8 of 12 CTL pairs displayed DSRs (remaining: no-DSR). Aggression increased from the 1st to 5th session (p < .001), was greater in no-DSR than DSR pairs (p = .04; consistent with the proposed function of DSRs to be the reduction of aggression in groups), and was higher in SS than CTL pairs (p = .05). Because the increased aggression of SS compared with CTL pairs did not result in a significant increase in their time at the feeder, the increased aggression may be considered maladaptive, and may reflect an increased motivation for food reward. These results add to evidence that SS in adolescence modifies the adult social repertoire of rats and highlight the importance of adolescent social experiences for adult behavior.

  19. Indolent T-cell lymphoproliferative disease of the gastrointestinal tract

    PubMed Central

    Perry, Anamarija M.; Warnke, Roger A.; Hu, Qinglong; Gaulard, Philippe; Copie-Bergman, Christiane; Alkan, Serhan; Wang, Huan-You; Cheng, Jason X.; Bacon, Chris M.; Delabie, Jan; Ranheim, Erik; Kucuk, Can; Hu, XiaoZhou; Weisenburger, Dennis D.

    2013-01-01

    Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4−/CD8+, 1 was CD4+/CD8−, and another was CD4−/CD8−. T-cell receptor-γ chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name “indolent T-LPD of the GI tract” for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy. PMID:24009234

  20. A case of extranodal NK/T-cell lymphoma, nasal type mimicking typical manifestations of adult-onset Still's disease (AOSD) with hemophagocytic syndrome: diagnostic consideration between malignant lymphoma without lymphadenopathy and AOSD.

    PubMed

    Kato, Takashi; Tanabe, Juichi; Kanemoto, Motoko; Kobayashi, Chiharu; Morita, Sho; Karahashi, Taro

    2009-01-01

    A 25-year-old Japanese man was suffering from high fever, sore throat, arthralgia, and macular salmon-pink eruption. The superficial lymph node was not palpable, and computed tomographic scans from the neck to pelvis demonstrated hepatosplenomegaly without apparent lymphadenopathy. Therefore, the possibility of malignant lymphoma was considered to be extremely low. Serology for Epstein Barr virus (EBV) and cytomegalovirus showed a postinfectious state, and blood culture was negative. Serum rheumatoid factor and antinuclear antibody were negative. Leukocytopenia (2.4 x 10(3)/mul) was observed, and thus a diagnosis of adult-onset Still's disease (AOSD) with hemophagocytic syndrome (HPS) was made. Fifty-five milligrams of prednisolone daily improved his symptoms and leukocytopenia promptly, but high fever with severe and progressive thrombocytopenia occurred 12 days later. Bone marrow aspiration revealed the presence of lymphoma cells and hemophagocytosis, and the CD45 gating analysis showed expanding population of CD2(+), CD3(-), and CD56(+) cells. Further, mucosal ulceration in the nasal cavity was detected. Therefore, a diagnosis of extranodal natural killer (NK)/T-cell lymphoma, nasal type, concomitant with HPS was made, and treatment with dexamethasone, etoposide, ifosfamide, carboplatin (DeVIC) regimen ameliorated his symptoms and platelet transfusion dependency. Later, a high titer of serum EBV-DNA was detected, which supported the diagnosis. Diagnosing AOSD, extranodal presentation of malignant lymphoma such as extranodal NK/T-cell lymphoma, nasal type, should be carefully considered. PMID:19609486

  1. NK/T cell lymphoma associated with peripheral eosinophilia.

    PubMed

    Yap, E; Wan Jamaluddin, W F; Tumian, N R; Mashuri, F; Mohammed, F; Tan, G C; Masir, N; Abdul Wahid, F S

    2014-12-01

    NK/T cell lymphoma, nasal type is an aggressive and uncommon malignancy. Disease that occurs outside of the aerodigestive tract exhibits an even more aggressive clinical behaviour and does not respond as well to conventional therapy compared to its nasal counterpart. We report such a case of NK/T cell lymphoma, nasal type, that presented as an anterior chest wall mass, arising from the left pectoralis muscle. An interesting feature we wish to highlight is the associated eosinophilia that corresponded to disease activity, exhibiting fluctuations with surgical resection and chemotherapy. To the best of our knowledge this is the third reported case of NK/T cell lymphoma that is associated with peripheral eosinophilia. Our case highlights the role of certain NK cell subsets that play a major role in eosinophilic activation in NK/T lymphomas and calls for more research into further classification of this disease by virtue of its NK cell subsets. PMID:25500520

  2. T cell and non-T cell compartments can independently determine resistance to Leishmania major

    PubMed Central

    1995-01-01

    In experimental murine cutaneous leishmaniasis caused by Leishmania major (Lm), the cellular determinants governing development of protective or exacerbative T cells are not well understood. We, therefore, attempted to determine the influence of T cell and non-T cell compartments on disease outcome. To this end, T cell chimeric mice were constructed using adult thymectomized lethally irradiated, bone marrow-reconstituted (ATXBM) animals of genetically resistant, C57BL/6, or susceptible, BALB/c, backgrounds. These hosts were engrafted with naive T cell populations from H-2-congenic susceptible, BALB.B6-H-2b, or resistant, C57BL/6.C-H-2d, animals, respectively. Chimeric mice were then infected with Lm, and disease outcome was monitored. BALB/c T cell chimeric mice, BALB/c ATXBM hosts given naive C57BL/6.C-H-2d T cells, resolved their infections as indicated by reductions in both lesion size and parasite numbers. Furthermore, the mice developed typical Th1 (interferon[IFN]-gamma hiinterleukin[IL]-4lo) cytokine patterns. In contrast, both sham chimeric, BALB/c ATXBM hosts given naive BALB/c T cells, and control irradiated euthymic mice succumbed to infection, producing Th2 profiles (IFN-gamma loIL-4hiIL-10hi). C57BL/6 T cell chimeras, C57BL/6 ATXBM hosts given naive BALB.B6-H-2b T cells, resolved their infections as did C57BL/6 sham chimeras and euthymic controls. Interestingly, whereas C57BL/6 control animals produced Th1 cytokines, chimeric animals progressed from Th0 (IFN-gamma hiIL-4hiIL- 10hi) to Th2 (IFN-gamma loIL-4hiIL-10hi) cytokine profiles as cure ensued. Both reconstitution and chimeric status of all mice were confirmed by flow cytometry. In addition, T cell receptor V beta usage of Lm-specific blasts was determined. In all cases, V beta use was multiclonal, involving primarily V beta 2, 4, 6, 8.1, 8.2, 8.3, 10, and 14, with relative V beta frequencies differing between H-2b and H-2d animals. Most importantly, however, these differences did not segregate

  3. Childhood Chronic Physical Aggression Associates with Adult Cytokine Levels in Plasma

    PubMed Central

    Provençal, Nadine; Suderman, Matthew J.; Vitaro, Frank; Szyf, Moshe; Tremblay, Richard E.

    2013-01-01

    Background An increasing number of animal and human studies are indicating that inflammation is associated with behavioral disorders including aggression. This study investigates the association between chronic physical aggression during childhood and plasma cytokine levels in early adulthood. Methodology/Principal Findings Two longitudinal studies were used to select males on a chronic physical aggression trajectory from childhood to adolescence (n = 7) and a control group from the same background (n = 25). Physical aggression was assessed yearly by teachers from childhood to adolescence and plasma levels of 10 inflammatory cytokines were assessed at age 26 and 28 years. Compared to the control group, males on a chronic physical aggression trajectory from childhood to adolescence had consistently lower plasma levels of five cytokines: lower pro-inflammatory interleukins IL-1α (T(28.7) = 3.48, P = 0.002) and IL-6 (T(26.9) = 3.76, P = 0.001), lower anti-inflammatory interleukin IL-4 (T(27.1) = 4.91, P = 0.00004) and IL-10 (T(29.8) = 2.84, P = 0.008) and lower chemokine IL-8 (T(26) = 3.69, P = 0.001). The plasma levels of four cytokines accurately predicted aggressive and control group membership for all subjects. Conclusions/Significance Physical aggression of boys during childhood is a strong predictor of reduced plasma levels of cytokines in early adulthood. The causal and physiological relations underlying this association should be further investigated since animal data suggest that some cytokines such as IL-6 and IL-1β play a causal role in aggression. PMID:23922720

  4. Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression.

    PubMed

    Smagin, Dmitry A; Park, June-Hee; Michurina, Tatyana V; Peunova, Natalia; Glass, Zachary; Sayed, Kasim; Bondar, Natalya P; Kovalenko, Irina N; Kudryavtseva, Natalia N; Enikolopov, Grigori

    2015-01-01

    Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights. PMID:26648838

  5. Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression

    PubMed Central

    Smagin, Dmitry A.; Park, June-Hee; Michurina, Tatyana V.; Peunova, Natalia; Glass, Zachary; Sayed, Kasim; Bondar, Natalya P.; Kovalenko, Irina N.; Kudryavtseva, Natalia N.; Enikolopov, Grigori

    2015-01-01

    Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights. PMID:26648838

  6. Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT.

    PubMed

    Cahu, X; Labopin, M; Giebel, S; Aljurf, M; Kyrcz-Krzemien, S; Socié, G; Eder, M; Bonifazi, F; Bunjes, D; Vigouroux, S; Michallet, M; Stelljes, M; Zuckerman, T; Finke, J; Passweg, J; Yakoub-Agha, I; Niederwieser, D; Sucak, G; Sengeløv, H; Polge, E; Nagler, A; Esteve, J; Mohty, M

    2016-03-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown. In this retrospective study, 601 patients were included. Patients received allo-SCT in CR1, CR2, CR >2 or in advanced disease in 69%, 15%, 2% and 14% of cases, respectively. With an overall follow-up of 58 months, 523 patients received a TBI-based regimen, whereas 78 patients received a chemotherapy-based regimen including IV busulfan-cyclophosphamide (IV Bu-Cy) (n=46). Unlike patients aged ⩾35 years, patients aged <35 years who received a TBI-based regimen displayed an improved outcome compared with patients who received a chemotherapy-based regimen (5-year leukemia-free survival (LFS) of 50% for TBI versus 18% for chemo-only regimen or IV Bu-Cy regimens, P=10(-5) and 10(-4), respectively). In multivariate analysis, use of TBI was associated with an improved LFS (hazard ratio (HR)=0.55 (0.34-0.86), P=0.01) and overall survival (HR=0.54 (0.34-0.87), P=0.01) in patients aged <35 years. In conclusion, younger adult patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens. PMID:26618548

  7. Peripheral T-Cell Lymphoma

    MedlinePlus

    ... consists of a group of rare and usually aggressive (fast-growing) NHLs that develop from mature T- ... also be involved. This group of PTCLs is aggressive and requires combination chemotherapy upon diagnosis. Anaplastic Large ...

  8. T-Cell Receptor-Transduced T Cells: Clinical Experience.

    PubMed

    Robbins, Paul F

    2015-01-01

    The large number of T-cell epitopes that have been found to be processed and presented on human tumors, now numbering in the hundreds, provides a rich source of targets for therapeutic interventions aimed at inducing durable tumor regression. Vaccination strategies aimed at inducing responses to these antigens have been largely ineffective, and it has been challenging to generate large numbers of T cells with the functional capacity to mediate durable tumor regressions in adoptive immunotherapy strategies in patients who have common epithelial malignancies. The ability to generate T-cell receptors that recognize shared as well as unique antigens expressed in a wide variety of common tumor types that include lung, breast, ovarian, gastrointestinal, urothelial, and genitourinary cancers provides an opportunity to develop widely applicable therapies based on the adoptive transfer of autologous T cells transduced with those receptors.

  9. Autologous Tax-specific CTL therapy in a primary adult T cell leukemia/lymphoma cell-bearing NOD/Shi-scid, IL-2Rγnull mouse model.

    PubMed

    Masaki, Ayako; Ishida, Takashi; Suzuki, Susumu; Ito, Asahi; Mori, Fumiko; Sato, Fumihiko; Narita, Tomoko; Yamada, Tomiko; Ri, Masaki; Kusumoto, Shigeru; Komatsu, Hirokazu; Tanaka, Yuetsu; Niimi, Akio; Inagaki, Hiroshi; Iida, Shinsuke; Ueda, Ryuzo

    2013-07-01

    We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute-type patient, whose postchemotherapeutic remission continued for >18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer. PMID:23733874

  10. MicroRNA Profile of Circulating CD4-positive Regulatory T Cells in Human Adults and Impact of Differentially Expressed MicroRNAs on Expression of Two Genes Essential to Their Function*

    PubMed Central

    Fayyad-Kazan, Hussein; Rouas, Redouane; Fayyad-Kazan, Mohammad; Badran, Rabih; El Zein, Nabil; Lewalle, Philippe; Najar, Medhi; Hamade, Eva; Jebbawi, Fadi; Merimi, Makram; Romero, Pedro; Burny, Arsène; Badran, Bassam; Martiat, Philippe

    2012-01-01

    Regulatory T cells (Tregs) are characterized by a high expression of IL-2 receptor α chain (CD25) and of forkhead box P3 (FOXP3), the latter being essential for their development and function. Another major player in the regulatory function is the cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) that inhibits cytotoxic responses. However, the regulation of CTLA-4 expression remains less well explored. We therefore studied the microRNA signature of circulating CD4+ Tregs isolated from adult healthy donors and identified a signature composed of 15 differentially expressed microRNAs. Among those, miR-24, miR-145, and miR-210 were down-regulated in Tregs compared with controls and were found to have potential target sites in the 3′-UTR of FOXP3 and CTLA-4; miR-24 and miR-210 negatively regulated FOXP3 expression by directly binding to their two target sites in its 3′-UTR. On the other hand, miR-95, which is highly expressed in adult peripheral blood Tregs, positively regulated FOXP3 expression via an indirect mechanism yet to be identified. Finally, we showed that miR-145 negatively regulated CTLA-4 expression in human CD4+ adult peripheral blood Tregs by binding to its target site in CTLA-4 transcript 3′-UTR. To our knowledge, this is the first identification of a human adult peripheral blood CD4+ Treg microRNA signature. Moreover, unveiling one mechanism regulating CTLA-4 expression is novel and may lead to a better understanding of the regulation of this crucial gene. PMID:22294691

  11. CMV-Specific T-cells Generated From Naïve T-cells Recognize Atypical Epitopes And May Be Protective in Vivo

    PubMed Central

    Hanley, Patrick J.; Melenhorst, Jan J.; Nikiforow, Sarah; Scheinberg, Phillip; Blaney, James W.; Demmler-Harrison, Gail; Cruz, C. Russell; Lam, Sharon; Krance, Robert A.; Leung, Kathryn S.; Martinez, Caridad A.; Liu, Hao; Heslop, Helen E.; Rooney, Cliona M.; Shpall, Elizabeth J.; Barrett, A. John; Rodgers, John R.; Bollard, Catherine M.

    2015-01-01

    Adoptive transfer of adult-seropositive, cytomegalovirus (CMV)-specific T-cells can effectively restore antiviral immunity after transplantation. Lack of CMV-specific memory T-cells in blood from CMV-seronegative adult and cord blood (CB) donors restricts the availability of donor-derived virus-specific T-cells for immunoprophylaxis. Here we demonstrate the feasibility of naïve-donor-derived CMV-specific T-cell therapy for transplant recipients. Primed naïve T-cells recognized only atypical epitopes and with a similar avidity to CMV-seropositive-derived T-cells recognizing typical epitopes, but T-cells from CMV-seropositive donors recognizing atypical epitopes had a lower avidity suggesting the loss of high-avidity T-cells over time. Clonotypic analysis revealed T-cells recognizing atypical CMVpp65 epitopes in the peripheral blood of recipients of CB grafts who did not develop CMV. T-cell receptors from atypical epitopes were most common in unmanipulated CB units explaining why these T-cells expanded. When infused to recipients, naïve donor-derived virus specific T-cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. PMID:25925682

  12. B and T cell screen

    MedlinePlus

    Direct immunofluorescence; E-rosetting; T and B lymphocyte assays; B and T lymphocyte assays ... to distinguish between T and B cells. The E-rosetting test identifies T cells and direct immunofluorescence ...

  13. Atypical Antipsychotic Medication Improves Aggression, but Not Self-Injurious Behaviour, in Adults with Intellectual Disabilities

    ERIC Educational Resources Information Center

    Ruedrich, S. L.; Swales, T. P.; Rossvanes, C.; Diana, L.; Arkadiev, V.; Lim, K.

    2008-01-01

    Objective: Atypical antipsychotic medications have largely supplanted their typical counterparts, both for psychosis and for the treatment of aggression and/or self-injurious behaviour (SIB), in persons with intellectual disabilities (ID). However, with the exception of risperidone, little systematic research supports their use in such persons.…

  14. Young adults' media use and attitudes toward interpersonal and institutional forms of aggression.

    PubMed

    Brady, Sonya S

    2007-01-01

    Links between media violence exposure and favorable attitudes toward interpersonal violence are well established, but few studies have examined whether associations extend to include favorable attitudes toward institutional forms of aggression. Studies on this topic have not assessed multiple forms of media use and statistically controlled for individual characteristics likely to influence attitudes beyond sociodemographic information. In this study, undergraduate students (N=319) aged 18-20 years (56% male) completed a survey assessing media use (number of hours per week spent playing videogames, watching movies/TV shows, watching TV sports) and attitudes toward interpersonal violence, punitive criminal justice policies, and different types of military activities (preparedness/defense and aggressive intervention). Greater number of hours spent watching TV contact sports was associated with more favorable attitudes toward military preparedness/defense, aggressive military intervention, and punitive criminal justice policies among men independently of parental education, lifetime violence exposure within the home and community, aggressive personality, and constrained problem solving style. Greater number of hours spent watching violent movies/TV was associated with more favorable attitudes toward military preparedness/defense among men and with more favorable attitudes toward interpersonal violence and punitive criminal justice policies among women, but these associations became non-significant when adjusting for covariates.

  15. Impact of Virtual Reality on Young Adults' Physiological Arousal and Aggressive Thoughts: Interaction versus Observation.

    ERIC Educational Resources Information Center

    Calvert, Sandra L.; Tan, Siu-Lan

    1994-01-01

    Compared to college students who only watched a violent virtual reality game, those who played the game exhibited a higher heart rate after the game, reported more dizziness and nausea during the game, and exhibited more aggressive thoughts on a posttest questionnaire. Results suggest support for arousal and cognitive, but not psychoanalytic,…

  16. Young adults' media use and attitudes toward interpersonal and institutional forms of aggression.

    PubMed

    Brady, Sonya S

    2007-01-01

    Links between media violence exposure and favorable attitudes toward interpersonal violence are well established, but few studies have examined whether associations extend to include favorable attitudes toward institutional forms of aggression. Studies on this topic have not assessed multiple forms of media use and statistically controlled for individual characteristics likely to influence attitudes beyond sociodemographic information. In this study, undergraduate students (N=319) aged 18-20 years (56% male) completed a survey assessing media use (number of hours per week spent playing videogames, watching movies/TV shows, watching TV sports) and attitudes toward interpersonal violence, punitive criminal justice policies, and different types of military activities (preparedness/defense and aggressive intervention). Greater number of hours spent watching TV contact sports was associated with more favorable attitudes toward military preparedness/defense, aggressive military intervention, and punitive criminal justice policies among men independently of parental education, lifetime violence exposure within the home and community, aggressive personality, and constrained problem solving style. Greater number of hours spent watching violent movies/TV was associated with more favorable attitudes toward military preparedness/defense among men and with more favorable attitudes toward interpersonal violence and punitive criminal justice policies among women, but these associations became non-significant when adjusting for covariates. PMID:17918280

  17. Sorafenib Tosylate in Treating Patients With Recurrent Aggressive Non-Hodgkin's Lymphoma

    ClinicalTrials.gov

    2015-08-05

    Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma

  18. Chimeric antigen receptor (CAR) and T cell receptor (TCR) Modified T cells Enter Main Street and Wall Street

    PubMed Central

    Barrett, David M; Grupp, Stephan A; June, Carl H

    2015-01-01

    The field of adoptive cell transfer (ACT) is currently comprised of CAR and TCR engineered T cells and has emerged from principles of basic immunology to paradigm-shifting clinical immunotherapy. ACT of T cells engineered to express artificial receptors that target cells of choice is an exciting new approach for cancer, and holds equal promise for chronic infection and autoimmunity. Using principles of synthetic biology, advances in immunology and genetic engineering have made it possible to generate human T-cells that display desired specificities and enhanced functionalities. Clinical trials in patients with advanced B cell leukemias and lymphomas treated with CD19-specific CAR T cells have induced durable remissions in adults and children. The prospects for the widespread availability of engineered T cells have changed dramatically given the recent entry of the pharmaceutical industry to this arena. Here, we discuss some of the challenges and opportunities that face the field of ACT. PMID:26188068

  19. Primary T-cell lymphoblastic lymphoma in the middle ear.

    PubMed

    Li, Bo; Liu, Shixi; Yang, Hui; Wang, Weiya

    2016-03-01

    T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive lymphoma characterized by precursor T-cell malignancy and lymphadenopathy or mediastinal involvement. We present the case of an 11-year-old boy with a diagnosis of middle ear T-LBL, which manifested as a headache, hearing loss and peripheral facial paralysis. The child was given intensive chemotherapy and had a complete response. To our knowledge, this is the first case reported in the literature of T-LBL originating in the middle ear. This case aims to help clinicians to be vigilant about the possibility of primary lesions at atypical sites in some special diseases.

  20. Cutting Edge: Innate Lymphoid Cells Suppress Homeostatic T Cell Expansion in Neonatal Mice.

    PubMed

    Bank, Ute; Deiser, Katrin; Finke, Daniela; Hämmerling, Günter J; Arnold, Bernd; Schüler, Thomas

    2016-05-01

    In adult mice, lymphopenia-induced proliferation (LIP) leads to T cell activation, memory differentiation, tissue destruction, and a loss of TCR diversity. Neonatal mice are lymphopenic within the first week of life. This enables some recent thymic emigrants to undergo LIP and convert into long-lived memory T cells. Surprisingly, however, most neonatal T cells do not undergo LIP. We therefore asked whether neonate-specific mechanisms prevent lymphopenia-driven T cell activation. In this study, we show that IL-7R-dependent innate lymphoid cells (ILCs) block LIP of CD8(+) T cells in neonatal but not adult mice. Importantly, CD8(+) T cell responses against a foreign Ag are not inhibited by neonatal ILCs. This ILC-based inhibition of LIP ensures the generation of a diverse naive T cell pool in lymphopenic neonates that is mandatory for the maintenance of T cell homeostasis and immunological self-tolerance later in life.

  1. T Cell Fate at the Single-Cell Level.

    PubMed

    Buchholz, Veit R; Schumacher, Ton N M; Busch, Dirk H

    2016-05-20

    T cell responses display two key characteristics. First, a small population of epitope-specific naive T cells expands by several orders of magnitude. Second, the T cells within this proliferating population take on diverse functional and phenotypic properties that determine their ability to exert effector functions and contribute to T cell memory. Recent technological advances in lineage tracing allow us for the first time to study these processes in vivo at single-cell resolution. Here, we summarize resulting data demonstrating that although epitope-specific T cell responses are reproducibly similar at the population level, expansion potential and diversification patterns of the offspring derived from individual T cells are highly variable during both primary and recall immune responses. In spite of this stochastic response variation, individual memory T cells can serve as adult stem cells that provide robust regeneration of an epitope-specific tissue through population averaging. We discuss the relevance of these findings for T cell memory formation and clinical immunotherapy.

  2. Predictors of Late HIV Diagnosis among Adult People Living with HIV/AIDS Who Undertake an Initial CD4 T Cell Evaluation, Northern Ethiopia: A Case-Control Study

    PubMed Central

    Beyene, Melkamu Bedimo; Beyene, Habtamu Bedimo

    2015-01-01

    Introduction Early HIV testing and timely initiation of ART is critical for the improved quality of life of PLWHIV. Having identified a higher rates of Late HIV diagnosis, this study was aimed to determine Determinants of late diagnosis of HIV among adult HIV patients in Bahir Dar, Northern Ethiopia. Methods A case control study was conducted between January 2010 to December 2011 at Bahir Dar Felege Hiwot Referral Hospital. The study subjects consisted of 267 cases and 267 controls. Cases were adult people living with HIV/AIDS whose initial CD4 T cell count was < 200/μl of blood. Controls were those with a CD4 T cell count of greater than 200/ μl. Trained staff nurses were involved in data collection using a semi-structured questionnaire. Data was entered and analyzed using SPSS version 20. Descriptive statistics and Binary logistic regression were performed. Results Subjects who hold a certificate and above (AOR = 0.26; 95% CI = 0.13. 0.54), being initiated by friends, families and other socials to undertake HIV testing (AOR = 0.65; 95% CI = 0.29, 1.48), who reported a medium and high knowledge score about HIV/AIDS and who undertake HIV testing while visiting a clinic for ANC (AOR = 0.40; 95% CI = 0.19, 0.83) were less likely to be diagnosed late. Subjects who undertake HIV testing due to providers’ initiation (AOR = 1.70; 95%CI = 1.08, 2.68), who reported a medium internalized stigma (AOR = 4.94; 95% CI = 3.13, 7.80) and who reported a high internalized stigma score towards HIV/AIDS (AOR = 16.64; 95% CI = 8.29, 33.4) had a high odds of being diagnosed late compared to their counterparts. Conclusion Internalized stigma, low knowledge level about HIV/AIDS, not to have attended formal education and failure to undertake HIV testing by own initiation were significant determinant factors associated with Late HIV diagnosis. Education about HIV/AIDS, promotion of general education, and encouraging people to motivate their social mates to undertake HIV testing are

  3. Monoclonal regulatory T cells provide insights into T cell suppression

    PubMed Central

    Gubser, Céline; Schmaler, Mathias; Rossi, Simona W.; Palmer, Ed

    2016-01-01

    Regulatory T cells (Tregs) have a crucial role in maintaining lymphocyte homeostasis. However an understanding of how Tregs function at a cellular and molecular level has not yet been fully elucidated. Here, we make use of a T cell receptor (TCR) transgenic, Rag−/− mouse expressing a Forkhead-Box-Protein P3 (Foxp3) transgene. This mouse provides a source of monoclonal CD4+ Foxp3+ T cells with a defined specificity. Here we show that monoclonal B3K506 Tregs are functional in vitro and in vivo and clearly require cognate antigen to be suppressive. We further show that the strength of Treg stimulation determines the strength of Treg mediated suppression. Finally we analysed various suppressive mechanisms used by monoclonal Tregs and found that Treg-Tconv proximity is a parameter, which correlates with enhanced suppression. PMID:27210828

  4. Primary Cutaneous CD8-Positive Epidermotropic Cytotoxic T Cell Lymphomas

    PubMed Central

    Berti, Emilio; Tomasini, Dario; Vermeer, Maarten H; Meijer, Chris JLM; Alessi, Elvio; Willemze, Rein

    1999-01-01

    Cutaneous T cell lymphomas (CTCL) generally have the phenotype of CD3+, CD4+, CD45RO+ memory T cells. CTCL expressing a CD8+ T cell phenotype are extremely rare and ill-defined. To elucidate whether these CD8+ CTCL represent a distinct disease entity, the clinical, histological, and immunophenotypical features of 17 CD8+ CTCL were reviewed. None of the 17 cases expressed markers characteristic of natural killer cells or γ/δ T cells. Nine of 17 cases showed the characteristic clinical and histological features as well as clinical behavior of well defined types of CTCL, such as mycosis fungoides (2 cases), pagetoid reticulosis (2 cases), lymphomatoid papulosis (2 cases), and CD30+ large T cell lymphoma (2 cases), all of which usually express a CD4+ T cell phenotype, and 1 case of subcutaneous panniculitis-like T cell lymphoma. The other 8 cases formed a homogeneous group showing a distinctive set of clinicopathological and immunophenotypical features, not consistent with that of other well defined types of CTCL. Clinical characteristics included presentation with generalized patches, plaques, papulonodules, and tumors mimicking disseminated pagetoid reticulosis; metastatic spread to unusual sites, such as the lung, testis, central nervous system, and oral cavity, but not to the lymph nodes; and an aggressive course (median survival, 32 months). Histologically, these lymphomas were characterized by band-like infiltrates consisting of pleomorphic T cells or immunoblasts, showing a diffuse infiltration of an acanthotic epidermis with variable degrees of spongiosis, intraepidermal blistering, and necrosis. The neoplastic cells showed a high Ki-67 proliferation index and expression of CD3, CD8, CD7, CD45RA, βF1, and TIA-1 markers, whereas CD2 and CD5 were frequently lost. Expression of TIA-1 pointed out that these lymphomas are derived from a cytotoxic T cell subset. The results of this and other studies reviewed herein suggest that these strongly epidermotropic

  5. Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

    PubMed Central

    Dimova, Tanya; Brouwer, Margreet; Gosselin, Françoise; Tassignon, Joël; Leo, Oberdan; Donner, Catherine; Marchant, Arnaud; Vermijlen, David

    2015-01-01

    γδ T cells are unconventional T cells recognizing antigens via their γδ T-cell receptor (TCR) in a way that is fundamentally different from conventional αβ T cells. γδ T cells usually are divided into subsets according the type of Vγ and/or Vδ chain they express in their TCR. T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are the predominant γδ T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementary-determining region 3 (CDR3) in response to encounters with microbes, especially those generating phosphoantigens derived from the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, Vγ9Vδ2 T cells are the predominant blood subset in the second-trimester fetus, whereas Vδ1+ and Vδ3+ γδ T cells are present only at low frequencies at this gestational time. Fetal blood Vγ9Vδ2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the Vγ9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3δ2. Furthermore, these fetal blood Vγ9Vδ2 T cells are functionally preprogrammed (e.g., IFN-γ and granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine γδ T cells than is usually articulated. PMID:25617367

  6. Linked T Cell Receptor and Cytokine Signaling Govern the Development of the Regulatory T cell Repertoire

    PubMed Central

    Burchill, Matthew A.; Yang, Jianying; Vang, Kieng B.; Moon, James J.; Chu, H. Hamlet; Lio, Chan-Wang J.; Vegoe, Amanda L.; Hsieh, Chyi-Song; Jenkins, Marc K.; Farrar, Michael A.

    2008-01-01

    Summary Appropriate development of regulatory T cells (Tregs) is necessary to prevent autoimmunity. Neonatal mice, unlike adults, lack factors required for Treg development. It is unclear what these missing factors are. However, signals emanating from the TCR, CD28 and γc-dependent cytokine receptors are required for Treg development. Herein we demonstrate that expression of a constitutively-active STAT5b transgene (STAT5b-CA) allows for Treg development in neonatal mice and restores Treg numbers in CD28−/− mice. Sequence analysis of TCR genes in STAT5b-CA Tregs indicates that ectopic STAT5 activation results in a TCR repertoire that more closely resembles that of naïve T cells. Using MHCII tetramers to identify antigen-specific T cells, we demonstrate that STAT5 signals divert thymocytes normally destined to become naïve T cells into the Treg lineage. Our data support a two-step model of Treg differentiation in which TCR/CD28 signals induce cytokine responsiveness; STAT5-inducing cytokines then complete the program of Treg differentiation. PMID:18199418

  7. Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma.

    PubMed

    Chung, Catherine G; Poligone, Brian

    2015-10-01

    Traditional chemotherapies, interleukins, phosphorylase inhibitors, and proteasome inhibitors are important therapies available to patients with cutaneous T-cell lymphoma (CTCL). Traditional chemotherapies, both in combination and as single agents, are commonly used in relapsed, refractory CTCLs that behave in an aggressive manner. Interleukins, phosphorylase inhibitors, and proteasome inhibitors are less commonly used but data support a role in patients with more refractory disease. PMID:26433850

  8. The Effect of Arthrospira platensis Capsules on CD4 T-Cells and Antioxidative Capacity in a Randomized Pilot Study of Adult Women Infected with Human Immunodeficiency Virus Not under HAART in Yaoundé, Cameroon

    PubMed Central

    Winter, Frank Stéphane; Emakam, Francois; Kfutwah, Anfumbom; Hermann, Johannes; Azabji-Kenfack, Marcel; Krawinkel, Michael B.

    2014-01-01

    Dietary supplements are often used to improve the nutritional status of people living with HIV/AIDS (PLHIV). Arthrospira platensis (Asp), also known as Spirulina, is a cyanobacterium rich in proteins and micronutrients. Cell and animal trials described immune-modulating, antiretroviral and antioxidant activities. This pilot study describes the effects of the supplementation of 5 g/day of Asp on a pre-highly-active antiretroviral therapy (pre-HAART), HIV-infected, adult female population. It was conducted as a three-month randomized controlled trial (RCT) that compared a cup supplementation of five grams/day of Asp with a placebo of equal protein content and energy. The study included 73 HIV-infected women. The immediate outcome variables were CD4 T-cells, viral load and immune activation by CD8 T-cells expressing CD38. The antioxidant status was assessed by way of the total antioxidant capacity of the serum (TAOS). The renal function was documented by way of creatinine, urea and the calculated glomerular filtration rate. Statistical analyses were carried out with non-parametric tests, and the effect size of each interaction was calculated. No differences in the immunological and virological markers between the Asp and the placebo group could be observed. In the placebo group, 21 of 30 patients (70%) developed concomitant events, while in the Asp group, only 12 of 28 patients (43%) did. Both groups registered a significant weight increase; 0.5 kg (p < 0.05) in the Asp group and 0.65 kg (p < 0.05) in the placebo group. The antioxidant capacity increase of 56 (1–98) µM for Asp was significantly different from the decrease observed in the placebo group (p < 0.001). A slight increase in the creatinine level of 0.1 g/dL (p < 0.001) was observed in the Asp group, and no effect was observed in the urea levels. The improvement of the antioxidant capacity under Asp, shown for the first time on PLHIV, could become a focus for future research on the nutritional and health

  9. The combination of IκB kinase β inhibitor and everolimus modulates expression of interleukin-10 in human T-cell lymphotropic virus type-1-infected T cells.

    PubMed

    Nishioka, Chie; Ikezoe, Takayuki; Yang, Jing; Udaka, Keiko; Yokoyama, Akihito

    2013-03-01

    Adult T-cell leukaemia-lymphoma (ATLL) is an aggressive malignancy of CD4(+)  CD25(+) T lymphocytes, characterized by a severely compromised immunosystem, in which the human T-cell lymphotropic virus type 1 (HTLV-1) has been recognized as the aetiological agent. This study found that an IκB kinase β (IKKβ) inhibitor Bay11-7082 inactivated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 and transcription factor nuclear factor-κB in HTLV-1-infected T cells; this was significantly enhanced in the presence of the mTOR inhibitor everolimus. In addition, Bay11-7082 decreased production of the immunosuppressive cytokine interleukin-10 (IL-10), which was further down-regulated when Bay11-7082 was combined with evelolimus in HTLV-1-infected T and ATLL cells isolated from patients. Interleukin-10 is known to inhibit maturation and the antigen-presenting function of dendritic cells (DCs). The culture media of HTLV-1-infected MT-1 cells, which contained a large amout of IL-10, hampered tumour necrosis factor-α-induced maturation of DCs isolated from healthy volunteers. Culture supernatant of MT-1 cells treated with a combination of Bay11-7082 and everolimus augmented maturation of DCs in association with a decrease in production of IL-10 and enhanced the allostimulatory function of DCs. Similarly, when DCs isolated from patients with ATLL were treated with the combination of Bay11-7082 and everolimus, they were fully matured and their capability to stimulate proliferation of lymphocytes was augmented. Taken together, the combination of Bay11-7082 and everolimus might exhibit immunostimulatory properties in HTLV-1-infected T and ATLL cells isolated from patients, and this combination may be potentially therapeutic to regain the compromised immunosystem in ATLL patients.

  10. Romidepsin and Lenalidomide in Treating Patients With Previously Untreated Peripheral T-Cell Lymphoma

    ClinicalTrials.gov

    2016-10-06

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Peripheral T-cell Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Stage IB Mycosis Fungoides/Sezary Syndrome; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Stage IIB Mycosis Fungoides/Sezary Syndrome; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Stage IVB Mycosis Fungoides/Sezary Syndrome

  11. Use of Deslorelin Acetate Implants to Mitigate Aggression in Two Adult Male Domestic Turkeys (Meleagris gallopavo) and Correlating Plasma Testosterone Concentrations.

    PubMed

    Molter, Christine M; Fontenot, Deidre K; Terrell, Scott P

    2015-09-01

    Two adult, male domestic turkeys were treated with implants of deslorelin acetate, a gonadotropin-releasing hormone agonist, to reduce intermale aggression and aggression directed toward the animal care team at a zoologic institution. The turkeys were manually restrained and either two 4.7-mg or two 9.4-mg implants were placed within the pectoral musculature on 3 occasions over the course of approximately 1.5 years. Plasma testosterone concentrations were measured by radioimmunoassay every 2 weeks for the first month after a new implant placement and then monthly thereafter. Testosterone concentrations remained low and aggressive behavior was decreased for a period of several months after implant placement. At necropsy of both birds, no adverse gross or histologic lesions were noted at the implantation sites in the pectoral musculature or within the gonadal tissue. Deslorelin acetate implants are a treatment modality to consider for mitigation of aggression in male domestic turkeys.

  12. Germinal Centers without T Cells

    PubMed Central

    de Vinuesa, Carola García; Cook, Matthew C.; Ball, Jennifer; Drew, Marion; Sunners, Yvonne; Cascalho, Marilia; Wabl, Matthias; Klaus, Gerry G.B.; MacLennan, Ian C.M.

    2000-01-01

    Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation. PMID:10662794

  13. Human regulatory T cells control TCR signaling and susceptibility to suppression in CD4+ T cells.

    PubMed

    Chellappa, Stalin; Lieske, Nora V; Hagness, Morten; Line, Pål D; Taskén, Kjetil; Aandahl, Einar M

    2016-07-01

    Human CD4(+)CD25(hi)FOXP3(+) regulatory T cells maintain immunologic tolerance and prevent autoimmune and inflammatory immune responses. Regulatory T cells undergo a similar activation cycle as conventional CD4(+) T cells upon antigen stimulation. Here, we demonstrate that T cell receptors and costimulation are required to activate the regulatory T cell suppressive function. Regulatory T cells suppressed the T cell receptor signaling in effector T cells in a time-dependent manner that corresponded with inhibition of cytokine production and proliferation. Modulation of the activation level and thereby the suppressive capacity of regulatory T cells imposed distinct T cell receptor signaling signatures and hyporesponsiveness in suppressed and proliferating effector T cells and established a threshold for effector T cell proliferation. The immune suppression of effector T cells was completely reversible upon removal of regulatory T cells. However, the strength of prior immune suppression by regulatory T cells and corresponding T cell receptor signaling in effector T cells determined the susceptibility to suppression upon later reexposure to regulatory T cells. These findings demonstrate how the strength of the regulatory T cell suppressive function determines intracellular signaling, immune responsiveness, and the later susceptibility of effector T cells to immune suppression and contribute to unveiling the complex interactions between regulatory T cells and effector T cells. PMID:26715685

  14. Epigenetics in T-cell acute lymphoblastic leukemia.

    PubMed

    Peirs, Sofie; Van der Meulen, Joni; Van de Walle, Inge; Taghon, Tom; Speleman, Frank; Poppe, Bruce; Van Vlierberghe, Pieter

    2015-01-01

    Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T-ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL. PMID:25510271

  15. Fish T cells: recent advances through genomics

    USGS Publications Warehouse

    Laing, Kerry J.; Hansen, John D.

    2011-01-01

    This brief review is intended to provide a concise overview of the current literature concerning T cells, advances in identifying distinct T cell functional subsets, and in distinguishing effector cells from memory cells. We compare and contrast a wealth of recent progress made in T cell immunology of teleost, elasmobranch, and agnathan fish, to knowledge derived from mammalian T cell studies. From genome studies, fish clearly have most components associated with T cell function and we can speculate on the presence of putative T cell subsets, and the ability to detect their differentiation to form memory cells. Some recombinant proteins for T cell associated cytokines and antibodies for T cell surface receptors have been generated that will facilitate studying the functional roles of teleost T cells during immune responses. Although there is still a long way to go, major advances have occurred in recent years for investigating T cell responses, thus phenotypic and functional characterization is on the near horizon.

  16. A Comparison of DRO to Movement Suppression Time-Out and DRO with Two Self-Injurious and Aggressive Mentally Retarded Adults.

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Keyes, Joseph B.

    1990-01-01

    The study compared the effectiveness of (1) reinforcement of other behavior, (2) verbal reprimands, and (3) movement suppression time-out in eliminating self injury and aggressive behaviors in two severely mentally retarded adult males. Improvements were only apparent when movement suppression was paired with either or both of the other…

  17. The Teaching-Family Model: A Program Description and Its Effects on the Aggressive Behaviors and Quality of Life of Two Adults with Intellectual Disabilities

    ERIC Educational Resources Information Center

    De Wein, Matthieu; Miller, L. Keith

    2009-01-01

    This article is a description of a program that may be effective for reducing the aggressive behaviors of adults with intellectual disabilities. Data are presented in the form of a naturally occurring multiple baseline across two participants. Results suggest that an intervention anchored in teaching-family model (TFM) procedures was effective to…

  18. Trajectories of adolescent hostile-aggressive behavior and family climate: Longitudinal implications for young adult romantic relationship competence.

    PubMed

    Fosco, Gregory M; Van Ryzin, Mark J; Xia, Mengya; Feinberg, Mark E

    2016-07-01

    The formation and maintenance of young adult romantic relationships that are free from violence and are characterized by love, connection, and effective problem-solving have important implications for later well-being and family functioning. In this study, we examined adolescent hostile-aggressive behavior (HAB) and family relationship quality as key individual and family level factors that may forecast later romantic relationship functioning. Guided by a family systems framework, we evaluated the reciprocal influences of adolescent hostility and family climate, to provide a more comprehensive picture of the etiology of romantic relationship functioning. We drew on a large sample (N = 974) of young adults (mean age = 19.5) that were followed starting in the fall of 6th grade, and subsequently in spring of 6th, 7th, 8th, 9th, and 10th grades prior to the young adult assessment. Using a latent difference score cross-lag model (McArdle, 2009), our results indicated that a more positive family climate was associated with decreases in HAB, but HAB was not associated with changes in family climate. Further, the influence of the family climate on HAB was consistent across all time points. HAB and family climate had different predictions for young adult romantic relationships: Increasing HAB over adolescence predicted relationship violence, while maintenance in family climate was a key predictor of relationship problem-solving skills. The only predictor of love and connection in relationships was early family functioning. Implications for developmental theory and prevention science are discussed. (PsycINFO Database Record PMID:27337516

  19. Long-term maintenance combination chemotherapy with OPEC/MPEC (vincristine or methotrexate, prednisolone, etoposide and cyclophosphamide) or with daily oral etoposide and prednisolone can improve survival and quality of life in adult T-cell leukemia/lymphoma.

    PubMed

    Matsushita, K; Matsumoto, T; Ohtsubo, H; Fujiwara, H; Imamura, N; Hidaka, S; Kukita, T; Tei, C; Matsumoto, M; Arima, N

    1999-12-01

    Acute leukemia and lymphoma varieties of adult T-cell leukemia/lymphoma (ATL) usually carry a poor prognosis. While etoposide is generally useful for treating ATL, especially as a daily oral maintenance regimen, etoposide has not proven effective in severe types of ATL efficient in some patients. Of 87 ATL patients whom we have treated, 51 had acute leukemia, 22 lymphoma and 14 progressive chronic leukemia. Seventy-nine patients were treated with a long term maintenance combination protocol, OPEC/MPEC (weekly doses of vincristine, 0.7 mg/m2 or methotrexate, 14 mg/m2; prednisolone, 20 mg/m2; etoposide, 70 mg/m2 and cyclophosphamide, 200 mg/m2). The other 8 patients, 3 with acute leukemia, 2 with lymphoma and 3 with progressive chronic leukemia, were treated with daily oral administration of 25 mg of etoposide and 10 mg of prednisolone (DOEP). The dose administered was modified in individual cases to maintain the granulocyte count and reduce the number of ATL cells. Considering both protocols, a complete response and a partial response were achieved in 31.0% and 58.6% patients, respectively. Median survival times (MST) of all patients and, acute leukemia, lymphoma and progressive chronic leukemia types were 7.5, 6.7, 9.6 and 12.4 months, respectively. Respective MST of patients treated with OPEC/MPEC or DOEP protocols were 7.1 and 18.0 months. Relatively normal WBC counts, lower lactate dehydrogenase concentration and normal calcium concentration, limited numbers of anatomic sites involved, good performance status and good response to chemotherapy were significantly associated with long survival time. Drug toxicity was not apparent, and about half of patients were treated in an outpatient setting. PMID:10613451

  20. T cell recognition of beryllium.

    PubMed

    Dai, Shaodong; Falta, Michael T; Bowerman, Natalie A; McKee, Amy S; Fontenot, Andrew P

    2013-12-01

    Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by a hypersensitivity to beryllium and characterized by the accumulation of beryllium-specific CD4(+) T cells in the lung. Genetic susceptibility to beryllium-induced disease is strongly associated with HLA-DP alleles possessing a glutamic acid at the 69th position of the β-chain (βGlu69). The structure of HLA-DP2, the most prevalent βGlu69-containing molecule, revealed a unique solvent-exposed acidic pocket that includes βGlu69 and represents the putative beryllium-binding site. The delineation of mimotopes and endogenous self-peptides that complete the αβTCR ligand for beryllium-specific CD4(+) T cells suggests a unique role of these peptides in metal ion coordination and the generation of altered self-peptides, blurring the distinction between hypersensitivity and autoimmunity.

  1. Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice.

    PubMed

    Kohl, Christine; Wang, Xiao-Dong; Grosse, Jocelyn; Fournier, Céline; Harbich, Daniela; Westerholz, Sören; Li, Ji-Tao; Bacq, Alexandre; Sippel, Claudia; Hausch, Felix; Sandi, Carmen; Schmidt, Mathias V

    2015-05-01

    Early-life stress is a key risk factor for the development of neuropsychiatric disorders later in life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that early-life stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics early-life stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the early-life stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating early-life stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders.

  2. Adoptive T-cell Immunotherapy

    PubMed Central

    Gottschalk, Stephen; Rooney, Cliona

    2015-01-01

    Epstein-Barr virus (EBV) is associated with a range of malignancies involving B-cells, T-cells, natural killer (NK)-cells, epithelial cells and smooth muscle. All of these are associated with the latent life cycles of EBV, but the pattern of latency-associated viral antigens expressed in tumor cells depends on the type of tumor. EBV-specific T cells (EBVSTs) have been explored as prophylaxis and therapy for EBV-associated malignancies for more than two decades. EBVSTs have been most successful as prophylaxis and therapy for post-transplant lymphoproliferative disease (PTLD), which expresses the full array of latent EBV antigens (type 3 latency), in hematopoietic stem cell transplant recipients. While less effective, clinical studies have also demonstrated their therapeutic potential for PTLD post solid organ transplant, and for EBV-associated malignancies such as Hodgkin’s Lymphoma, Non-Hodgkin’s Lymphoma, and nasopharyngeal carcinoma that express a limited array of latent EBV antigens (type 2 latency),. Several approaches are actively being pursued to improve the antitumor activity of EBVSTs including activation and expansion of T cells specific for the EBV antigens expressed in type 2 latency, genetic approaches to render EBVSTs resistant to the immunosuppressive tumor environment and combination approaches with other immune-modulating modalities. Given the recent advances and renewed interest in cell therapy, we hope that EBVSTs will become an integral part of our treatment armamentarium against EBV-positive malignancies in the near future. PMID:26428384

  3. Hepatosplenic alphabeta T cell lymphoma.

    PubMed

    Nagai, Yuya; Ikegame, Kazuhiro; Mori, Minako; Inoue, Daichi; Kimura, Takaharu; Shimoji, Sonoko; Togami, Katsuhiro; Tabata, Sumie; Kurata, Masayuki; Imai, Yukihiro; Matsushita, Akiko; Nagai, Kenichi; Ogawa, Hiroyasu; Takahashi, Takayuki

    2010-04-01

    A 32-year-old male with chronic hepatitis B was admitted to a hospital with cellulitis in the right leg in September 2006. Pancytopenia, hepatosplenomegaly, and systemic superficial lymph node swelling were noted, and he was referred to our hospital. He developed fever and liver dysfunction in June 2007 and underwent a splenectomy. His pancytopenia subsequently improved. A pathologic diagnosis of hepatosplenic alphabeta T cell lymphoma was made by examining spleen tissue and biopsy specimens of the liver and mesenteric lymph node. He had stage IVB disease because neoplastic T cells were noted in the bone marrow. The response of the lymphoma to conventional chemotherapy including the CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) and DeVIC (dexamethasone, etoposide, ifoshamide, carboplatin) regimens was poor and transient. A partial remission was obtained with an ESHAP (etoposide, cisplatin, cytarabine, methylprednisolone) regimen. Therefore, we planned a bone marrow transplantation (BMT) from an HLA-haploidentical sibling donor. He was moved to the Department of Hematology, Hyogo Medical College, to receive this BMT as part of a clinical trial. During the conditioning procedure for the transplantation, however, he died of septicemia. Since hepatosplenic alphabeta T cell lymphoma is very rare with only 23 reported cases to date, herein we report this case and discuss the therapeutic strategy. PMID:20217452

  4. Induction of IL-10- and IFN-gamma-producing T-cell responses by autoreactive T-cells expressing human T-cell leukemia virus type I Tax.

    PubMed

    Takatsuka, Natsuko; Hasegawa, Atsuhiko; Takamori, Ayako; Shimizu, Yukiko; Kato, Hirotomo; Ohashi, Takashi; Amagasa, Teruo; Masuda, Takao; Kannagi, Mari

    2009-09-01

    Human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell leukemia, HTLV-I-associated myelopathy/tropical spastic paraparesis and various autoimmune-like disorders. T-cell immune suppression is also associated with HTLV-I infection. Mechanisms of diverse immune dysregulation in HTLV-I infection are obscure. Here, we investigated a potential link between autoimmunity and immune suppression in HTLV-I infection. G14, an IL-2-dependent HTLV-I-negative CD4(+)CD8(+) T-cell line previously established from an HTLV-I-infected rat, constantly proliferated and produced IFN-gamma. IFN-gamma production by G14 cells was dependent on interactions between CD4 and MHC-II, suggesting that G14 cells recognized self-antigens presented by MHC-II on themselves. To examine immune response to G14 cells, we inoculated G14 cells into syngeneic naive rats. Interestingly, T-cells isolated from these rats vigorously proliferated when stimulated with G14-Tax cells that stably expressed HTLV-I Tax, but not with G14 cells. G14-Tax-mediated T-cell proliferation was abrogated by antibodies to CD80 and CD86 that were up-regulated in G14-Tax cells. T-cells propagated by repetitive G14-Tax cell stimulations in culture with IL-2 expressed CD4, CD25 and cytolytic T lymphocyte-associated antigen 4 (CTLA-4), produced abundant amounts of IL-10 and IFN-gamma in response to G14 cells and suppressed growth of G14 cells mainly through supernatant-mediated mechanisms. Similar IL-10- and IFN-gamma-producing CD4(+)CD25(+)CTLA-4(+) T-cells were predominantly induced in culture of splenocytes from HTLV-I-infected rats following stimulation with G14-Tax cells. These results implied that expression of Tax in the otherwise low immunogenic autoreactive T-cells induced IL-10- and IFN-gamma-producing T-cell responses with regulatory effects against the autoreactive cells. Our findings provide new insights into the complex immune conditions underlying HTLV-I-associated diseases. PMID:19654198

  5. Associations between childhood abuse and interpersonal aggression and suicide attempt among U.S. adults in a national study.

    PubMed

    Harford, Thomas C; Yi, Hsiao-ye; Grant, Bridget F

    2014-08-01

    The aim of this study is to examine associations among childhood physical, emotional, or sexual abuse and violence toward self (suicide attempts [SA]) and others (interpersonal aggression [IA]). Data were obtained from the National Epidemiologic Survey on Alcohol and Related Conditions Waves 1 and 2 (n=34,653). Multinomial logistic regression examined associations between type of childhood abuse and violence categories, adjusting for demographic variables, other childhood adversity, and DSM-IV psychiatric disorders. The prevalence of reported childhood abuse was 4.60% for physical abuse, 7.83% for emotional abuse, and 10.20% for sexual abuse. Approximately 18% of adults reported some form of violent behavior, distributed as follows: IA, 13.37%; SA, 2.64%; and SA with IA, 1.85%. After adjusting for demographic variables, other childhood adversity, and psychiatric disorders, each type of childhood abuse was significantly related to increased risk for each violence category as compared with the no violence category. Furthermore, the odds ratio of childhood physical abuse was significantly higher for SA with IA when compared with IA, and the odds ratio of childhood sexual abuse was significantly higher for SA and SA with IA when compared with IA. Childhood physical, emotional, and sexual abuse is directly related to the risk for violent behaviors to self and others. Both internalizing and externalizing psychiatric disorders impact the association between childhood abuse and violence. The inclusion of suicidal behaviors and interpersonal aggression and internalizing/externalizing psychiatric disorders within an integrated conceptual framework will facilitate more effective interventions for long-lasting effects of child abuse.

  6. Biology and treatment of HTLV-1 associated T-cell lymphomas.

    PubMed

    Tsukasaki, Kunihiro; Tobinai, Kensei

    2013-03-01

    Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-lymphocytic malignancy associated with human T-cell lymphotropic virus type I (HTLV-1) endemics in several regions of the world including the south-west Japan. The three major routes of HTLV-1 transmission are mother-to-child infections via breast milk, sexual intercourse, and blood transfusions. A HTLV-1 infection early in life, presumably from breast feeding, is crucial to the development of ATL. The estimated cumulative risk of developing ATL among HTLV-1-positive individuals is about 3% after transmission from the mother. The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into acute, lymphoma, chronic, and smoldering types defined by organ involvement, lactate dehydrogenase (LDH) and calcium values. For the acute, lymphoma and unfavorable chronic subtypes (aggressive ATL), and the favorable chronic and smoldering subtypes (indolent ATL), intensive chemotherapy followed by allogeneic stem cell transplantation and watchful waiting until disease progression has been recommended, respectively, in Japan. A retrospective analysis suggested that the combination of interferon alpha and zidovudine was promising for the treatment of ATL, especially for leukemic subtypes. There are several new trials for ATL, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody, histone deacetylase inhibitors, a purine nucleoside phosphorylase inhibitor, a proteasome inhibitor and lenalidomide. PMID:23768636

  7. Gag-Specific CD4 and CD8 T-Cell Proliferation in Adolescents and Young Adults with Perinatally Acquired HIV-1 Infection Is Associated with Ethnicity — The ANRS-EP38-IMMIP Study

    PubMed Central

    Le Chenadec, Jérôme; Scott-Algara, Daniel; Blanche, Stéphane; Didier, Céline; Montange, Thomas; Viard, Jean-Paul; Dollfus, Catherine; Avettand-Fenoel, Véronique; Rouzioux, Christine; Warszawski, Josiane; Buseyne, Florence

    2015-01-01

    The ANRS-EP38-IMMIP study aimed to provide a detailed assessment of the immune status of perinatally infected youths living in France. We studied Gag-specific CD4 and CD8 T-cell proliferation and the association between the proliferation of these cells, demographic factors and HIV disease history. We included 93 youths aged between 15 and 24 years who had been perinatally infected with HIV. Sixty-nine had undergone valid CFSE-based T-cell proliferation assays. Gag-specific proliferation of CD4 and CD8 T cells was detected in 12 (16%) and 30 (38%) patients, respectively. The Gag-specific proliferation of CD4 and CD8 T cells was more frequently observed in black patients than in patients from other ethnic groups (CD4: 32% vs. 4%, P = 0.001; CD8: 55% vs. 26%, P = 0.02). Among aviremic patients, the duration of viral suppression was shorter in CD8 responders than in CD8 nonresponders (medians: 54 vs. 20 months, P = 0.04). Among viremic patients, CD8 responders had significantly lower plasma HIV RNA levels than CD8 nonresponders (2.7 vs. 3.7 log10 HIV-RNA copies/ml, P = 0.02). In multivariate analyses including sex and HIV-1 subtype as covariables, Gag-specific CD4 T-cell proliferation was associated only with ethnicity, whereas Gag-specific CD8 T-cell proliferation was associated with both ethnicity and the duration of viral suppression. Both CD4 and CD8 responders reached their nadir CD4 T-cell percentages at younger ages than their nonresponder counterparts (6 vs. 8 years, P = 0.04 for both CD4 and CD8 T-cell proliferation). However, these associations were not significant in multivariate analysis. In conclusion, after at least 15 years of HIV infection, Gag-specific T-cell proliferation was found to be more frequent in black youths than in patients of other ethnic groups, despite all the patients being born in the same country, with similar access to care. PMID:26650393

  8. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival

    PubMed Central

    Wainwright, Derek A.; Balyasnikova, Irina V.; Chang, Alan L.; Ahmed, Atique U.; Moon, Kyung-Sub; Auffinger, Brenda; Tobias, Alex L.; Han, Yu; Lesniak, Maciej S.

    2012-01-01

    Purpose Glioblastoma multiforme (GBM) is an aggressive adult brain tumor with a poor prognosis. One hallmark of GBM is the accumulation of immunosuppressive and tumor-promoting CD4+FoxP3+GITR+ regulatory T cells (Tregs). Here, we investigated the role of indoleamine 2,3 dioxygenase (IDO) in brain tumors and the impact on Treg recruitment. Experimental Design To determine the clinical relevance of IDO expression in brain tumors, we first correlated patient survival to the level of IDO expression from resected glioma specimens. We also used novel orthotopic and transgenic models of glioma to study how IDO affects Tregs. The impact of tumor-derived and peripheral IDO expression on Treg recruitment, GITR expression and long-term survival was determined. Results Downregulated IDO expression in glioma predicted a significantly better prognosis in patients. Co-incidently, both IDO -competent and -deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared to IDO-competent brain tumors. Moreover, IDO-deficiency was associated with a significant decrease in brain-resident Tregs, both in orthotopic and transgenic mouse glioma models. IDO-deficiency was also associated with lower GITR expression levels on Tregs. Interestingly, the long-term survival advantage conferred by IDO-deficiency was lost in T cell-deficient mice. Conclusions These clinical and pre-clinical data confirm that IDO expression increases the recruitment of immunosuppressive Tregs which leads to tumor outgrowth. In contrast, IDO deficiency decreases Treg recruitment and enhances T cell-mediated tumor rejection. Thus, the data suggest a critical role for IDO-mediated immunosuppression in glioma and supports the continued investigation of IDO-Treg interactions in the context of brain tumors. PMID:22932670

  9. Leukemia -- Chronic T-Cell Lymphocytic

    MedlinePlus

    ... Chronic T-Cell Lymphocytic: Overview Print to PDF Leukemia - Chronic T-Cell Lymphocytic: Overview Approved by the ... Platelets that help the blood to clot About leukemia Types of leukemia are named after the specific ...

  10. T cell tolerance induced by therapeutic antibodies.

    PubMed

    Cobbold, Stephen P

    2005-09-29

    Ever since the discovery of Medawar, over 50 years ago, that immunological tolerance was an acquired phenomenon that could be manipulated in neonatal mice, the ability to induce therapeutic tolerance against autoantigens, allergens and organ grafts has been a major driving force in immunology. Within the last 20 years we have found that a brief treatment with monoclonal antibodies that block certain functional molecules on the surface of the T cell is able to reprogramme the established immune repertoire of the adult mouse, allowing indefinite acceptance of allografts or effective curing of autoimmune diseases. We are only now just beginning to define many of the regulatory mechanisms that induce and maintain the tolerant state with the aim of being able to safely and reliably apply these technologies to human clinical situations. PMID:16147534

  11. Genetic modification of T cells.

    PubMed

    Morgan, Richard A; Kakarla, Sunitha

    2014-01-01

    Gene transfer technology has advanced rapidly from simple physical-chemical laboratory methods in the 1970s and 1980s to the sophisticated viral and nonviral methods currently in clinical practice. Herein, we review 4 gene transfer methodologies applied in human gene therapy clinical trials transferring chimeric antigen receptors into T cells for the treatment of B-cell malignancies. The 4 methods include 2 viral vector gene transfer technologies, gamma retroviral vectors and lentiviral vectors, and 2 nonviral methods, transposons and mRNA electroporation.

  12. Therapeutic implications of autoimmune vitiligo T cells

    PubMed Central

    Oyarbide-Valencia, Kepa; van den Boorn, Jasper G.; Denman, Cecele J.; Li, Mingli; Carlson, Jeremy M.; Hernandez, Claudia; Nishimura, Michael I.; Das, Pranab K.; Luiten, Rosalie M.; Le Poole, I. Caroline

    2007-01-01

    Vitiligo is an autoimmune disease presenting with progressive loss of skin pigmentation. The disease strikes 1% of the world population, generally during teenage years. The progressive loss of melanocytes from depigmenting vitiligo skin is accompanied by cellular infiltrates containing both CD4+ and CD8+ T lymphocytes. Infiltrating cytotoxic T cells with high affinity T cell receptors have likely escaped clonal deletion in the thymus, allowing such T cells to enter the circulation. Through the expression of CLA, these T cells home to the skin where they express type 1-cytokine profiles and mediate melanocyte apoptosis via the granzyme/perforin pathway. T cells found juxtapositionally apposed to remaining melanocytes can be isolated from the skin. Vitiligo T cells have demonstrated reactivity to antigens previously recognized as target antigens for T cells infiltrating melanoma tumors. In a comparison to existing melanoma-derived T cells, vitiligo T cells displayed superior reactivity towards melanoma cells. It is thought that genes encoding the TCRs expressed by vitiligo skin infiltrating T cells can be cloned and expressed in melanoma T cells, thereby generating a pool of circulating T cells with high affinity for their targets that can re-direct the immune response towards the tumor. PMID:16920575

  13. CEOP/IVE/GDP Compared With CEOP as the First-line Therapy for Newly Diagnosed Adult Patients With PTCL

    ClinicalTrials.gov

    2016-04-18

    Peripheral T-Cell Lymphoma; Angioimmunoblastic T Cell Lymphoma; ALK-negative Anaplastic Large Cell Lymphoma; Enteropathy Associated T Cell Lymphoma; Subcutaneous Panniculitis Like T Cell Lymphoma; Acute Adult T-Cell Leukemia/Lymphoma

  14. Arsenic trioxide and interferon-alpha synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells.

    PubMed

    Bazarbachi, A; El-Sabban, M E; Nasr, R; Quignon, F; Awaraji, C; Kersual, J; Dianoux, L; Zermati, Y; Haidar, J H; Hermine, O; de Thé, H

    1999-01-01

    Human T-cell lymphotropic virus type I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive proliferation of mature activated T cells associated with a poor prognosis. The combination of the antiviral agents, zidovudine (AZT) and interferon (IFN), is a potent treatment of ATL. Recently, arsenic trioxide (As) was shown to be an effective treatment of acute promyelocytic leukemia (APL). We have tested the effects of the combination of As and IFN on cell proliferation, cell cycle phases distribution, and apoptosis in ATL-derived or control T-cell lines. A high synergistic effect between IFN and As was observed in ATL-derived cell lines in comparison to the control cell lines, with a dramatic inhibition of cell proliferation, G1 arrest, and induction of apoptosis. Similar results were obtained with fresh leukemia cells derived from an ATL patient. Although the mechanisms involved are unclear, these results could provide a rational basis for combined As and IFN treatments in ATL. PMID:9864171

  15. The influence of age on T cell generation and TCR diversity.

    PubMed

    Naylor, Keith; Li, Guangjin; Vallejo, Abbe N; Lee, Won-Woo; Koetz, Kerstin; Bryl, Ewa; Witkowski, Jacek; Fulbright, James; Weyand, Cornelia M; Goronzy, Jörg J

    2005-06-01

    The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between thymic production, homeostatic T cell proliferation and TCR beta-chain diversity in young (approximately 25 years), middle-aged ( approximately 60 years), and elderly adults (approximately 75 years). TCR excision circles (TREC) as a marker of thymic output exponentially decreased by >95% between 25 and 60 years of age. The frequency of Ki67(+) cycling CD4 T cells remained steady, and surprisingly, the diversity of the naive CD4 T cell repertoire was maintained at approximately 2 x 10(7) different TCR beta-chains. After the age of 70 years, TRECs only slightly declined, but homeostatic proliferation doubled. The diversity of the T cell pool drastically contracted to 200,000 TCR beta-chains. Also, the phenotypic distinction between naive and memory CD4 T cells became fuzzy. The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment.

  16. Tracking and treating activated T cells

    PubMed Central

    Kim, N.H.; Nadithe, V.; Elsayed, M.; Merkel, O.M.

    2014-01-01

    Upon activation, T cells of various subsets are the most important mediators in cell-mediated immune responses. Activated T cells play an important role in immune system related diseases such as chronic inflammatory diseases, viral infections, autoimmune disease, transplant rejection, Crohn disease, diabetes, and many more. Therefore, efforts have been made to both visualize and treat activated T cells specifically. This review summarizes imaging approaches and selective therapeutics for activated T cells and gives an outlook on how tracking and treating can be combined into theragnositc agents for activated T cells. PMID:24660025

  17. Nelarabine in the Treatment of Refractory T-Cell Malignancies

    PubMed Central

    Roecker, Andrew M.; Stockert, Amy; Kisor, David F.

    2010-01-01

    Nelarabine is a nucleoside analog indicated for the treatment of adult and pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that is refractory or has relapsed after treatment with at least two chemotherapy regimens. After being first synthesized in the late 1970s and receiving FDA approval in 2005, the appropriate use of nelarabine for refractory hematologic malignancies is still being elucidated. Nelarabine is the prodrug of 9-β-D-arabinofuranosylguanine (ara-G) which when phosphorylated intracellularly to ara-G triphosphate (ara-GTP), preferentially accumulates in cancerous T-cells. Dose-dependent toxicities, including neurotoxicity and myelosuppression, have been documented and may, in turn, limit the ability to appropriately treat the diagnosed malignancy. This article will summarize the pharmacologic properties of nelarabine and will address the current place in therapy nelarabine holds based upon the results of the available clinical trials to date. PMID:21151585

  18. A Randomized Trial of Punctuated Antiretroviral Therapy in Ugandan HIV-Seropositive Adults With Pulmonary Tuberculosis and CD4+ T-Cell Counts of ≥350 cells/μL

    PubMed Central

    Nanteza, M. W.; Mayanja-Kizza, H.; Charlebois, E.; Srikantiah, P.; Lin, R.; Mupere, E.; Mugyenyi, P.; Boom, W. H.; Mugerwa, R. D.; Havlir, D. V.

    2011-01-01

    Background. Optimal treatment of human immunodeficiency virus (HIV)–associated tuberculosis in patients with high CD4+ T-cell counts is unknown. Suppression of viral replication during therapy for tuberculosis may block effects of immune activation on T cells and slow HIV disease progression. Methods. We conducted a randomized trial in 214 HIV-infected patients with active tuberculosis and CD4+ T-cell counts of ≥350 cells/μL to determine whether 6 months of antiretroviral therapy given during tuberculosis treatment would improve clinical outcomes. Subjects were randomized to receive 6 months of abacavir-lamivudine-zidovudine concurrent with tuberculosis therapy or delayed antiretroviral therapy. Endpoints were CD4+ T-cell counts of <250 cells/μL, AIDS, or death. Results. Intervention and comparison arms had similar median CD4+ counts (517 and 534 cells/μL, respectively) and HIV RNA levels (4.6 and 4.7 log10 copies/μL, respectively). Viral suppression was achieved in 86% of patients allocated to intervention. Seventeen subjects (15.6%) in the intervention arm developed study outcome compared to 25 subjects (22.8%) in the comparison arm (P = .17). Grade 3 or 4 adverse events were less frequent in the intervention arm. By 2 months, 90% of subjects in both arms were culture-negative for tuberculosis. Conclusions. Short-term antiretroviral therapy during tuberculosis treatment in patients with CD4+ T-cell counts of >350 cells/μL was safe and associated with clinical benefits. PMID:21849285

  19. Cytotoxic polyfunctionality maturation of cytomegalovirus-pp65-specific CD4 + and CD8 + T-cell responses in older adults positively correlates with response size

    PubMed Central

    Chiu, Yen-Ling; Lin, Chung-Hao; Sung, Bo-Yi; Chuang, Yi-Fang; Schneck, Jonathan P.; Kern, Florian; Pawelec, Graham; Wang, George C.

    2016-01-01

    Cytomegalovirus (CMV) infection is one of the most common persistent viral infections in humans worldwide and is epidemiologically associated with many adverse health consequences during aging. Previous studies yielded conflicting results regarding whether large, CMV-specific T-cell expansions maintain their function during human aging. In the current study, we examined the in vitro CMV-pp65-reactive T-cell response by comprehensively studying five effector functions (i.e., interleukin-2, tumor necrosis factor-α, interferon-γ, perforin, and CD107a expression) in 76 seropositive individuals aged 70 years or older. Two data-driven, polyfunctionality panels (IL-2-associated and cytotoxicity-associated) derived from effector function co-expression patterns were used to analyze the results. We found that, CMV-pp65-reactive CD8 + and CD4 + T cells contained similar polyfunctional subsets, and the level of polyfunctionality was related to the size of antigen-specific response. In both CD8 + and CD4 + cells, polyfunctional cells with high cytotoxic potential accounted for a larger proportion of the total response as the total response size increased. Notably, a higher serum CMV-IgG level was positively associated with a larger T-cell response size and a higher level of cytotoxic polyfunctionality. These findings indicate that CMV-pp65-specific CD4 + and CD8 + T cell undergo simultaneous cytotoxic polyfunctionality maturation during aging. PMID:26778409

  20. Antihelper T cell autoantibody in acquired agammaglobulinemia.

    PubMed Central

    Rubinstein, A; Sicklick, M; Mehra, V; Rosen, F S; Levey, R H

    1981-01-01

    A patient with acquired agammaglobulinemia had an antihelper T cell factor that was identified as an immunoglobulin of the IgG class. The factor specifically bound to the TH2- T cell subset and, in the presence of complement, abolished the helper effect of normal T cells. The antihelper T cell antibody preceded by several years the appearance of suppressor TH2+Ia+ T cells, at which time the clinical course rapidly deteriorated. Plasmapheresis resulted in lymphocytosis and reappearance of a functionally intact helper T cell population. It did not affect the suppressor cells. Conversely, total thymectomy resulted in a temporary disappearance of the TH2+Ia+ suppressor cells, but did not decrease the levels of the autoantibody to helper T cells. Neither of these treatments reversed the state of agammaglobulinemia. PMID:6450224

  1. Immunometabolism of regulatory T cells

    PubMed Central

    Newton, Ryan; Priyadharshini, Bhavana; Turka, Laurence A

    2016-01-01

    The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells. PMID:27196520

  2. T cell tolerance in transplantation: possibilities for therapeutic intervention.

    PubMed

    Cobbold, Stephen P

    2002-10-01

    It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. These include the use of non-depleting monoclonal antibodies against T cell co-receptor and costimulation molecules, and immunisation with tolerogenic antigen-presenting cells. It is a common finding to all of these models of peripheral tolerance, as well as to various mouse models of autoimmune disease, that regulatory CD4(+) T cells are the principle mediators. There are currently no specific markers for regulatory T cells and their activity has been associated with different T cell subsets defined by the expression of activation markers, such as CD25 and cytotoxic T lymphocyte antigen-4 (CTLA-4), or anti-inflammatory cytokines, such as IL-10 and TGF-beta. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells and to find novel targets for therapeutic manipulation of the immune system. The challenge now is to understand the biological principles that allow such immune reprogramming so that they can be safely applied to clinical situations. PMID:12387682

  3. A Large Scale Study of the Psychometric Characteristics of the IBR Modified Overt Aggression Scale: Findings and Evidence for Increased Self-Destructive Behaviors in Adult Females with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Cohen, Ira L.; Tsiouris, John A.; Flory, Michael J.; Kim, Soh-Yule; Freedland, Robert; Heaney, Glenn; Pettinger, Jill; Brown, W. Ted

    2010-01-01

    The psychometric characteristics of the IBR Modified Overt Aggression Scale were studied in over 2,000 people with Intellectual Disability (ID). Reliability ranged from good to excellent. Aggression toward others and objects was highest in the youngest adults, in those in the moderate to severe range of ID, and in those with an autism spectrum…

  4. Incidence, Types and Characteristics of Aggressive Behaviour in Treatment Facilities for Adults with Mild Intellectual Disability and Severe Challenging Behaviour

    ERIC Educational Resources Information Center

    Tenneij, N. H.; Koot, H. M.

    2008-01-01

    Background: Inpatient aggression in treatment facilities for persons with intellectual disability (ID) can have aversive consequences, for co-clients and staff, but also for the aggressors themselves. To manage and eventually prevent inpatient aggressive incidents, more knowledge about their types and characteristics is necessary. Method: In four…

  5. Adult Attachment and Male Aggression in Couple Relationships: The Demand-Withdraw Communication Pattern and Relationship Satisfaction as Mediators

    ERIC Educational Resources Information Center

    Fournier, Benoit; Brassard, Audrey; Shaver, Phillip R.

    2011-01-01

    This study examines men's domestic aggression as a function of attachment insecurities, considering the mediating roles of the demand-withdraw communication pattern and relationship satisfaction. The sample included 55 Canadian men undergoing counseling for relationship difficulties including aggression. The men completed questionnaires assessing…

  6. A Human T-Cell Lymphotropic Virus Type 1 Enhancer of Myc Transforming Potential Stabilizes Myc-TIP60 Transcriptional Interactions

    PubMed Central

    Awasthi, Soumya; Sharma, Anima; Wong, Kasuen; Zhang, Junyu; Matlock, Elizabeth F.; Rogers, Lowery; Motloch, Pamela; Takemoto, Shigeki; Taguchi, Hirokuni; Cole, Michael D.; Lüscher, Bernhard; Dittrich, Oliver; Tagami, Hideaki; Nakatani, Yoshihiro; McGee, Monnie; Girard, Anne-Marie; Gaughan, Luke; Robson, Craig N.; Monnat, Raymond J.; Harrod, Robert

    2005-01-01

    The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4+ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30II/Myc-TIP60 chromatin-remodeling complexes. The p30II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30II interact with the TIP60 HAT, and p30II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis. PMID:15988028

  7. Isolation of viable and functional T-cells from human palatine tonsils.

    PubMed

    Weigel, Cynthia; Geißler, Katharina; Markwart, Robby; Schubert, Katja; Rubio, Ignacio; Guntinas-Lichius, Orlando; Requardt, Robert Pascal

    2015-12-01

    Increasing clinical evidence indicates that removal of the palatine tonsils enhances the risk for adults to suffer from severe illnesses. Together with recent experimental findings pointing to the presence of immunologically competent immune cells these findings illustrate that adult palatine tonsils likely play an appreciable role in the host immune response. T-cells are abundant in the palatine tonsil and are a pivotal entity of the adaptive immune response. However, investigation of T-cells from tonsils has been widely neglected and largely restricted to immune phenotyping. Accordingly, methodological literature describing the experimental preparation and isolation of T-cells from tonsils is scarce and has rarely been complemented with rigorous tests of T-cell functionality. We report here on a comparative investigation of three isolation protocols composed of permutations of different tissue grinding approaches, density gradient centrifugation and automated magnetic collection of CD4/CD8 T-cells. Importantly we put a strong emphasis on assessing the impact of the preparative procedures on the functionality of T-cells at the level of viability and functional response to T-cell receptor (TCR) ligation. The reported, optimized preparation protocols allow for the rapid isolation of highly viable, functional T-cells within 2.5h and represent a useful, affordable approach for the analysis of tonsillar T-cells. PMID:26472683

  8. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells.

    PubMed

    van den Broek, Theo; Delemarre, Eveline M; Janssen, Willemijn J M; Nievelstein, Rutger A J; Broen, Jasper C; Tesselaar, Kiki; Borghans, Jose A M; Nieuwenhuis, Edward E S; Prakken, Berent J; Mokry, Michal; Jansen, Nicolaas J G; van Wijk, Femke

    2016-03-01

    The generation of naive T cells is dependent on thymic output, but in adults, the naive T cell pool is primarily maintained by peripheral proliferation. Naive T cells have long been regarded as relatively quiescent cells; however, it was recently shown that IL-8 production is a signatory effector function of naive T cells, at least in newborns. How this functional signature relates to naive T cell dynamics and aging is unknown. Using a cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4+ T cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic tissue regeneration later in life resulted in functional restoration of the naive T cell compartment, implicating the thymus as having functional regenerative capacity. Together, these data shed further light on functional differentiation within the naive T cell compartment and the importance of the thymus in human naive T cell homeostasis and premature aging. In addition, these results affect and alter our current understanding on the identification of truly naive T cells and recent thymic emigrants. PMID:26901814

  9. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells

    PubMed Central

    van den Broek, Theo; Delemarre, Eveline M.; Janssen, Willemijn J.M.; Nievelstein, Rutger A.J.; Broen, Jasper C.; Tesselaar, Kiki; Borghans, Jose A.M.; Nieuwenhuis, Edward E.S.; Prakken, Berent J.; Mokry, Michal; Jansen, Nicolaas J.G.

    2016-01-01

    The generation of naive T cells is dependent on thymic output, but in adults, the naive T cell pool is primarily maintained by peripheral proliferation. Naive T cells have long been regarded as relatively quiescent cells; however, it was recently shown that IL-8 production is a signatory effector function of naive T cells, at least in newborns. How this functional signature relates to naive T cell dynamics and aging is unknown. Using a cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4+ T cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic tissue regeneration later in life resulted in functional restoration of the naive T cell compartment, implicating the thymus as having functional regenerative capacity. Together, these data shed further light on functional differentiation within the naive T cell compartment and the importance of the thymus in human naive T cell homeostasis and premature aging. In addition, these results affect and alter our current understanding on the identification of truly naive T cells and recent thymic emigrants. PMID:26901814

  10. TCR Signaling in T Cell Memory.

    PubMed

    Daniels, Mark A; Teixeiro, Emma

    2015-01-01

    T cell memory plays a critical role in our protection against pathogens and tumors. The antigen and its interaction with the T cell receptor (TCR) is one of the initiating elements that shape T cell memory together with inflammation and costimulation. Over the last decade, several transcription factors and signaling pathways that support memory programing have been identified. However, how TCR signals regulate them is still poorly understood. Recent studies have shown that the biochemical rules that govern T cell memory, strikingly, change depending on the TCR signal strength. Furthermore, TCR signal strength regulates the input of cytokine signaling, including pro-inflammatory cytokines. These highlight how tailoring antigenic signals can improve immune therapeutics. In this review, we focus on how TCR signaling regulates T cell memory and how the quantity and quality of TCR-peptide-MHC interactions impact the multiple fates a T cell can adopt in the memory pool. PMID:26697013

  11. T cell migration, search strategies and mechanisms.

    PubMed

    Krummel, Matthew F; Bartumeus, Frederic; Gérard, Audrey

    2016-03-01

    T cell migration is essential for T cell responses; it allows for the detection of cognate antigen at the surface of antigen-presenting cells and for interactions with other cells involved in the immune response. Although appearing random, growing evidence suggests that T cell motility patterns are strategic and governed by mechanisms that are optimized for both the activation stage of the cell and for environment-specific cues. In this Opinion article, we discuss how the combined effects of T cell-intrinsic and -extrinsic forces influence T cell motility patterns in the context of highly complex tissues that are filled with other cells involved in parallel motility. In particular, we examine how insights from 'search theory' can be used to describe T cell movement across an 'exploitation-exploration trade-off' in the context of activation versus effector function and lymph nodes versus peripheral tissues. PMID:26852928

  12. Principles of adoptive T cell cancer therapy

    PubMed Central

    June, Carl H.

    2007-01-01

    The transfusion of T cells, also called adoptive T cell therapy, is an effective treatment for viral infections and has induced regression of cancer in early-stage clinical trials. However, recent advances in cellular immunology and tumor biology are guiding new approaches to adoptive T cell therapy. For example, use of engineered T cells is being tested as a strategy to improve the functions of effector and memory T cells, and manipulation of the host to overcome immunotoxic effects in the tumor microenvironment has led to promising results in early-stage clinical trials. Challenges that face the field and must be addressed before adoptive T cell therapy can be translated into routine clinical practice are discussed. PMID:17476350

  13. Asymptomatic memory CD8+ T cells

    PubMed Central

    Khan, Arif Azam; Srivastava, Ruchi; Lopes, Patricia Prado; Wang, Christine; Pham, Thanh T; Cochrane, Justin; Thai, Nhi Thi Uyen; Gutierrez, Lucas; BenMohamed, Lbachir

    2014-01-01

    Generation and maintenance of high quantity and quality memory CD8+ T cells determine the level of protection from viral, bacterial, and parasitic re-infections, and hence constitutes a primary goal for T cell epitope-based human vaccines and immunotherapeutics. Phenotypically and functionally characterizing memory CD8+ T cells that provide protection against herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections, which cause blinding ocular herpes, genital herpes, and oro-facial herpes, is critical for better vaccine design. We have recently categorized 2 new major sub-populations of memory symptomatic and asymptomatic CD8+ T cells based on their phenotype, protective vs. pathogenic function, and anatomical locations. In this report we are discussing a new direction in developing T cell-based human herpes vaccines and immunotherapeutics based on the emerging new concept of “symptomatic and asymptomatic memory CD8+ T cells.” PMID:24499824

  14. T cell exhaustion during persistent viral infections.

    PubMed

    Kahan, Shannon M; Wherry, E John; Zajac, Allan J

    2015-05-01

    Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control.

  15. Necrobiotic cutaneous T-cell lymphoma.

    PubMed

    Woollons, A; Darvay, A; Khorshid, S M; Whittaker, S; Jones, R R

    1999-11-01

    We report 3 patients with granulomatous cutaneous T-cell lymphoma (CTCL) who showed necrobiosis histologically with palisading granulomas. Although granulomatous change may be present in up to 4% of cases of CTCL, necrobiosis is rare. Misdiagnosis may occur if epidermotropism is minimal or if atypical cells are masked by the granulomatous infiltrate. T-cell receptor gene analysis confirmed the presence of clonal T-cell populations in lesional skin from all 3 cases.

  16. Pathogen-Specific T Cell Polyfunctionality Is a Correlate of T Cell Efficacy and Immune Protection

    PubMed Central

    Boyd, Anders; Almeida, Jorge R.; Darrah, Patricia A.; Sauce, Delphine; Seder, Robert A.; Appay, Victor; Gorochov, Guy; Larsen, Martin

    2015-01-01

    Introduction Understanding the factors that delineate the efficacy of T cell responses towards pathogens is crucial for our ability to develop potent therapies against infectious diseases. Multidimensional evaluation of T cell functionality at the single-cell level enables exhaustive analysis of combinatorial functional properties, hence polyfunctionality. We have recently invented an algorithm that quantifies polyfunctionality, the Polyfunctionality Index (Larsen et al. PLoS One 2012). Here we demonstrate that quantitative assessment of T cell polyfunctionality correlates with T cell efficacy measured as the capacity to kill target cells in vitro and control infection in vivo. Methods We employed the polyfunctionality index on two datasets selected for their unique ability to evaluate the polyfunctional imprint on T cell efficacy. 1) HIV-specific CD8+ T cells and 2) Leishmania major-specific CD4+ T cells were analysed for their capacity to secrete multiple effector molecules, kill target cells and control infection. Briefly, employing the Polyfunctionality Index algorithm we determined the parameter estimates resulting in optimal correlation between T cell polyfunctionality and T cell efficacy. Results T cell polyfunctionality is correlated with T cell efficacy measured as 1) target killing (r=0.807, P<0.0001) and 2) lesion size upon challenge with Leishmania major (r=-0.50, P=0.004). Contrary to an approach relying on the Polyfunctionality Index algorithm, quantitative evaluation of T cell polyfunctionality traditionally ignores the gradual contribution of more or less polyfunctional T cells. Indeed, comparing both approaches we show that optimal description of T cell efficacy is obtained when gradually integrating all levels of polyfunctionality in accordance with the Polyfunctionality Index. Conclusions Our study presents a generalizable methodology to objectively evaluate the impact of polyfunctionality on T cell efficacy. We show that T cell polyfunctionality

  17. CAR-T cells are serial killers

    PubMed Central

    Davenport, Alexander J; Jenkins, Misty R; Ritchie, David S; Prince, H Miles; Trapani, Joseph A; Kershaw, Michael H; Darcy, Phillip K; Neeson, Paul J

    2015-01-01

    Chimeric antigen receptor (CAR) T cells have enjoyed unprecedented clinical success against haematological malignancies in recent years. However, several aspects of CAR T cell biology remain unknown. We recently compared CAR and T cell receptor (TCR)-based killing in the same effector cell and showed that CAR T cells can not only efficiently kill single tumor targets, they can also kill multiple tumor targets in a sequential manner. Single and serial killing events were not sustained long term due to CAR down-regulation after 20 hours. PMID:26587330

  18. T cell receptor usage in rheumatic disease.

    PubMed

    Richardson, B C

    1992-01-01

    Protection against microbial attack or invasion is a fundamental function of the immune system. Crucial to this function is the ability to distinguish "self" from the invading organism, and tolerate "self" while removing "non-self". The ability to distinguish self from non-self is not inherent in the immune system, but rather is acquired and continuously maintained. Unfortunately, the mechanisms maintaining self-tolerance are not perfect, and at times break down. In these instances an autoimmune disease results. T cells initiate normal immune responses, and it is now clear that T cells can also initiate pathologic immune responses. In animal models, T cells produce diseases resembling rheumatoid arthritis (RA) (1-3), systemic lupus erythematosus (4-6) and progressive systemic sclerosis (7,8). It is likely that T cells participate in human autoimmune diseases as well. The molecular basis of T cell antigen recognition has been clarified over the past decade. These advances now allow direct examination of the T cell receptor (TCR) molecules participating in autoimmune responses, and raise the exciting possibility that the cells inducing autoimmune responses may finally be identified. Selective agents might then be developed which would interfere with or inhibit the cells. Understanding these developments requires detailed knowledge of how T cells recognize antigen, and of the receptors involved in autoimmune diseases. This article reviews the current literature on T cell receptor structure, and summarizes what is currently known about the usage of specific T cell receptors in autoimmune rheumatic disease. PMID:1582073

  19. T-cell prolymphocytic leukaemia (T-PLL): a rare disease with a grave prognosis.

    PubMed

    Vivekanandarajah, Abhirami; Atallah, Jean Paul; Gupta, Shilpi

    2013-05-02

    T-cell prolymphocytic leukaemia (T-PLL) is an extremely uncommon haematological malignancy that has an aggressive course and a grave prognosis. We describe a patient who presented with lymphocytosis, scalp erythema, ascites and splenomegaly and was diagnosed with T-PLL. He was treated with alemtuzumab with a good response and was referred for allogeneic stem cell transplantation.

  20. REGULATORY T CELLS AND VASECTOMY

    PubMed Central

    Rival, Claudia; Wheeler, Karen; Jeffrey, Sarah; Qiao, Hui; Luu, Brian; Tewalt, Eric F; Engelhard, Victor H; Tardif, Stephen; Hardy, Daniel; del Rio, Roxana; Teuscher, Cory; Tung, Kenneth

    2013-01-01

    CD4+CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24 hours of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12–16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at seven months, the antibody titers fluctuated over time, suggesting a dynamic “balance” between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance. PMID:24080233

  1. Clinical and pathological heterogeneity in cutaneous gamma-delta T-cell lymphoma: a report of three cases and a review of the literature.

    PubMed

    Munn, S E; McGregor, J M; Jones, A; Amlot, P; Rustin, M H; Russell Jones, R; Whittaker, S

    1996-12-01

    Cutaneous gamma-delta (gamma delta) T-cell lymphoma is rare. Eleven cases have been reported to date including four cases of mycosis fungoides (MF), two of pagetoid reticulosis and five of pleomorphic cutaneous T-cell lymphoma (CTCL). We report three further cases of cutaneous gamma delta T-cell lymphoma; one of MF, one of a pleomorphic CTCL and one of a subcutaneous T-cell lymphoma. Combined data suggest that although cutaneous gamma delta T-cell lymphomas do not appear to comprise a single clinicopathological entity, they may be associated with aggressive clinical behaviour and a poor prognosis.

  2. Differential DNA Methylation Regions in Cytokine and Transcription Factor Genomic Loci Associate with Childhood Physical Aggression

    PubMed Central

    Provençal, Nadine; Suderman, Matthew J.; Caramaschi, Doretta; Wang, Dongsha; Hallett, Michael; Vitaro, Frank

    2013-01-01

    Background Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence. Methodology/Principal Findings We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group) from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression. Conclusions We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression. PMID:23977113

  3. Kinetic discrimination in T-cell activation.

    PubMed Central

    Rabinowitz, J D; Beeson, C; Lyons, D S; Davis, M M; McConnell, H M

    1996-01-01

    We propose a quantitative model for T-cell activation in which the rate of dissociation of ligand from T-cell receptors determines the agonist and antagonist properties of the ligand. The ligands are molecular complexes between antigenic peptides and proteins of the major histocompatibility complex on the surfaces of antigen-presenting cells. Binding of ligand to receptor triggers a series of biochemical reactions in the T cell. If the ligand dissociates after these reactions are complete, the T cell receives a positive activation signal. However, dissociation of ligand after completion of the first reaction but prior to generation of the final products results in partial T-cell activation, which acts to suppress a positive response. Such a negative signal is brought about by T-cell ligands containing the variants of antigenic peptides referred to as T-cell receptor antagonists. Results of recent experiments with altered peptide ligands compare favorably with T-cell responses predicted by this model. PMID:8643643

  4. Visualizing T Cell Migration in situ

    PubMed Central

    Benechet, Alexandre P.; Menon, Manisha; Khanna, Kamal M.

    2014-01-01

    Mounting a protective immune response is critically dependent on the orchestrated movement of cells within lymphoid tissues. The structure of secondary lymphoid organs regulates immune responses by promoting optimal cell–cell and cell–extracellular matrix interactions. Naïve T cells are initially activated by antigen presenting cells in secondary lymphoid organs. Following priming, effector T cells migrate to the site of infection to exert their functions. Majority of the effector cells die while a small population of antigen-specific T cells persists as memory cells in distinct anatomical locations. The persistence and location of memory cells in lymphoid and non-lymphoid tissues is critical to protect the host from re-infection. The localization of memory T cells is carefully regulated by several factors including the highly organized secondary lymphoid structure, the cellular expression of chemokine receptors and compartmentalized secretion of their cognate ligands. This balance between the anatomy and the ordered expression of cell surface and soluble proteins regulates the subtle choreography of T cell migration. In recent years, our understanding of cellular dynamics of T cells has been advanced by the development of new imaging techniques allowing in situ visualization of T cell responses. Here, we review the past and more recent studies that have utilized sophisticated imaging technologies to investigate the migration dynamics of naïve, effector, and memory T cells. PMID:25120547

  5. Carbohydrates and T cells: a sweet twosome.

    PubMed

    Avci, Fikri Y; Li, Xiangming; Tsuji, Moriya; Kasper, Dennis L

    2013-04-01

    Carbohydrates as T cell-activating antigens have been generating significant interest. For many years, carbohydrates were thought of as T-independent antigens, however, more recent research had demonstrated that mono- or oligosaccharides glycosidically linked to peptides can be recognized by T cells. T cell recognition of these glycopeptides depends on the structure of both peptide and glycan portions of the antigen. Subsequently, it was discovered that natural killer T cells recognized glycolipids when presented by the antigen presenting molecule CD1d. A transformative insight into glycan-recognition by T cells occurred when zwitterionic polysaccharides were discovered to bind to and be presented by MHCII to CD4+ T cells. Based on this latter observation, the role that carbohydrate epitopes generated from glycoconjugate vaccines had in activating helper T cells was explored and it was found that these epitopes are presented to specific carbohydrate recognizing T cells through a unique mechanism. Here we review the key interactions between carbohydrate antigens and the adaptive immune system at the molecular, cellular and systems levels exploring the significant biological implications in health and disease.

  6. Kinetic Discrimination in T-Cell Activation

    NASA Astrophysics Data System (ADS)

    Rabinowitz, Joshua D.; Beeson, Craig; Lyons, Daniel S.; Davis, Mark M.; McConnell, Harden M.

    1996-02-01

    We propose a quantitative model for T-cell activation in which the rate of dissociation of ligand from T-cell receptors determines the agonist and antagonist properties of the ligand. The ligands are molecular complexes between antigenic peptides and proteins of the major histocompatibility complex on the surfaces of antigen-presenting cells. Binding of ligand to receptor triggers a series of biochemical reactions in the T cell. If the ligand dissociates after these reactions are complete, the T cell receives a positive activation signal. However, dissociation of ligand after completion of the first reaction but prior to generation of the final products results in partial T-cell activation, which acts to suppress a positive response. Such a negative signal is brought about by T-cell ligands containing the variants of antigenic peptides referred to as T-cell receptor antagonists. Results of recent experiments with altered peptide ligands compare favorably with T-cell responses predicted by this model.

  7. Donor T Cells After Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2016-07-20

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood

  8. Endothelial microparticles interact with and support the proliferation of T cells.

    PubMed

    Wheway, Julie; Latham, Sharissa L; Combes, Valery; Grau, Georges E R

    2014-10-01

    Endothelial cells closely interact with circulating lymphocytes. Aggression or activation of the endothelium leads to an increased shedding of endothelial cell microparticles (MP). Endothelial MP (EMP) are found in high plasma levels in numerous immunoinflammatory diseases, such as atherosclerosis, sepsis, multiple sclerosis, and cerebral malaria, supporting their role as effectors and markers of vascular dysfunction. Given our recently described role for human brain microvascular endothelial cells (HBEC) in modulating immune responses, we investigated how HBEC-derived MP could interact with and support the proliferation of T cells. Like their mother cells, EMP expressed molecules important for Ag presentation and T cell costimulation, that is, β2-microglobulin, MHC II, CD40, and ICOSL. HBEC were able to take up fluorescently labeled Ags with EMP also containing fluorescent Ags, suggestive of Ag carryover from HBEC to EMP. In cocultures, fluorescently labeled EMP from resting or cytokine-stimulated HBEC formed conjugates with both CD4(+) and CD8(+) subsets, with higher proportions of T cells binding EMP from cytokine-stimulated cells. The increased binding of EMP from cytokinestimulated HBEC to T cells was VCAM-1 and ICAM-1 dependent. Finally, in CFSE T cell proliferation assays using anti-CD3 mAb or T cell mitogens, EMP promoted the proliferation of CD4(+) T cells and that of CD8(+) T cells in the absence of exogenous stimuli and in the T cell mitogenic stimulation. Our findings provide novel evidence that EMP can enhance T cell activation and potentially ensuing Ag presentation, thereby pointing toward a novel role for MP in neuroimmunological complications of infectious diseases.

  9. Targeting T cell metabolism for therapy

    PubMed Central

    O’Sullivan, David

    2015-01-01

    In the past several years, a wealth of evidence has emerged illustrating how metabolism supports many aspects of T cell biology, as well as how metabolic changes drive T cell differentiation and fate. Here we outline developing principles in the regulation of T cell metabolism, and discuss how these processes are impacted in settings of inflammation and cancer. In this context we discuss how metabolic pathways might be manipulated for the treatment of human disease, including how metabolism may be targeted to prevent T cell dysfunction in inhospitable microenvironments, to generate more effective adoptive cellular immunotherapies in cancer, and to direct T cell differentiation and function towards non-pathogenic phenotypes in settings of autoimmunity. PMID:25601541

  10. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells.

    PubMed

    Swaims, Alison Y; Khani, Francesca; Zhang, Yingyu; Roberts, Arthur I; Devadas, Satish; Shi, Yufang; Rabson, Arnold B

    2010-10-21

    Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals. PMID:20634377

  11. Inhibitory Receptors Beyond T Cell Exhaustion

    PubMed Central

    Fuertes Marraco, Silvia A.; Neubert, Natalie J.; Verdeil, Grégory; Speiser, Daniel E.

    2015-01-01

    Inhibitory receptors (iRs) are frequently associated with “T cell exhaustion”. However, the expression of iRs is also dependent on T cell differentiation and activation. Therapeutic blockade of various iRs, also referred to as “checkpoint blockade”, is showing ­unprecedented results in the treatment of cancer patients. Consequently, the clinical potential in this field is broad, calling for increased research efforts and rapid refinements in the understanding of iR function. In this review, we provide an overview on the significance of iR expression for the interpretation of T cell functionality. We summarize how iRs have been strongly associated with “T cell exhaustion” and illustrate the parallel evidence on the importance of T cell differentiation and activation for the expression of iRs. The differentiation subsets of CD8 T cells (naïve, effector, and memory cells) show broad and inherent differences in iR expression, while activation leads to strong upregulation of iRs. Therefore, changes in iR expression during an immune response are often concomitant with T cell differentiation and activation. Sustained expression of iRs in chronic infection and in the tumor microenvironment likely reflects a specialized T cell differentiation. In these situations of prolonged antigen exposure and chronic inflammation, T cells are “downtuned” in order to limit tissue damage. Furthermore, we review the novel “checkpoint blockade” treatments and the potential of iRs as biomarkers. Finally, we provide recommendations for the immune monitoring of patients to interpret iR expression data combined with parameters of activation and differentiation of T cells. PMID:26167163

  12. A T-cell prolymphocytic leukemia case with central nervous system involvement

    PubMed Central

    Malkan, Umit Yavuz; Gunes, Gursel; Yayar, Okan; Demiroglu, Haluk; Yesilirmak, Aysun; Uner, Aysegul

    2015-01-01

    T-cell prolymphocytic leukemia (T-PLL) is an aggressive mature T cell neoplasm that typically involves peripheral blood, bone marrow, lymph nodes and spleen. It is a rare disease that comprises 2-5% of mature lymphocytic leukemia in adults. Here we present a T-PLL patient with CNS involvement. A 74-year-old man admitted to a hospital in April 2014 with vomiting. He was diagnosed as chronic lymphocytic leukemia (CLL) and R-CVP (Rituximab, cyclophosphamide, vincristine and prednisolone) chemotherapy protocol was started. After the first two cycles of chemotherapy, the patient’s mental functions improved. However after the 3rd cycle of chemotherapy was given in July 2014 the general situation of the patient deteriorated and ptosis of the left eye and facial paralysis developed. Then the patient was referred to our medical center. An MR of the brain revealed linear contrast enhancement around the bilateral 3rd, 7th and 8th cranial nerves which indicated cranial involvement by the lymphoproliferative process (Figure 1). Cerebrospinal fluid cytological examination confirmed the diagnosis. Based on these and bone marrow aspiration and biopsy findings a diagnosis of T-PLL was rendered (Figure 3). In September 2014 the patient died suddenly due to a cardiac arrest. Differential diagnosis is very important in T-PLL. Both T-PLL and chronic lymphocytic leukemia (CLL) may present with splenomegaly and lymphocytosis as well as circulating prolymphocytes in blood. Typical CLL cells are like mature lymphocytes with dense nucleus and aggregated chromatin. To conclude, CNS involvement in T-PLL is a rare finding and differential diagnosis of T-PLL is very important. PMID:26550397

  13. A T-cell prolymphocytic leukemia case with central nervous system involvement.

    PubMed

    Malkan, Umit Yavuz; Gunes, Gursel; Yayar, Okan; Demiroglu, Haluk; Yesilirmak, Aysun; Uner, Aysegul

    2015-01-01

    T-cell prolymphocytic leukemia (T-PLL) is an aggressive mature T cell neoplasm that typically involves peripheral blood, bone marrow, lymph nodes and spleen. It is a rare disease that comprises 2-5% of mature lymphocytic leukemia in adults. Here we present a T-PLL patient with CNS involvement. A 74-year-old man admitted to a hospital in April 2014 with vomiting. He was diagnosed as chronic lymphocytic leukemia (CLL) and R-CVP (Rituximab, cyclophosphamide, vincristine and prednisolone) chemotherapy protocol was started. After the first two cycles of chemotherapy, the patient's mental functions improved. However after the 3(rd) cycle of chemotherapy was given in July 2014 the general situation of the patient deteriorated and ptosis of the left eye and facial paralysis developed. Then the patient was referred to our medical center. An MR of the brain revealed linear contrast enhancement around the bilateral 3(rd), 7(th) and 8(th) cranial nerves which indicated cranial involvement by the lymphoproliferative process (Figure 1). Cerebrospinal fluid cytological examination confirmed the diagnosis. Based on these and bone marrow aspiration and biopsy findings a diagnosis of T-PLL was rendered (Figure 3). In September 2014 the patient died suddenly due to a cardiac arrest. Differential diagnosis is very important in T-PLL. Both T-PLL and chronic lymphocytic leukemia (CLL) may present with splenomegaly and lymphocytosis as well as circulating prolymphocytes in blood. Typical CLL cells are like mature lymphocytes with dense nucleus and aggregated chromatin. To conclude, CNS involvement in T-PLL is a rare finding and differential diagnosis of T-PLL is very important.

  14. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues.

    PubMed

    Thome, Joseph J C; Bickham, Kara L; Ohmura, Yoshiaki; Kubota, Masaru; Matsuoka, Nobuhide; Gordon, Claire; Granot, Tomer; Griesemer, Adam; Lerner, Harvey; Kato, Tomoaki; Farber, Donna L

    2016-01-01

    It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life. PMID:26657141

  15. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues.

    PubMed

    Thome, Joseph J C; Bickham, Kara L; Ohmura, Yoshiaki; Kubota, Masaru; Matsuoka, Nobuhide; Gordon, Claire; Granot, Tomer; Griesemer, Adam; Lerner, Harvey; Kato, Tomoaki; Farber, Donna L

    2016-01-01

    It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.

  16. Intestinal alpha beta T cells differentiate and rearrange antigen receptor genes in situ in the human infant.

    PubMed

    Williams, Amanda M; Bland, Paul W; Phillips, Anne C; Turner, Susan; Brooklyn, Trevor; Shaya, Gabriel; Spicer, Richard D; Probert, Christopher S J

    2004-12-15

    Intestinal Ag exposure during neonatal life influences appropriate adult immune responses. To define the mechanisms shaping the T cell repertoire during this period, we examined T cell differentiation and receptor diversity in the intestine of human infants. Developmental phenotypes of intraepithelial and lamina propria intestinal T cells from infants aged 1 day to 2 years were assessed ex vivo by flow cytometry and in situ by triple-fluorescent immunohistochemistry. Gene recombination-specific enzymes were assessed by PCR. TCR beta-chain V region gene diversity was determined by sequencing. Several different early lineage T cell populations were present neonatally: CD3(+)4(-)8(-) T cells were present at birth and numbers decreased during the neonatal period; CD3(+)4(+)8(+) T cells were present in low numbers throughout infancy; and CD3(+)4(+)8(-) or CD3(+)4(-)8(+) T cells increased with age. Very early lineage T cells, CD3(-)2(-)7(+) and CD3(-)2(+)7(+), were present neonatally, but were essentially absent at 1 year. Most lamina propria T cells differentiated rapidly after birth, but maturation of intraepithelial T cells took place over 1 year. Intestinal samples from infants less than 6 mo old contained transcripts of T early alpha and TdT, and 15 of 19 infant samples contained mRNA for RAG-1, some coexpressing RAG-2. TCR beta-chain repertoires were polyclonal in infants. Immature T cells, pre-T cells, and genes involved in T cell recombination were found in the intestine during infancy. T cell differentiation occurs within the neonatal human intestine, and the TCR repertoire of these developing immature T cells is likely to be influenced by luminal Ags. Thus, mucosal T cell responsiveness to environmental Ag is shaped in situ during early life.

  17. CD8{sup +}CD25{sup +} T cells reduce atherosclerosis in apoE(−/−) mice

    SciTech Connect

    Zhou, Jianchang; Dimayuga, Paul C.; Zhao, Xiaoning; Yano, Juliana; Lio, Wai Man; Trinidad, Portia; Honjo, Tomoyuki; Cercek, Bojan; Shah, Prediman K.; Chyu, Kuang-Yuh

    2014-01-17

    Highlights: •The role of a sub-population of CD8{sup +} T cells with suppressor functions was investigated in atherosclerosis. •CD8{sup +}CD25{sup +} T cells from adult apoE(−/−) mice had phenotype characteristics of T suppressor cells. •These CD8{sup +}CD25{sup +} T cells reduced CD4{sup +} T cell proliferation and CD8{sup +} cytotoxic activity in vitro. •Adoptive transfer of CD8{sup +}CD25{sup +} T cells significantly reduced atherosclerosis. •CD8{sup +}CD25{sup +} T cells have a suppressive function in atherosclerosis. -- Abstract: Background: It is increasingly evident that CD8{sup +} T cells are involved in atherosclerosis but the specific subtypes have yet to be defined. CD8{sup +}CD25{sup +} T cells exert suppressive effects on immune signaling and modulate experimental autoimmune disorders but their role in atherosclerosis remains to be determined. The phenotype and functional role of CD8{sup +}CD25{sup +} T cells in experimental atherosclerosis were investigated in this study. Methods and results: CD8{sup +}CD25{sup +} T cells were observed in atherosclerotic plaques of apoE(−/−) mice fed hypercholesterolemic diet. Characterization by flow cytometric analysis and functional evaluation using a CFSE-based proliferation assays revealed a suppressive phenotype and function of splenic CD8{sup +}CD25{sup +} T cells from apoE(−/−) mice. Depletion of CD8{sup +}CD25{sup +} from total CD8{sup +} T cells rendered higher cytolytic activity of the remaining CD8{sup +}CD25{sup −} T cells. Adoptive transfer of CD8{sup +}CD25{sup +} T cells into apoE(−/−) mice suppressed the proliferation of splenic CD4{sup +} T cells and significantly reduced atherosclerosis in recipient mice. Conclusions: Our study has identified an athero-protective role for CD8{sup +}CD25{sup +} T cells in experimental atherosclerosis.

  18. T Cell Receptor Gene Therapy for Cancer

    PubMed Central

    Schmitt, Thomas M.; Ragnarsson, Gunnar B.

    2009-01-01

    Abstract T cell-based adoptive immunotherapy has been shown to be a promising treatment for various types of cancer. However, adoptive T cell therapy currently requires the custom isolation and characterization of tumor-specific T cells from each patient—a process that can be not only difficult and time-consuming but also often fails to yield high-avidity T cells, which together have limited the broad application of this approach as a clinical treatment. Employing T cell receptor (TCR) gene therapy as a component of adoptive T cell therapy strategies can overcome many of these obstacles, allowing autologous T cells with a defined specificity to be generated in a much shorter time period. Initial studies using this approach have been hampered by a number of technical difficulties resulting in low TCR expression and acquisition of potentially problematic specificities due to mispairing of introduced TCR chains with endogenous TCR chains. The last several years have seen substantial progress in our understanding of the multiple facets of TCR gene therapy that will have to be properly orchestrated for this strategy to succeed. Here we outline the challenges of TCR gene therapy and the advances that have been made toward realizing the promise of this approach. PMID:19702439

  19. Developmental exposure to trichloroethylene promotes CD4{sup +} T cell differentiation and hyperactivity in association with oxidative stress and neurobehavioral deficits in MRL+/+ mice

    SciTech Connect

    Blossom, Sarah J. Doss, Jason C.; Hennings, Leah J.; Jernigan, Stefanie; Melnyk, Stepan; James, S. Jill

    2008-09-15

    The non adult immune system is particularly sensitive to perinatal and early life exposures to environmental toxicants. The common environmental toxicant, trichloroethylene (TCE), was shown to increase CD4+ T cell production of the proinflammatory cytokine IFN-{gamma} following a period of prenatal and lifetime exposure in autoimmune-prone MRL+/+ mice. In the current study, MRL+/+ mice were used to further examine the impact of TCE on the immune system in the thymus and periphery. Since there is considerable cross-talk between the immune system and the brain during development, the potential relationship between TCE and neurobehavioral endpoints were also examined. MRL+/+ mice were exposed to 0.1 mg/ml TCE ({approx} 31 mg/kg/day) via maternal drinking water or direct exposure via the drinking water from gestation day 1 until postnatal day (PD) 42. TCE exposure did not impact gross motor skills but instead significantly altered social behaviors and promoted aggression associated with indicators of oxidative stress in brain tissues in male mice. The immunoregulatory effects of TCE involved a redox-associated promotion of T cell differentiation in the thymus that preceded the production of proinflammatory cytokines, IL-2, TNF-{alpha}, and IFN-{gamma} by mature CD4+ T cells. The results demonstrated that developmental and early life TCE exposure modulated immune function and may have important implications for neurodevelopmental disorders.

  20. Pushing the frontiers of T-cell vaccines: accurate measurement of human T-cell responses

    PubMed Central

    Saade, Fadi; Gorski, Stacey Ann; Petrovsky, Nikolai

    2013-01-01

    There is a need for novel approaches to tackle major vaccine challenges such as malaria, tuberculosis and HIV, among others. Success will require vaccines able to induce a cytotoxic T-cell response – a deficiency of most current vaccine approaches. The successful development of T-cell vaccines faces many hurdles, not least being the lack of consensus on a standardized T-cell assay format able to be used as a correlate of vaccine efficacy. Hence, there remains a need for reproducible measures of T-cell immunity proven in human clinical trials to correlate with vaccine protection. The T-cell equivalent of a neutralizing antibody assay would greatly accelerate the development and commercialization of T-cell vaccines. Recent advances have seen a plethora of new T-cell assays become available, including some like cytometry by time-of-flight with extreme multiparameter T-cell phenotyping capability. However, whether it is historic thymidine-based proliferation assays or sophisticated new cytometry assays, each assay has its relative advantages and disadvantages, and relatively few of these assays have yet to be validated in large-scale human vaccine trials. This review examines the current range of T-cell assays and assesses their suitability for use in human vaccine trials. Should one or more of these assays be accepted as an agreed surrogate of T-cell protection by a regulatory agency, this would significantly accelerate the development of T-cell vaccines. PMID:23252389

  1. A Comparison of Girls' and Boys' Aggressive-Disruptive Behavior Trajectories across Elementary School: Prediction to Young Adult Antisocial Outcomes

    ERIC Educational Resources Information Center

    Schaeffer, Cindy M.; Petras, Hanno; Ialongo, Nicholas; Masyn, Katherine E.; Hubbard, Scott; Poduska, Jeanne; Kellam, Sheppard

    2006-01-01

    Multiple group analysis and general growth mixture modeling was used to determine whether aggressive-disruptive behavior trajectories during elementary school, and their association with young adulthood antisocial outcomes, vary by gender. Participants were assessed longitudinally beginning at age 6 as part of an evaluation of 2 school-based…

  2. Reprogramming T cell Lymphocytes to Induced Pluripotent Stem Cells

    NASA Astrophysics Data System (ADS)

    Bared, Kalia

    The discovery of induced pluripotent stem cells (iPSC) provided a novel technology for the study of development and pharmacology and complement embryonic stem cells (ES) for cell therapy applications. Though iPSC are derived from adult tissue they are comparable to ES cells in their behavior; multi-lineage differentiation and self-renewal. This makes iPSC research appealing because they can be studied in great detail and expanded in culture broadly. Fibroblasts were the first cell type reprogrammed to an iPSC using a retrovirus vector, since then alternative cell types including lymphocytes have been used to generate iPSC. Different types of vectors have also been developed to enhance iPSC formation and quality. However, specific T lymphocyte subsets have not been shown to reprogram to a pluripotent state to date. Here, we proposed to derive iPSC from peripheral blood effector and central memory T cells, reasoning that the resultant iPSC will maintain the epigenetic memory of a T lymphocyte, including the T cell receptor (TCR) gene rearrangement. This epigenetic memory will enable the differentiation and expansion of T cell iPSC into professional T cells containing a specific TCR. These could then be used for cell therapy to target specific antigens, as well as to improve culture techniques to expand T cells in vitro. We studied different gene delivery methods to derive iPSC from different types of T lymphocytes. We assessed the viability of viral transduction using flow cytometry to detect green fluorescent marker contained in the viral construct and quantitative real time polymerase chain reaction (qRT-PCR) to detect Oct4, Klf4, Sox2, and c-Myc gene expression. Our results demonstrate that the Sendai virus construct is the most feasible platform to reprogram T lymphocytes. We anticipate that this platform will provide an efficient and safe approach to derive iPSC from different T cell subsets, including memory T cells.

  3. T cells, precocious aging, and familial neoplasia.

    PubMed

    Fudenberg, H H; Schuman, S H; Goust, J M; Jorgenson, R

    1978-01-01

    A 15-year-old girl presented with precocious aging and was found to have low levels of active and total T cells. Family history revealed a high familial incidence of cancer on both the maternal and paternal sides, and activ T cell levels were found to be low in several living family members. The patient developed osteogenic sarcoma 13 months after initial study. Since our previous studies have reported low active and total T cells in patients with cancer, the present results suggest that subjects with low active T cells should be monitored frequently to detect possible neoplasia in it early stages. They also suggest that impaired cellular immunity in humans is associated with, if not the cause of, accelerated aging. PMID:304823

  4. Preventing T cell rejection of pig xenografts.

    PubMed

    Higginbotham, Laura; Ford, Mandy L; Newell, Kenneth A; Adams, Andrew B

    2015-11-01

    Xenotransplantation is a potential solution to the limited supply of donor organs. While early barriers to xenograft acceptance, such as hyperacute rejection, are now largely avoided through genetic engineering, the next frontier in successful xenograft survival will require prevention of T cell-mediated rejection. Most successful immunosuppressive regimens in xenotransplantation utilize T cell depletion with antibody therapy. Additionally, the use of T cell costimulatory blockade - specifically blockade of the CD40-CD154 pathway - shows promise with several reports of long-term xenograft survival. Additional therapies, such as transgenic expression of T cell coinhibitory molecules or transfer of immunomodulatory cells to promote tolerance, may be necessary to achieve reliable long-term xenograft acceptance. Further studies in pre-clinical models are essential in order to optimize these regimens prior to trials in patients.

  5. Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) T cells via the PD-1/PD-L1 axis.

    PubMed

    Rabe, Hardis; Nordström, Inger; Andersson, Kerstin; Lundell, Anna-Carin; Rudin, Anna

    2014-03-01

    The gut microbiota provides an important stimulus for the induction of regulatory T (Treg) cells in mice, whether this applies to newborn children is unknown. In Swedish children, Staphylococcus aureus has become a common early colonizer of the gut. Here, we sought to study the effects of bacterial stimulation on neonatal CD4(+) T cells for the induction of CD25(+) CD127(low) Treg cells in vitro. The proportion of circulating CD25(+) CD127(low) Treg cells and their expression of FOXP3, Helios and CTLA-4 was examined in newborns and adults. To evaluate if commensal gut bacteria could induce Treg cells, CellTrace violet-stained non-Treg cells from cord or peripheral blood from adults were co-cultured with autologous CD25(+) CD127(low) Treg cells and remaining mononuclear cells and stimulated with S. aureus. Newborns had a significantly lower proportion of CD25(+) CD127(low) Treg cells than adults, but these cells were Helios(+) and CTLA-4(+) to a higher extent than in adults. FOXP3(+) CD25(+) CD127(low) T cells were induced mainly in neonatal CellTrace-stained non-Treg cells after stimulation with S. aureus. In cell cultures from adults, S. aureus induced CD25(+) CD127(low) T cells only if sorted naive CD45RA(+) non-Treg cells were used, but these cells expressed less FOXP3 than those induced from newborns. Sorted neonatal CD25(+) CD127(low) T cells from S. aureus-stimulated cultures were still suppressive. Finally, blocking PD-L1 during stimulation reduced the induction of FOXP3(+) CD25(+) CD127(low) T cells. These results suggest that newborns have a higher proportion of circulating thymically derived Helios(+) Treg cells than adults and that S. aureus possess an ability to convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127(low) Treg cells via the PD-1/PD-L1 axis.

  6. CCR7 signaling inhibits T cell proliferation.

    PubMed

    Ziegler, Ekkehard; Oberbarnscheidt, Martin; Bulfone-Paus, Silvia; Förster, Reinhold; Kunzendorf, Ulrich; Krautwald, Stefan

    2007-11-15

    CCR7 and its ligands, CCL19 and CCL21, are responsible for directing the migration of T cells and dendritic cells into lymph nodes, where these cells play an important role in the initiation of the immune response. Recently, we have shown that systemic application of CCL19-IgG is able to inhibit the colocalization of T cells and dendritic cells within secondary lymphoid organs, resulting in pronounced immunosuppression with reduced allograft rejection after organ transplantation. In this study, we demonstrate that the application of sustained high concentrations of either soluble or immobilized CCL19 and CCL21 elicits an inhibitory program in T cells. We show that these ligands specifically interfere with cell proliferation and IL-2 secretion of CCR7(+) cells. This could be demonstrated for human and murine T cells and was valid for both CD4(+) and CD8(+) T cells. In contrast, CCL19 had no inhibitory effect on T cells from CCR7 knockout mice, but CCR7(-/-) T cells showed a proliferative response upon TCR-stimulation similar to that of CCL19-treated wild-type cells. Furthermore, the inhibition of proliferation is associated with delayed degradation of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) and the down-regulation of CDK1. This shows that CCR7 signaling is linked to cell cycle control and that sustained engagement of CCR7, either by high concentrations of soluble ligands or by high density of immobilized ligands, is capable of inducing cell cycle arrest in TCR-stimulated cells. Thus, CCR7, a chemokine receptor that has been demonstrated to play an essential role during activation of the immune response, is also competent to directly inhibit T cell proliferation. PMID:17982037

  7. Circulating rotavirus-specific T cells have a poor functional profile

    SciTech Connect

    Parra, Miguel; Herrera, Daniel; Jácome, María Fernanda; Mesa, Martha C.; Rodríguez, Luz-Stella; Guzmán, Carolina; Angel, Juana; Franco, Manuel A.

    2014-11-15

    Frequencies of circulating T cells producing IFN-γ, TNF-α, and IL-2, and percentages of T cells proliferating after stimulation with rotavirus (RV), tetanus toxoid, and influenza were evaluated in PBMC derived from healthy adults and children. In addition, the potential anergic state of RV-specific T cells was analyzed by stimulation of PBMC with RV antigen in the presence of three anergy inhibitors (rIL-2, rIL-12, or DGKα-i). The quality and magnitude of RV-T cell responses were significantly lower than those of tetanus toxoid and influenza antigens. RV-CD4 T cell response was enriched in monofunctional IFN-γ{sup +} cells, while influenza-CD4 and tetanus toxoid-CD4 T cell responses were enriched in multifunctional T cells. Moreover, rIL-2 – unlike rIL-12 or DGKα-i – increased the frequencies of RV-CD4 TNF-α{sup +}, CD4 IFN-γ{sup +}, and CD8 IFN-γ{sup +} cells. Thus, circulating RV-T cells seem to have a relatively poor functional profile that may be partially reversed in vitro by the addition of rIL-2. - Highlights: • The quality and magnitude of circulating RV-T cell responses are relatively poor. • Circulating RV-CD4 T cells are enriched in monofunctional IFN-γ+ cells. • Treatment with rIL-2 increased the frequencies of cytokine secreting RV-T cells.

  8. γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation.

    PubMed

    Daley, Donnele; Zambirinis, Constantinos Pantelis; Seifert, Lena; Akkad, Neha; Mohan, Navyatha; Werba, Gregor; Barilla, Rocky; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu Raj Kumar; Avanzi, Antonina; Tippens, Daniel; Narayanan, Rajkishen; Jang, Jung-Eun; Newman, Elliot; Pillarisetty, Venu Gopal; Dustin, Michael Loran; Bar-Sagi, Dafna; Hajdu, Cristina; Miller, George

    2016-09-01

    Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

  9. γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation.

    PubMed

    Daley, Donnele; Zambirinis, Constantinos Pantelis; Seifert, Lena; Akkad, Neha; Mohan, Navyatha; Werba, Gregor; Barilla, Rocky; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu Raj Kumar; Avanzi, Antonina; Tippens, Daniel; Narayanan, Rajkishen; Jang, Jung-Eun; Newman, Elliot; Pillarisetty, Venu Gopal; Dustin, Michael Loran; Bar-Sagi, Dafna; Hajdu, Cristina; Miller, George

    2016-09-01

    Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk. PMID:27569912

  10. [Cerebriform variant type of T cell prolymphocytic leukemia: Report of one case].

    PubMed

    Peña, Camila; Valladares, Ximena; Soto, Carolina; Encina, Andrea; Marinov, Neda; Undurraga, María Soledad; Cabrera, María Elena

    2016-01-01

    T cell Prolymphocytic Leukemia (T-PLL) is a rare and aggressive mature T cell Lymphocyte Leukemia. Twenty five percent of cases present as a small cell variant, and only 5% as a cerebriform variant. We report a 58 year-old man with rapidly progressive severe leukocytosis, skin lesions, lymphadenopathy, hepatosplenomegaly and pleural effusion. The lymphocytes had a cerebriform type. The diagnosis of T-PLL variant was made by morphology and immunophenotype study of peripheral blood. Karyotype was found to be complex. He was refractory to chemotherapy and died two months later.

  11. T Cell Migration in Rheumatoid Arthritis.

    PubMed

    Mellado, Mario; Martínez-Muñoz, Laura; Cascio, Graciela; Lucas, Pilar; Pablos, José L; Rodríguez-Frade, José Miguel

    2015-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints, associated with synovial hyperplasia and with bone and cartilage destruction. Although the primacy of T cell-related events early in the disease continues to be debated, there is strong evidence that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. In addition, T cells are key components of the immune cell infiltrate detected in the joints of RA patients. Initial analysis of the cytokines released into the synovial membrane showed an imbalance, with a predominance of proinflammatory mediators, indicating a deleterious effect of Th1 T cells. There is nonetheless evidence that Th17 cells also play an important role in RA. T cells migrate from the bloodstream to the synovial tissue via their interactions with the endothelial cells that line synovial postcapillary venules. At this stage, selectins, integrins, and chemokines have a central role in blood cell invasion of synovial tissue, and therefore in the intensity of the inflammatory response. In this review, we will focus on the mechanisms involved in T cell attraction to the joint, the proteins involved in their extravasation from blood vessels, and the signaling pathways activated. Knowledge of these processes will lead to a better understanding of the mechanism by which the systemic immune response causes local joint disorders and will help to provide a molecular basis for therapeutic strategies.

  12. T Cell Migration in Rheumatoid Arthritis

    PubMed Central

    Mellado, Mario; Martínez-Muñoz, Laura; Cascio, Graciela; Lucas, Pilar; Pablos, José L.; Rodríguez-Frade, José Miguel

    2015-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints, associated with synovial hyperplasia and with bone and cartilage destruction. Although the primacy of T cell-related events early in the disease continues to be debated, there is strong evidence that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. In addition, T cells are key components of the immune cell infiltrate detected in the joints of RA patients. Initial analysis of the cytokines released into the synovial membrane showed an imbalance, with a predominance of proinflammatory mediators, indicating a deleterious effect of Th1 T cells. There is nonetheless evidence that Th17 cells also play an important role in RA. T cells migrate from the bloodstream to the synovial tissue via their interactions with the endothelial cells that line synovial postcapillary venules. At this stage, selectins, integrins, and chemokines have a central role in blood cell invasion of synovial tissue, and therefore in the intensity of the inflammatory response. In this review, we will focus on the mechanisms involved in T cell attraction to the joint, the proteins involved in their extravasation from blood vessels, and the signaling pathways activated. Knowledge of these processes will lead to a better understanding of the mechanism by which the systemic immune response causes local joint disorders and will help to provide a molecular basis for therapeutic strategies. PMID:26284069

  13. Malaria drives T cells to exhaustion

    PubMed Central

    Wykes, Michelle N.; Horne-Debets, Joshua M.; Leow, Chiuan-Yee; Karunarathne, Deshapriya S.

    2014-01-01

    Malaria is a significant global burden but after >30 years of effort there is no vaccine on the market. While the complex life cycle of the parasite presents several challenges, many years of research have also identified several mechanisms of immune evasion by Plasmodium spp. Recent research on malaria, has investigated the programmed cell death-1 (PD-1) pathway which mediates exhaustion of T cells, characterized by poor effector functions and recall responses and in some cases loss of the cells by apoptosis. Such studies have shown exhaustion of CD4+ T cells and an unappreciated role for CD8+ T cells in promoting sterile immunity against blood stage malaria. This is because PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8+ T cells, thus masking their role in protection. The role of T cell exhaustion during malaria provides an explanation for the absence of sterile immunity following the clearance of acute disease which will be relevant to future malaria-vaccine design and suggests the need for novel therapeutic solutions. This review will thus examine the role of PD-1-mediated T cell exhaustion in preventing lasting immunity against malaria. PMID:24904561

  14. Infratentorial low-grade oligoastrocytoma with aggressive clinical behavior in an adult: a case report with genetic characterization.

    PubMed

    Sano, Keisho; Toda, Masahiro; Sasaki, Hikaru; Kitamura, Yohei; Mikami, Shuji; Hirato, Junko; Inoue, Satoshi; Kawase, Takeshi; Yoshida, Kazunari

    2013-04-01

    Oligoastrocytoma preferentially arises in the cerebral hemisphere, and a cerebellar location is unusual. We report the case of a 35-year-old woman with an aggressive cerebellar tumor histopathologically diagnosed as oligoastrocytoma World Health Organization (WHO) grade II. After partial removal of the tumor, she underwent concomitant temozolomide (TMZ) therapy with local irradiation followed by additional TMZ monotherapy. However, her symptoms gradually worsened, and chronological magnetic resonance imaging showed remarkable tumor enlargement. In accordance with the aggressive clinical course, unfavorable genetic characteristics such as the gain of the entire chromosome 7, loss of 9p, absence of 1p/19q codeletion, absence of methylation of the O6-methylguanine-deoxyribonucleic acid methyltransferase promoter, and absence of the isocitrate dehydrogenase-1 mutation were observed. The present case illustrates that these molecular characteristics represent the biological features of gliomas more closely than the histopathological diagnosis and may also suggest that infratentorial gliomas arise through a distinct tumorigenic pathway from their supratentorial counterparts.

  15. T Cell Repertoire Development in XSCID Dogs Following Non-conditioned Allogeneic Bone Marrow Transplantation

    PubMed Central

    Vernau, William; Hartnett, Brian J.; Kennedy, Douglas R.; Moore, Peter F.; Henthorn, Paula S.; Weinberg, Kenneth I.; Felsburg, Peter J.

    2007-01-01

    Dogs with X-linked severe combined immunodeficiency (XSCID) can be successfully treated by bone marrow transplants (BMT) resulting in full immunologic reconstitution and engraftment of both donor B and T cells without the need for pre-transplant conditioning. In this study, we evaluated the T cell diversity in XSCID dogs 4 months to 10 1/2 years following BMT. At 4 months post transplantation, when the number of CD45RA+ (naïve) T cells had peaked and plateaued, the T cells in the transplanted dogs showed the same complex, diverse repertoire as those of normal young adult dogs. A decline in T cell diversity became evident approximately 3 1/2 years post transplant, but the proportion of Vβ families showing a polyclonal Gaussian spectratype still predominated up to 7 1/2 years post transplant. In two dogs evaluated at 7 1/2 and 10 1/2 years post transplant, >75% of the Vβ families consisted of a skewed or oligoclonal spectratype that was associated with a CD4/CD8 ratio of <0.5. The decline in the complexity of T cell diversity in the transplanted XSCID dogs is similar to that reported for XSCID patients following BMT. However, in contrast to transplanted XSCID boys who show a significant decline in their T cell diversity by 10 to 12 years following BMT, transplanted XSCID dogs maintain a polyclonal, diverse T cell repertoire through mid-life. PMID:17697962

  16. Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies.

    PubMed

    Nakazawa, Yozo

    2016-06-01

    Chimeric antigen receptor (CAR) is the generic name for synthetic T cell receptors redirected to tumor-associated antigens. Most CARs consist of an ectodomain (scFv or ligand), a hinge region, a transmembrane domain, and signaling endodomains derived from one or two co-stimulatory molecules (CD28, 4-1BB, etc) and from a CD3-ζ chain. CD19-targeted CAR T cell therapy has achieved major success in the treatment of B cell malignancies. CD19 CAR-T cells elicited complete remission in 70-90% of adult and pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). CD19 CAR T cell therapy from allogeneic donors including third party donors is a potential option for B-cell malignancies. CAR T cell therapies for myeloma, acute myeloid leukemia, and T-cell leukemia are still under development. Our group is currently preparing a phase I study of CD19 CAR T cell therapy in pediatric and young adult patients with ALL using a non-viral gene transfer method, the piggyBac-transposon system. PMID:27384848

  17. NK Cells and γδ T Cells Mediate Resistance to Polyomavirus–Induced Tumors

    PubMed Central

    Mishra, Rabinarayan; Chen, Alex T.; Welsh, Raymond M.; Szomolanyi-Tsuda, Eva

    2010-01-01

    NK and γδ T cells can eliminate tumor cells in many experimental models, but their effect on the development of tumors caused by virus infections in vivo is not known. Polyomavirus (PyV) induces tumors in neonatally infected mice of susceptible strains and in adult mice with certain immune deficiencies, and CD8+ αβ T cells are regarded as the main effectors in anti-tumor immunity. Here we report that adult TCRβ knockout (KO) mice that lack αβ but have γδ T cells remain tumor-free after PyV infection, whereas TCRβ×δ KO mice that lack all T cells develop tumors. In addition, E26 mice, which lack NK and T cells, develop the tumors earlier than TCRβ×δ KO mice. These observations implicate γδ T and NK cells in the resistance to PyV-induced tumors. Cell lines established from PyV-induced tumors activate NK and γδ T cells both in culture and in vivo and express Rae-1, an NKG2D ligand. Moreover, these PyV tumor cells are killed by NK cells in vitro, and this cytotoxicity is prevented by treatment with NKG2D-blocking antibodies. Our findings demonstrate a protective role for NK and γδ T cells against naturally occurring virus-induced tumors and suggest the involvement of NKG2D-mediated mechanisms. PMID:20523894

  18. Intrahepatic Xenograft of Cutaneous T-Cell Lymphoma Cell Lines: A Useful Model for Rapid Biological and Therapeutic Evaluation.

    PubMed

    Andrique, Laetitia; Poglio, Sandrine; Prochazkova-Carlotti, Martina; Kadin, Marshall Edward; Giese, Alban; Idrissi, Yamina; Beylot-Barry, Marie; Merlio, Jean-Philippe; Chevret, Edith

    2016-07-01

    Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases primarily involving the skin that could have an aggressive course with circulating blood cells, especially in Sézary syndrome and transformed mycosis fungoides. So far, few CTCL cell lines have been adapted for in vivo experiments and their tumorigenicity has not been adequately assessed, hampering the use of a reproducible model for CTCL biological evaluation. In fact, both patient-derived xenografts and cell line xenografts at subcutaneous sites failed to provide a robust tool, because engraftment was dependent on mice strain and cell line subtype. Herein, we describe an original method of intrahepatic injection into adult NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice liver of both aggressive (My-La, HUT78, HH, MAC2A, and MAC2B) and indolent (FE-PD and MAC1) CTCL cell lines. Six of the seven CTCL cell lines were grafted with a high rate of success (80%). Moreover, this model provided a quick (15 days) and robust assay for in vivo evaluation of CTCL cell lines tumorigenicity and therapeutic response in preclinical studies. Such a reproducible model can be therefore used for further functional studies and in vivo drug testing. PMID:27181405

  19. Novel targets for natural killer/T-cell lymphoma immunotherapy.

    PubMed

    Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

    2016-01-01

    Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL. PMID:26642249

  20. Novel targets for natural killer/T-cell lymphoma immunotherapy.

    PubMed

    Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

    2016-01-01

    Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL.

  1. Primary cutaneous CD8+ cytotoxic T-cell lymphoma involving the epidermis and subcutis in a young child.

    PubMed

    Wang, Lei; Gao, Tianwen; Wang, Gang

    2015-04-01

    CD8+ cytotoxic T-cell lymphoma involving the skin represents a heterogeneous group of diseases that include subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, and 'type D' lymphomatoid papulosis. In this report, we describe a case of CD8+ cytotoxic T-cell lymphoma involving both the epidermis and subcutis. The patient was a 6-year-old girl who presented with a 3-year history of multiple plaques on her trunk and legs. The lesions had relapsed twice but responded well to prednisone. Histopathologic examination showed the proliferation of atypical lymphocytes in the epidermis, dermis and subcutaneous tissue. On immunohistochemical analysis, the atypical lymphocytes were positive for βF1, CD3, CD8, perforin, granzyme B and TIA-1, but negative for T-cell receptor (TCR) γ, CD4, CD30 and CD56. It was difficult to classify this tumor in terms of the known types of cutaneous lymphoma, and this case should be differentiated with subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma.

  2. CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors

    PubMed Central

    Kalekar, Lokesh A.; Schmiel, Shirdi E.; Nandiwada, Sarada L.; Lam, Wing Y.; Barsness, Laura O.; Zhang, Na; Stritesky, Gretta L.; Malhotra, Deepali; Pauken, Kristen E.; Linehan, Jonathan L.; O’Sullivan, M. Gerard; Fife, Brian T.; Hogquist, Kristin A.; Jenkins, Marc K.; Mueller, Daniel L.

    2015-01-01

    The role that anergy, an acquired state of T cell functional unresponsiveness, plays in natural peripheral tolerance remains unclear. In this study, we demonstrate that anergy is selectively induced in fetal antigen-specific maternal CD4+ T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4+ T cells, enriched in self antigen-specific T cell receptors, is also observed in healthy hosts. Neuropilin-1 expression in anergic conventional CD4+ T cells is associated with thymic regulatory T cell (Treg cell)-related gene hypomethylation, and this correlates with their capacity to differentiate into Foxp3+ Treg cells that suppress immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity, but it also generates the precursors for peripheral Treg cell differentiation. PMID:26829766

  3. Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations

    PubMed Central

    Lage, Luis Alberto de Pádua Covas; Cabral, Tamara Carvalho dos Santos; Costa, Renata de Oliveira; Gonçalves, Marianne de Castro; Levy, Debora; Zerbini, Maria Cláudia Nogueira; Pereira, Juliana

    2015-01-01

    Nodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term “peripheral T-cell lymphomas”. According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+), and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK−). Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients. PMID:26190436

  4. Regulation of naïve fetal T-cell migration by the chemokines Exodus-2 and Exodus-3.

    PubMed

    Christopherson, K; Brahmi, Z; Hromas, R

    1999-08-01

    We and other workers have recently isolated three novel CC chemokines termed Exodus-1/LARC/Mip-3alpha, Exodus-2/6Ckine/SLC/TCA4, and Exodus-3/Mip-3beta/CKbeta11/ELC. These chemokines share an amino terminal Asp-Cys-Cys-Leu sequence, unique among all chemokines. They also selectively regulate migration of adult T cells. Indeed, there is evidence that Exodus-2 and -3 are critical for adult T-cell adhesion to high endothelial venules in lymph nodes, a rate-limiting step for T-cell trafficking through nodal tissue. Less is known of the factors controlling migration of naïve human fetal T cells. We tested whether these chemokines could regulate chemotaxis in cord blood T-cell populations, and compared that efficacy with normal peripheral blood adult T cells. The findings indicated that naive CD45RA+ cord blood T-cell migration is stimulated by Exodus-2 and -3, and CD4+ cord blood T cells are attracted preferentially by Exodus-2 or -3 as compared with CD8+. Exodus-2 and -3 are likely to be critical in regulating the flux of naive CD4 + fetal T-cell population of secondary lymphoid tissue.

  5. Choice of Unmanipulated T Cell Replete Graft for Haploidentical Stem Cell Transplant and Posttransplant Cyclophosphamide in Hematologic Malignancies in Adults: Peripheral Blood or Bone Marrow—Review of Published Literature

    PubMed Central

    Farhan, Shatha; Peres, Edward; Janakiraman, Nalini

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (SCT) is often the only curative option for many patients with malignant and benign hematological stem cell disorders. However, some issues are still of concern regarding finding a donor like shrinking family sizes in many societies, underrepresentation of the ethnic minorities in the registries, genetic variability for some races, and significant delays in obtaining stem cells after starting the search. So there is a considerable need to develop alternate donor stem cell sources. The rapid and near universal availability of the haploidentical donor is an advantage of the haploidentical SCT and an opportunity that is being explored currently in many centers especially using T cell replete graft and posttransplant cyclophosphamide. This is probably because it does not require expertise in graft manipulation and because of the lower costs. However, there are still lots of unanswered questions, like the effect of use of bone marrow versus peripheral blood as the source of stem cells on graft-versus-host disease, graft versus tumor, overall survival, immune reconstitution, and quality of life. Here we review the available publications on bone marrow and peripheral blood experience in the haploidentical SCT setting. PMID:27118973

  6. Serial analysis of gene expression provides new insights into regulatory T cells.

    PubMed

    Cobbold, Stephen P; Adams, Elizabeth; Graca, Luis; Waldmann, Herman

    2003-08-01

    It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system. PMID:14690045

  7. Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition

    PubMed Central

    Condomines, Maud; Arnason, Jon; Benjamin, Reuben; Gunset, Gertrude; Plotkin, Jason; Sadelain, Michel

    2015-01-01

    Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway. Repeated in vitro antigen-specific stimulations indicated that 19-28z+ T cells secreted higher levels of Th1 cytokines and showed enhanced proliferation compared to those of 19z1+ or 19z1-CD80+ T cells. In an aggressive pre-B cell leukemia model, mice treated with 19-28z+ T cells had 10-fold reduced tumor progression compared to those treated with 19z1+ or 19z1-CD80+ T cells. shRNA-mediated CTLA-4 down-regulation in 19z1-CD80+ T cells significantly increased their in vivo expansion and anti-tumor properties, but had no effect in 19-28z+ T cells. Our results establish that CTLA-4 down-regulation may benefit human adoptive T cell therapy and demonstrate that CAR design can elude negative checkpoints to better sustain T cell function. PMID:26110267

  8. Romidepsin for the Treatment of Peripheral T-Cell Lymphoma.

    PubMed

    Barbarotta, Lisa; Hurley, Kristen

    2015-01-01

    Peripheral T-cell lymphomas (PTCLs) are a rare, heterogeneous group of T-cell- or natural killer cell-derived non-Hodgkin lymphomas. The majority of patients with PTCL experience an aggressive disease course and poor overall survival. Historically, PTCL has been treated with chemotherapy regimens used to treat B-cell lymphomas; however, a lack of durable responses to frontline therapies and few effective options for salvage treatment have led to the development of newer therapies. Romidepsin is a structurally unique, potent, bicyclic class 1 selective histone deacetylase (HDAC) inhibitor that has demonstrated durable clinical responses in patients with relapsed/refractory PTCL, leading to its approval by the US Food and Drug Administration in 2011 for the treatment of PTCL in patients who have received at least one prior therapy. Here, the authors provide an overview of PTCL, review the role of HDAC inhibitors as anticancer agents, discuss romidepsin use in PTCL, and highlight considerations for advanced practitioners (including the management of side effects).

  9. A stochastic T cell response criterion

    PubMed Central

    Currie, James; Castro, Mario; Lythe, Grant; Palmer, Ed; Molina-París, Carmen

    2012-01-01

    The adaptive immune system relies on different cell types to provide fast and coordinated responses, characterized by recognition of pathogenic challenge, extensive cellular proliferation and differentiation, as well as death. T cells are a subset of the adaptive immune cellular pool that recognize immunogenic peptides expressed on the surface of antigen-presenting cells by means of specialized receptors on their membrane. T cell receptor binding to ligand determines T cell responses at different times and locations during the life of a T cell. Current experimental evidence provides support to the following: (i) sufficiently long receptor–ligand engagements are required to initiate the T cell signalling cascade that results in productive signal transduction and (ii) counting devices are at work in T cells to allow signal accumulation, decoding and translation into biological responses. In the light of these results, we explore, with mathematical models, the timescales associated with T cell responses. We consider two different criteria: a stochastic one (the mean time it takes to have had N receptor–ligand complexes bound for at least a dwell time, τ, each) and one based on equilibrium (the time to reach a threshold number N of receptor–ligand complexes). We have applied mathematical models to previous experiments in the context of thymic negative selection and to recent two-dimensional experiments. Our results indicate that the stochastic criterion provides support to the thymic affinity threshold hypothesis, whereas the equilibrium one does not, and agrees with the ligand hierarchy experimentally established for thymic negative selection. PMID:22745227

  10. T-cell adoptive immunotherapy using tumor-infiltrating T cells and genetically engineered TCR-T cells.

    PubMed

    Ikeda, Hiroaki

    2016-07-01

    Immunotherapy has received the expectation that it should contribute to the therapy of cancer patients for >100 years. At long last, recent clinical trials of immunotherapy with immune checkpoint inhibitors and adoptive cell therapy with genetically engineered T cells have reported their remarkable efficacies. Nowadays, it is expected that T-cell adoptive immunotherapy can not only control tumor progression but even cure cancer in some patients. Conversely, severe adverse events associated with efficacy have frequently been reported in clinical trials, suggesting that the assessment and control of safety will be indispensable in the future development of the therapy. New approaches in T-cell adoptive immunotherapy such as reduction of adverse events, targeting of new antigens or utilization of allogeneic cells will open a new gate for less harmful and more effective immunological treatment of cancer patients. PMID:27127191

  11. Immunoregulatory T Cell Function in Multiple Myeloma

    PubMed Central

    Ozer, H.; Han, T.; Henderson, E. S.; Nussbaum, A.; Sheedy, D.

    1981-01-01

    Multiple myeloma is a malignancy characterized by uncontrolled monoclonal B cell differentiation and immunoglobulin production. In most instances, there is concomitant reduction in polyclonal differentiation and immunoglobulin synthesis both in vivo and in vitro. In in vitro pokeweed mitogen-induced B cell differentiation assays, proliferation and polyclonal immunoglobulin secretion optimally requires T cell help and can be inhibited both by monocytes and suppressor T cells. Helper function and monocyte-mediated suppression are relatively radio-resistant whereas T suppressor function is sensitive to 2,000 rad x-irradiation. We have examined myeloma T cell subset function in this assay using recombinations of isolated patient and normal B cells, T cells, and T cell subsets. Monocytes were removed by a carbonyl iron ingestion technique, normal and myeloma T cells were fractionated on the basis of Fc receptors for immunoglobulin (Ig) G (Tγ) or IgM (Tμ or T non-γ), and proliferation and IgG secretion after co-culture determined by [3H]thymidine incorporation and radio-immunoassay, respectively. Myeloma B cells demonstrate quantitatively and qualitatively normal blastogenic responses and are appropriately regulated by either autologous or allogeneic T helper and suppressor subsets. Despite normal proliferation, however, myeloma B cells remain deficient in subsequent differentiation and immunoglobulin secretion even when co-cultured in the absence of monocytes or suppressor T cells and the presence of normal helper cells. Myeloma T cell populations, in contrast, are entirely normal in helper capacity over a range of T:B ratios but are markedly deficient in radiosensitive and concanavalin A-induced suppressor activity. T suppressor cell dysfunction in multiple myeloma is apparently due to a deficit in the T non-γ suppressor subset, whereas Tγ cells, although proportionately reduced, are functionally normal. This unique T suppressor deficit reflects the heterogeneity

  12. Primary uterine T-cell lymphoma with metastasis in an Atlantic spotted dolphin (Stenella frontalis), Canary Islands, Spain.

    PubMed

    Díaz-Delgado, Josué; Sierra, Eva; Arbelo, Manuel; Suárez-Bonnet, Alejandro; Suárez-Santana, Cristian; Grau-Bassas, Enrique; Fernández, Antonio

    2015-04-01

    We describe gross, histopathologic, and immunonocytologic features of a primary uterine T-cell lymphoma with multiple metastases in an adult female Atlantic spotted dolphin (Stenella frontalis). Neoplastic T-cell lymphocytes (CD3+) partially effaced the uterus, ovaries, mesosalpinx, and urinary bladder and variably infiltrated abdominal and thoracic organs. Herpesvirus and morbillivirus PCR were negative. PMID:25855862

  13. Regulatory T Cells in Melanoma Revisited by a Computational Clustering of FOXP3+ T Cell Subpopulations

    PubMed Central

    Fujii, Hiroko; Josse, Julie; Tanioka, Miki; Miyachi, Yoshiki; Husson, François

    2016-01-01

    CD4+ T cells that express the transcription factor FOXP3 (FOXP3+ T cells) are commonly regarded as immunosuppressive regulatory T cells (Tregs). FOXP3+ T cells are reported to be increased in tumor-bearing patients or animals and are considered to suppress antitumor immunity, but the evidence is often contradictory. In addition, accumulating evidence indicates that FOXP3 is induced by antigenic stimulation and that some non-Treg FOXP3+ T cells, especially memory-phenotype FOXP3low cells, produce proinflammatory cytokines. Accordingly, the subclassification of FOXP3+ T cells is fundamental for revealing the significance of FOXP3+ T cells in tumor immunity, but the arbitrariness and complexity of manual gating have complicated the issue. In this article, we report a computational method to automatically identify and classify FOXP3+ T cells into subsets using clustering algorithms. By analyzing flow cytometric data of melanoma patients, the proposed method showed that the FOXP3+ subpopulation that had relatively high FOXP3, CD45RO, and CD25 expressions was increased in melanoma patients, whereas manual gating did not produce significant results on the FOXP3+ subpopulations. Interestingly, the computationally identified FOXP3+ subpopulation included not only classical FOXP3high Tregs, but also memory-phenotype FOXP3low cells by manual gating. Furthermore, the proposed method successfully analyzed an independent data set, showing that the same FOXP3+ subpopulation was increased in melanoma patients, validating the method. Collectively, the proposed method successfully captured an important feature of melanoma without relying on the existing criteria of FOXP3+ T cells, revealing a hidden association between the T cell profile and melanoma, and providing new insights into FOXP3+ T cells and Tregs. PMID:26864030

  14. Early signaling defects in human T cells anergized by T cell presentation of autoantigen

    PubMed Central

    1992-01-01

    Major histocompatibility complex class II-positive human T cell clones are nontraditional antigen-presenting cells (APCs) that are able to simultaneously present and respond to peptide or degraded antigen, but are unable to process intact protein. Although T cell presentation of peptide antigen resulted in a primary proliferative response, T cells that had been previously stimulated by T cells presenting antigen were completely unresponsive to antigen but not to interleukin 2 (IL-2). In contrast, peptide antigen presented by B cells or DR2+ L cell transfectants resulted in T cell activation and responsiveness to restimulation. The anergy induced by T cell presentation of peptide could not be prevented by the addition of either autologous or allogeneic B cells or B7+ DR2+ L cell transfectants, suggesting that the induction of anergy could occur in the presence of costimulation. T cell anergy was induced within 24 h of T cell presentation of antigen and was long lasting. Anergized T cells expressed normal levels of T cell receptor/CD3 but were defective in their ability to release [Ca2+]i to both alpha CD3 and APCs. Moreover, anergized T cells did not proliferate to alpha CD2 monoclonal antibodies or alpha CD3 plus phorbol myristate acetate (PMA), nor did they synthesize IL-2, IL-4, or interferon gamma mRNA in response to either peptide or peptide plus PMA. In contrast, ionomycin plus PMA induced both normal proliferative responses and synthesis of cytokine mRNA, suggesting that the signaling defect in anergized cells occurs before protein kinase C activation and [Ca2+]i release. PMID:1535366

  15. Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells.

    PubMed

    Berger, Carolina; Sommermeyer, Daniel; Hudecek, Michael; Berger, Michael; Balakrishnan, Ashwini; Paszkiewicz, Paulina J; Kosasih, Paula L; Rader, Christoph; Riddell, Stanley R

    2015-02-01

    Genetic engineering of T cells for adoptive transfer by introducing a tumor-targeting chimeric antigen receptor (CAR) is a new approach to cancer immunotherapy. A challenge for the field is to define cell surface molecules that are both preferentially expressed on tumor cells and can be safely targeted with T cells. The orphan tyrosine kinase receptor ROR1 is a candidate target for T-cell therapy with CAR-modified T cells (CAR-T cells) because it is expressed on the surface of many lymphatic and epithelial malignancies and has a putative role in tumor cell survival. The cell surface isoform of ROR1 is expressed in embryogenesis but absent in adult tissues except for B-cell precursors and low levels of transcripts in adipocytes, pancreas, and lung. ROR1 is highly conserved between humans and macaques and has a similar pattern of tissue expression. To determine if low-level ROR1 expression on normal cells would result in toxicity or adversely affect CAR-T cell survival and/or function, we adoptively transferred autologous ROR1 CAR-T cells into nonhuman primates. ROR1 CAR-T cells did not cause overt toxicity to normal organs and accumulated in bone marrow and lymph node sites, where ROR1-positive B cells were present. The findings support the clinical evaluation of ROR1 CAR-T cells for ROR1(+) malignancies and demonstrate the utility of nonhuman primates for evaluating the safety of immunotherapy with engineered T cells specific for tumor-associated molecules that are homologous between humans and nonhuman primates.

  16. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

    PubMed Central

    Alho, Ana C.; Kim, Haesook T.; Chammas, Marie J.; Reynolds, Carol G.; Matos, Tiago R.; Forcade, Edouard; Whangbo, Jennifer; Nikiforow, Sarah; Cutler, Corey S.; Koreth, John; Ho, Vincent T.; Armand, Philippe; Antin, Joseph H.; Alyea, Edwin P.; Lacerda, Joao F.; Soiffer, Robert J.

    2016-01-01

    The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. PMID:26670634

  17. Serotonergic antidepressant effects on aggressive, self-injurious and destructive/disruptive behaviours in intellectually disabled adults: a retrospective, open-label, naturalistic trial.

    PubMed

    Janowsky, David S; Shetty, Mahesh; Barnhill, Jarrett; Elamir, Belal; Davis, John M

    2005-03-01

    There is a growing body of evidence that serotonergic antidepressants are useful in the treatment of maladaptive behaviours in the intellectually disabled. However, not all studies have shown positive results due to lack of efficacy, tolerance development, and troublesome side-effects. The current study consisted of a review of the treatment response to a variety of serotonergic antidepressants, consisting of selective serotonin reuptake inhibitors (SSRIs ) (n = 36) and clomipramine (n = 2) in 38 institutionalized intellectually disabled adults (20 males, 18 females; mean age 45.6 yr, age range 18-74 yr). Those studied were treated for aggression, self-injurious behaviours, destructive/disruptive behaviours, depression/dysphoria, or a combination of these or other challenging behaviours. Most were receiving concurrent psychotropic and/or anticonvulsant medications. Effectiveness was determined by a retrospective review of the summaries of multidisciplinary Neuropsychiatric Behavioural Reviews (NBRs) in which global and specific maladaptive behaviours were rated on a 1- to 7-point scale, and by psychologists' ratings of target behaviours. Overall, statistically significant decreases in the ratings of global maladaptive behaviour and aggression, self-injurious behaviour, destruction/disruption and depression/dysphoria and in psychologists' ratings occurred in the subject group after the initiation of antidepressants. The results suggest that serotonergic antidepressants are useful in the treatment of challenging/maladaptive behaviours in the intellectually disabled. PMID:15482629

  18. T-cell/histiocyte-rich large B-cell lymphoma of stomach.

    PubMed

    Barut, Figen; Kandemir, Nilufer Onak; Gun, Banu Dogan; Ozdamar, Sukru Oguz

    2016-07-01

    T-cell/histiocyte-rich large B-cell lymphoma is an unusually encountered lymphoid neoplasm of stomach with aggressive course, and is an uncommon morphologic variant of diffuse large B-cell lymphoma. An ulcerated mass, 7x5x1 cm in size was observed within the gastrectomy specimen of a 76-year-old female patient. In cross sections, besides mature lymphoid cells displaying T-cell phenotype, a neoplastic formation composed of large, pleomorphic atypical lymphoid cells with, prominent nucleoli, vesicular nuclei and abundant eosinophilic cytoplasm displaying B-cell phenotype were observed. Meanwhile, histiocyte-like mononuclear cells and Reed-Sternberg-like multinuclear cells expressing CD68 and Mac387 were also observed. The diagnosis of the case was T cell/histiocyte-rich large B-cell lymphoma. This rarely encountered neoplasm should be kept in mind in the differential diagnosis of primary gastric lymphomas. PMID:27427148

  19. Romidepsin for peripheral T-cell lymphoma.

    PubMed

    Khot, Amit; Dickinson, Michael; Prince, H Miles

    2013-08-01

    Peripheral T-cell lymphoma (PTCL) is comprised of a rare heterogeneous group of diseases with diverse clinical presentations; however outcomes associated with conventional chemotherapy are generally poor in the majority of patients. Newer approaches, which include dose-intensification and agents with novel mechanisms of action, are needed to improve outcomes in this group of patients. In this review we examine the results of two recent large Phase II trials with romidepsin, a histone deacetylase inhibitor which shows considerable activity and good tolerability in patients with T-cell lymphoma. These initial results observed with single-agent romidepsin provide a foundation for exploring combination strategies and demonstrates proof-of-principle that other such drugs with similar mechanisms of action may be effective in T-cell lymphoma.

  20. Regulatory T cells and tumor immunity.

    PubMed

    Chattopadhyay, Subhasis; Chakraborty, Nitya G; Mukherji, Bijay

    2005-12-01

    Central deletion of "self-reactive" T cells has been the textbook paradigm for inducing "self-tolerance" in the periphery and the concept of a role of T cell-mediated suppression in this process has long been controversial. A decisive shift in the opinion on suppressor T cells has lately occurred with the observations of Sakaguchi's group that linked a class of CD4+CD25+ T cells to the prevention of autoimmunity from neonatal thymectomy in mice. These CD4+CD25+ T cells have been named T regulatory (Treg) cells. They are believed to be selected in the thymus as an anti-self repertoire. Hence they were referred to as natural T regulatory (nTreg) cells. Presently, in addition to their role in autoimmunity, they are believed to exert regulatory function in infection, in transplantation immunity as well as in tumor immunity. In contrast to these nTreg cells, another class of CD4+ Treg cells also exercises regulatory function in the periphery. These Treg cells are also CD4+ T cells and after activation they also become phenotypically CD4+CD25+. They are, however induced in the periphery as Treg cells. Hence, they are termed as induced Treg (iTreg) cells. There are major differences in the biology of these two types of Treg cells. They differ in their requirements for activation and in their mode of action. Nonetheless, evidence indicates that both nTreg cells and iTreg cells are involved in the control of tumor immunity. The question of how to circumvent their regulatory constraints, therefore, has become a major challenge for tumor immunologists. PMID:15868167

  1. The signaling symphony: T cell receptor tunes cytokine-mediated T cell differentiation.

    PubMed

    Huang, Weishan; August, Avery

    2015-03-01

    T cell development, differentiation, and maintenance are orchestrated by 2 key signaling axes: the antigen-specific TCR and cytokine-mediated signals. The TCR signals the recognition of self- and foreign antigens to control T cell homeostasis for immune tolerance and immunity, which is regulated by a variety of cytokines to determine T cell subset homeostasis and differentiation. TCR signaling can synergize with or antagonize cytokine-mediated signaling to fine tune T cell fate; however, the latter is less investigated. Murine models with attenuated TCR signaling strength have revealed that TCR signaling can function as regulatory feedback machinery for T cell homeostasis and differentiation in differential cytokine milieus, such as IL-2-mediated Treg development; IL-7-mediated, naïve CD8(+) T cell homeostasis; and IL-4-induced innate memory CD8(+) T cell development. In this review, we discuss the symphonic cross-talk between TCR and cytokine-mediated responses that differentially control T cell behavior, with a focus on the negative tuning by TCR activation on the cytokine effects.

  2. Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells

    PubMed Central

    1989-01-01

    We report here a mAb, 14-2, reactive with TCRs that include V beta 14. The frequency of V beta 14+ T cells varies with CD4 and CD8 subset and is controlled by the H-2 genes. Thus CD8+ T cells from H-2b mice include approximately 2.3% V beta 14+ T cells while CD8+ T cells from mice expressing K kappa include greater than 8% V beta 14+ T cells. In all strains examined, 7-8% of CD4+ T cells express V beta 14. The frequent usage of V beta 14 in CD8+ T cells of K kappa-expressing mice is a result of preferential positive selection of V beta 14+ CD8+ T cells as demonstrated by analysis of radiation chimeras. These studies demonstrate that H-2-dependent positive selection occurs in unmanipulated mice. Furthermore, the results imply that positive selection, and possibly H-2 restriction, can be strongly influenced by a V beta domain, with some independence from the beta-junctional sequence and alpha chain. PMID:2501444

  3. Genomic landscape of cutaneous T cell lymphoma

    PubMed Central

    Choi, Jaehyuk; Goh, Gerald; Walradt, Trent; Hong, Bok S.; Bunick, Christopher G.; Chen, Kan; Bjornson, Robert D.; Maman, Yaakov; Wang, Tiffany; Tordoff, Jesse; Carlson, Kacie; Overton, John D.; Liu, Kristina J.; Lewis, Julia M.; Devine, Lesley; Barbarotta, Lisa; Foss, Francine M.; Subtil, Antonio; Vonderheid, Eric C.; Edelson, Richard L.; Schatz, David G.; Boggon, Titus J.; Girardi, Michael; Lifton, Richard P.

    2015-01-01

    Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole genome DNA sequence and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NFκB signaling, chromatin remodeling, and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs vs. 1.0 somatic single nucleotide variants per CTCL). These findings have implications for novel therapeutics. PMID:26192916

  4. The T-Cell Response to HIV

    PubMed Central

    Walker, Bruce; McMichael, Andrew

    2012-01-01

    HIV is a disease in which the original clinical observations of severe opportunistic infections gave the first clues regarding the underlying pathology, namely that HIV is essentially an infection of the immune system. HIV infects and deletes CD4+ T cells that normally coordinate the adaptive T- and B-cell response to defend against intracellular pathogens. The immune defect is immediate and profound: At the time of acute infection with an AIDS virus, typically more than half of the gut-associated CD4+ T cells are depleted, leaving a damaged immune system to contend with a life-long infection. PMID:23002014

  5. Romidepsin for cutaneous T-cell lymphoma.

    PubMed

    Prince, H Miles; Dickinson, Michael; Khot, Amit

    2013-12-01

    Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.

  6. Synthetic Biology Approaches to Engineer T cells

    PubMed Central

    Wu, Chia-Yung; Rupp, Levi J.; Roybal, Kole T.; Lim, Wendell A.

    2015-01-01

    There is rapidly growing interest in learning how to engineer immune cells, such as T lymphocytes, because of the potential of these engineered cells to be used for therapeutic applications such as the recognition and killing of cancer cells. At the same time, our knowhow and capability to logically engineer cellular behavior is growing rapidly with the development of synthetic biology. Here we describe how synthetic biology approaches are being used to rationally alter the behavior of T cells to optimize them for therapeutic functions. We also describe future developments that will be important in order to construct safe and precise T cell therapeutics. PMID:26218616

  7. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  8. Polyfunctional T cells accumulate in large human cytomegalovirus-specific T cell responses.

    PubMed

    Lachmann, Raskit; Bajwa, Martha; Vita, Serena; Smith, Helen; Cheek, Elizabeth; Akbar, Arne; Kern, Florian

    2012-01-01

    Large cytomegalovirus (CMV)-specific CD8 T-cell responses are observed in both young and, somewhat more often, old people. Frequent CMV reactivation is thought to exhaust these cells and render them dysfunctional so that larger numbers of them are needed to control CMV. Expansions of CMV-specific CD4 T cells are also seen but are less well studied. In this study, we examined the T-cell response to the dominant CMV pp65 and IE-1 antigens in healthy CMV-infected people across a wide age range (20 to 84 years) by using multicolor flow cytometry. CMV-specific T cells were characterized by the activation markers CD40 ligand (CD40L), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) and the memory markers CD27 and CD45RA. The proportions of effector memory T cells increased in large responses, as did the proportions of polyfunctional CD8 (IFN-γ(+) IL-2(+/-) TNF-α(+)) and CD4 (CD40L(+/-) IFN-γ(+) IL-2(+) TNF-α(+)) T-cell subsets, while the proportion of naïve T cells decreased. The bigger the CD4 or CD8 T-cell response to pp65, the larger was the proportion of T cells with an advanced memory phenotype in the entire (including non-CMV-specific) T-cell compartment. In addition, the number of activation markers per cell correlated with the degree of T-cell receptor downregulation, suggesting increased antigen sensitivity in polyfunctional cells. In summary, our findings show that polyfunctional CMV-specific T cells were not superseded by dysfunctional cells, even in very large responses. At the same time, however, the memory subset composition of the entire T-cell compartment correlated with the size of the T-cell response to CMV pp65, confirming a strong effect of CMV infection on the immune systems of some, but not all, infected people. PMID:22072753

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

    PubMed

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

    2014-12-01

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

  10. Specificity of regulatory CD4+CD25+ T cells for self-T cell receptor determinants.

    PubMed

    Buenafe, Abigail C; Tsaknaridis, Laura; Spencer, Leslie; Hicks, Kevin S; McMahan, Rachel H; Watson, Lisa; Culbertson, Nicole E; Latocha, Dorian; Wegmann, Keith; Finn, Tom; Bartholomew, Richard; Burrows, Gregory G; Whitham, Ruth; Bourdette, Dennis N; Jones, Richard E; Offner, Halina; Chou, Yuan K; Vandenbark, Arthur A

    2004-04-01

    Although the phenotypic and regulatory properties of the CD4(+)CD25(+) T cell lineage (Treg cells) have been well described, the specificities remain largely unknown. We demonstrate here that the CD4(+)CD25(+) Treg population includes the recognition of a broad spectrum of human TCR CDR2 determinants found in the germline V gene repertoire as well as that of a clonotypic nongermline-encoded CDR3beta sequence present in a recombinant soluble T cell receptor (TCR) protein. Regulatory activity was demonstrated in T cell lines responsive to TCR but not in T cell lines responsive to control antigens. Inhibitory activity of TCR-reactive T cells required cell-cell contact and involved CTLA-4, GITR, IL-10, and IL-17. Thus, the T-T regulatory network includes Treg cells with specificity directed toward self-TCR determinants.

  11. Adoptive T-cell therapy for cancer: The era of engineered T cells.

    PubMed

    Bonini, Chiara; Mondino, Anna

    2015-09-01

    Tumors originate from a number of genetic events that deregulate homeostatic mechanisms controlling normal cell behavior. The immune system, devoted to patrol the organism against pathogenic events, can identify transformed cells, and in several cases cause their elimination. It is however clear that several mechanisms encompassing both central and peripheral tolerance limit antitumor immunity, often resulting into progressive diseases. Adoptive T-cell therapy with either allogeneic or autologous T cells can transfer therapeutic immunity. To date, genetic engineering of T cells appears to be a powerful tool for shaping tumor immunity. In this review, we discuss the most recent achievements in the areas of suicide gene therapy, and TCR-modified T cells and chimeric antigen receptor gene-modified T cells. We provide an overview of current strategies aimed at improving the safety and efficacy of these approaches, with an outlook on prospective developments.

  12. Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help

    NASA Astrophysics Data System (ADS)

    Sun, Joseph C.; Bevan, Michael J.

    2003-04-01

    The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.

  13. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans.

    PubMed

    Wertheimer, Anne M; Bennett, Michael S; Park, Byung; Uhrlaub, Jennifer L; Martinez, Carmine; Pulko, Vesna; Currier, Noreen L; Nikolich-Žugich, Dragana; Kaye, Jeffrey; Nikolich-Žugich, Janko

    2014-03-01

    The impact of intrinsic aging upon human peripheral blood T cell subsets remains incompletely quantified and understood. This impact must be distinguished from the influence of latent persistent microorganisms, particularly CMV, which has been associated with age-related changes in the T cell pool. In a cross-sectional cohort of 152 CMV-negative individuals, aged 21-101 y, we found that aging correlated strictly to an absolute loss of naive CD8, but not CD4, T cells but, contrary to many reports, did not lead to an increase in memory T cell numbers. The loss of naive CD8 T cells was not altered by CMV in 239 subjects (range 21-96 y), but the decline in CD4(+) naive cells showed significance in CMV(+) individuals. These individuals also exhibited an absolute increase in the effector/effector memory CD4(+) and CD8(+) cells with age. That increase was seen mainly, if not exclusively, in older subjects with elevated anti-CMV Ab titers, suggesting that efficacy of viral control over time may determine the magnitude of CMV impact upon T cell memory, and perhaps upon immune defense. These findings provide important new insights into the age-related changes in the peripheral blood pool of older adults, demonstrating that aging and CMV exert both distinct and joint influence upon blood T cell homeostasis in humans. PMID:24501199

  14. Aggression, Recognition and Qualification: On the Social Psychology of Adult Education in Everyday Life. [Publications from the Adult Education Research Group].

    ERIC Educational Resources Information Center

    Weber, Kirsten

    This paper discusses the impact of life history and everyday life in the context of training unskilled adults for social work in Denmark. It describes origins of these two texts used as empirical material: a discussion by a group of long-term unemployed skilled adult male workers who went through a 2-year training program to obtain permanent…

  15. Phenotypic models of T cell activation.

    PubMed

    Lever, Melissa; Maini, Philip K; van der Merwe, P Anton; Dushek, Omer

    2014-09-01

    T cell activation is a crucial checkpoint in adaptive immunity, and this activation depends on the binding parameters that govern the interactions between T cell receptors (TCRs) and peptide-MHC complexes (pMHC complexes). Despite extensive experimental studies, the relationship between the TCR-pMHC binding parameters and T cell activation remains controversial. To make sense of conflicting experimental data, a variety of verbal and mathematical models have been proposed. However, it is currently unclear which model or models are consistent or inconsistent with experimental data. A key problem is that a direct comparison between the models has not been carried out, in part because they have been formulated in different frameworks. For this Analysis article, we reformulated published models of T cell activation into phenotypic models, which allowed us to directly compare them. We find that a kinetic proofreading model that is modified to include limited signalling is consistent with the majority of published data. This model makes the intriguing prediction that the stimulation hierarchy of two different pMHC complexes (or two different TCRs that are specific for the same pMHC complex) may reverse at different pMHC concentrations.

  16. Genetic engineering with T cell receptors.

    PubMed

    Zhang, Ling; Morgan, Richard A

    2012-06-01

    In the past two decades, human gene transfer research has been translated from a laboratory technology to clinical evaluation. The success of adoptive transfer of tumor-reactive lymphocytes to treat the patients with metastatic melanoma has led to new strategies to redirect normal T cells to recognize tumor antigens by genetic engineering with tumor antigen-specific T cell receptor (TCR) genes. This new strategy can generate large numbers of defined antigen-specific cells for therapeutic application. Much progress has been made to TCR gene transfer systems by optimizing gene expression and gene transfer protocols. Vector and protein modifications have enabled excellent expression of introduced TCR chains in human lymphocytes with reduced mis-pairing between the introduced and endogenous TCR chains. Initial clinical studies have demonstrated that TCR gene-engineered T cells could mediate tumor regression in vivo. In this review, we discuss the progress and prospects of TCR gene-engineered T cells as a therapeutic strategy for treating patients with melanoma and other cancers.

  17. Designing CAR T cells for glioblastoma

    PubMed Central

    Maus, Marcela V

    2015-01-01

    Chimeric antigen receptor (CAR)-modified T cells directed against CD19 can mediate long-term durable remissions in B cell malignancies, but bringing a new target antigen to the clinic requires extensive modeling to avoid on-target and off-target toxicity. We recently described a systematic approach to test a new CAR directed against EGFR variant III. PMID:26587317

  18. Reprogramming the T Cell Response to Tuberculosis.

    PubMed

    Woodworth, Joshua S; Andersen, Peter

    2016-02-01

    Coscolla, Copin et al. recently used comparative genomics of M. tuberculosis (Mtb) strains to show that most human T cell-recognized epitopes are hyperconserved, but bona fide variable epitopes also exist. This identification of two sets of antigens implies opposing evolutionary processes and will have an important impact on tuberculosis (TB) vaccine strategy and design.

  19. T Cell Allorecognition via Molecular Mimicry

    SciTech Connect

    Macdonald, Whitney A.; Chen, Zhenjun; Gras, Stephanie; Archbold, Julia K.; Tynan, Fleur E.; Clements, Craig S.; Bharadwaj, Mandvi; Kjer-Nielsen, Lars; Saunders, Philippa M.; Wilce, Matthew C.J.; Crawford, Fran; Stadinsky, Brian; Jackson, David; Brooks, Andrew G.; Purcell, Anthony W.; Kappler, John W.; Burrows, Scott R.; Rossjohn, Jamie; McCluskey, James

    2010-08-16

    T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B*0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B*4402 and HLA-B*4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B*0801, HLA-B*4402, and HLA-B*4405 and the disparate sequences of the viral and allopeptides, the LC13 TCR engaged these peptide-HLA (pHLA) complexes identically, accommodating mimicry of the viral peptide by the allopeptide. The viral and allopeptides adopted similar conformations only after TCR ligation, revealing an induced-fit mechanism of molecular mimicry. The LC13 T cells did not alloreact against HLA-B*4403, and the single residue polymorphism between HLA-B*4402 and HLA-B*4403 affected the plasticity of the allopeptide, revealing that molecular mimicry was associated with TCR specificity. Accordingly, molecular mimicry that is HLA and peptide dependent is a mechanism for human T cell alloreactivity between disparate cognate and allogeneic pHLA complexes.

  20. Defining the Alloreactive T Cell Repertoire Using High-Throughput Sequencing of Mixed Lymphocyte Reaction Culture

    PubMed Central

    Konieczna, Iwona M.; Robins, Harlan S.; Leventhal, Joseph R.

    2014-01-01

    The cellular immune response is the most important mediator of allograft rejection and is a major barrier to transplant tolerance. Delineation of the depth and breadth of the alloreactive T cell repertoire and subsequent application of the technology to the clinic may improve patient outcomes. As a first step toward this, we have used MLR and high-throughput sequencing to characterize the alloreactive T cell repertoire in healthy adults at baseline and 3 months later. Our results demonstrate that thousands of T cell clones proliferate in MLR, and that the alloreactive repertoire is dominated by relatively high-abundance T cell clones. This clonal make up is consistently reproducible across replicates and across a span of three months. These results indicate that our technology is sensitive and that the alloreactive TCR repertoire is broad and stable over time. We anticipate that application of this approach to track donor-reactive clones may positively impact clinical management of transplant patients. PMID:25365040

  1. Essential flexibility in the T-cell recognition of antigen

    NASA Astrophysics Data System (ADS)

    Kersh, Gilbert J.; Allen, Paul M.

    1996-04-01

    αβ T cells specifically recognize a ligand composed of a peptide bound to a self-major-histocompatibility-complex molecule, but the recognition of slightly altered ligands by T cells can lead to a partial activation. This flexibility is crucial for T-cell development and can have both beneficial and harmful effects on peripheral T cells.

  2. T-Cell Tumor Elimination as a Result of T-Cell Receptor-Mediated Activation

    NASA Astrophysics Data System (ADS)

    Ashwell, Jonathan D.; Longo, Dan L.; Bridges, Sandra H.

    1987-07-01

    It has recently been shown that activation of murine T-cell hybridomas with antigen inhibits their growth in vitro. The ``suicide'' of these neoplastic T cells upon stimulation with antigen suggested the possibility that activation via the antigen-specific receptor could also inhibit the growth of neoplastic T cells in vivo. To test this, mice were subcutaneously inoculated with antigen-specific T-cell hybridomas and then treated intraperitoneally with antigen. Administration of the appropriate antigen immediately after inoculation with the T-cell hybridoma abrogated tumor formation; antigen administered after tumors had become established decreased the tumor burden and, in a substantial fraction of animals, led to long-term survival. The efficacy of antigen therapy was due to both a direct inhibitory effect on tumor growth and the induction of host immunity. These studies demonstrate the utility of cellular activation as a means of inhibiting neoplastic T-cell growth in vivo and provide a rationale for studying the use of less selective reagents that can mimic the activating properties of antigen, such as monoclonal antibodies, in the treatment of T-cell neoplasms of unknown antigen specificity.

  3. Epstein-Barr virus in a CD8-positive T-cell lymphoma.

    PubMed Central

    Richel, D. J.; Lepoutre, J. M.; Kapsenberg, J. G.; Ooms, E. C.; Boom, W. R.; Boucher, C. A.; Kluin, P. M.

    1990-01-01

    In contrast to its role in B-lymphomagenesis, Epstein-Barr Virus (EBV) only incidentally has been associated with T-cell lymphomas. In the present report we describe a fourth patient with EBV-related T-cell lymphoma. The patient presented with an angio-immunoblastic lymphadenopathy (AILD)-like T-cell lymphoma. Serology was compatible with chronic Epstein-Barr (EBV) infection. After a 1-year period of waxing and waning lymphadenopathy, this lymphoma evolved to an aggressive CD8+ Immunoblastic T-cell lymphoma. A relationship with the chronic EBV infection was indicated by the finding of EBV genome in the tumor tissue by Southern blot analysis. Moreover, EBV nuclear antigen (EBNA) was detected in situ within individually defined CD8+ tumor cells by two-color immunofluorescence. Two alternative possibilities, namely that EBV primarily played a role in lymphomagenesis of the AILD-like T-cell lymphoma or that the virus was an additional oncogenic event in the final process of tumor progression to the immunoblastic lymphoma, are discussed. Images Figure 1 Figure 2 Figure 4 Figure 3 Figure 5 PMID:2161617

  4. Engineering higher affinity T cell receptors using a T cell display system

    PubMed Central

    Chervin, Adam S.; Aggen, David H.; Raseman, John M.; Kranz, David M.

    2008-01-01

    The T cell receptor (TCR) determines the cellular response to antigens, which are presented on the surface of target cells in the form of a peptide bound to a product of the major histocompatibility complex (pepMHC). The response of the T cell depends on the affinity of the TCR for the pepMHC, yet many TCRs have been shown to be of low affinity, and some naturally occurring T cell responses are poor due to low affinities. Accordingly, engineering the TCR for increased affinity for pepMHC, particularly tumor-associated antigens, has become an increasingly desirable goal, especially with the advent of adoptive T cell therapies. For largely technical reasons, to date there have been only a handful of TCRs engineered in vitro for higher affinity using well established methods of protein engineering. Here we report the use of a T cell display system, using a retroviral vector, for generating a high affinity TCR from the mouse T cell clone 2C. The method relies on the display of the TCR, in its normal, signaling competent state, as a CD3 complex on the T cell surface. A library in the CDR3α of the 2C TCR was generated in the MSCV retroviral vector and transduced into a TCR-negative hybridoma. Selection of a high affinity, CD8-independent TCR was accomplished after only two rounds of flow cytometric sorting using the pepMHC SIYRYYGL/Kb (SIY/Kb). The selected TCR contained a sequence motif in the CDR3α with characteristics of several other TCRs previously selected by yeast display. In addition, it was possible to directly use the selected T cell hybridoma in functional assays without the need for sub-cloning, revealing that the selected TCR was capable of mediating CD8-independent activity. The method may be useful in the direct isolation and characterization of TCRs that could be used in therapies with adoptive transferred T cells. PMID:18854190

  5. Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ciurea, Stefan O.; Mulanovich, Victor; Saliba, Rima M.; Bayraktar, Ulas D.; Jiang, Ying; Bassett, Roland; Wang, Sa A.; Konopleva, Marina; Fernandez-Vina, Marcelo; Montes, Nivia; Bosque, Doyle; Chen, Julianne; Rondon, Gabriela; Alatrash, Gheath; Alousi, Amin; Bashir, Qaiser; Korbling, Martin; Qazilbash, Muzaffar; Parmar, Simrit; Shpall, Elizabeth; Nieto, Yago; Hosing, Chitra; Kebriaei, Partow; Khouri, Issa; Popat, Uday; de Lima, Marcos; Champlin, Richard E.

    2014-01-01

    Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II–IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT. PMID:22796535

  6. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation.

    PubMed

    Ciurea, Stefan O; Mulanovich, Victor; Saliba, Rima M; Bayraktar, Ulas D; Jiang, Ying; Bassett, Roland; Wang, Sa A; Konopleva, Marina; Fernandez-Vina, Marcelo; Montes, Nivia; Bosque, Doyle; Chen, Julianne; Rondon, Gabriela; Alatrash, Gheath; Alousi, Amin; Bashir, Qaiser; Korbling, Martin; Qazilbash, Muzaffar; Parmar, Simrit; Shpall, Elizabeth; Nieto, Yago; Hosing, Chitra; Kebriaei, Partow; Khouri, Issa; Popat, Uday; de Lima, Marcos; Champlin, Richard E

    2012-12-01

    Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.

  7. CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells.

    PubMed

    Zhu, Ziqiang; Cuss, Steven M; Singh, Vinod; Gurusamy, Devikala; Shoe, Jennifer L; Leighty, Robert; Bronte, Vincenzo; Hurwitz, Arthur A

    2015-10-01

    Maintaining antitumor immunity remains a persistent impediment to cancer immunotherapy. We and others have previously reported that high-avidity CD8(+) T cells are more susceptible to tolerance induction in the tumor microenvironment. In the present study, we used a novel model where T cells derived from two independent TCR transgenic mouse lines recognize the same melanoma antigenic epitope but differ in their avidity. We tested whether providing CD4(+) T cell help would improve T cell responsiveness as a function of effector T cell avidity. Interestingly, delivery of CD4(+) T cell help during in vitro priming of CD8(+) T cells improved cytokine secretion and lytic capacity of high-avidity T cells, but not low-avidity T cells. Consistent with this observation, copriming with CD4(+) T cells improved antitumor immunity mediated by higher avidity, melanoma-specific CD8(+) T cells, but not T cells with similar specificity but lower avidity. Enhanced tumor immunity was associated with improved CD8(+) T cell expansion and reduced tolerization, and it was dependent on presentation of both CD4(+) and CD8(+) T cell epitopes by the same dendritic cell population. Our findings demonstrate that CD4(+) T cell help preferentially augments high-avidity CD8(+) T cells and provide important insight for understanding the requirements to elicit and maintain durable tumor immunity.

  8. Mechanism of T cell mediated protection in newborn mice against a Chlamydia infection

    PubMed Central

    Pal, Sukumar; de la Maza, Luis M.

    2013-01-01

    To determine the immune components needed for protection of newborn mice against Chlamydia muridarum, animals born to Chlamydia-immunized and to sham-immunized dams were infected intranasally with C. muridarum at 2 post-natal days. T-cells isolated from immunized or sham-immunized adult mice were adoptively transferred to newborn mice at the time of infection. Also, to establish what cytokines are involved in protection, IFN-γ TNF-α, IL-10, and IL-12 were passively transferred to newborn mice. To assess the Chlamydia burden in the lungs mice were euthanized at 12 post-natal days. When T-cells from immunized adult mice were transferred, mice born to and fed by immunized dams were significantly protected as evidenced by the reduced number of Chlamydia isolated from the lungs compared to mice born to and fed by sham-immunized dams. Transfer of IFN-γ and TNF-α also significantly reduced the number of Chlamydia in the lungs of mice born to immunized dams. Transfer of IL-10 or IL-12 did not result in a significant reduction of Chlamydia. In vitro T-cell proliferation data suggest that neonatal antigen presenting cells can present Chlamydia antigens to adult T-cells. In conclusion, maternal antibodies and Chlamydia specific T-cells or Th1 cytokines are required for protection of neonates against this pathogen. PMID:23644176

  9. Mechanism of T-cell mediated protection in newborn mice against a Chlamydia infection.

    PubMed

    Pal, Sukumar; de la Maza, Luis M

    2013-01-01

    To determine the immune components needed for protection of newborn mice against Chlamydia muridarum, animals born to Chlamydia-immunized and to sham-immunized dams were infected intranasally with C. muridarum at 2 post-natal days. T-cells isolated from immunized or sham-immunized adult mice were adoptively transferred to newborn mice at the time of infection. Also, to establish what cytokines are involved in protection, IFN-γ, TNF-α, IL-10, and IL-12 were passively transferred to newborn mice. To assess the Chlamydia burden in the lungs mice were euthanized at 12 post-natal days. When T-cells from immunized adult mice were transferred, mice born to and fed by immunized dams were significantly protected as evidenced by the reduced number of Chlamydia isolated from the lungs compared to mice born to and fed by sham-immunized dams. Transfer of IFN-γ and TNF-α also significantly reduced the number of Chlamydia in the lungs of mice born to immunized dams. Transfer of IL-10 or IL-12 did not result in a significant reduction of Chlamydia. In vitro T-cell proliferation data suggest that neonatal antigen presenting cells can present Chlamydia antigens to adult T-cells. In conclusion, maternal antibodies and Chlamydia specific T-cells or Th1 cytokines are required for protection of neonates against this pathogen.

  10. Variation in fecal testosterone levels, inter-male aggression, dominance rank and age during mating and post-mating periods in wild adult male ring-tailed lemurs (Lemur catta).

    PubMed

    Gould, L; Ziegler, T E

    2007-12-01

    In primate species exhibiting seasonal reproduction, patterns of testosterone excretion in adult males are variable: in some species, peaks correlate with female receptivity periods and heightened male-male aggression over access to estrous females, in others, neither heightened aggression nor marked elevations in testosterone have been noted. In this study, we examined mean fecal testosterone ( f T) levels and intermale aggression in wild adult male ring-tailed lemurs residing in three groups at Beza Mahafaly Reserve, Madagascar. Results obtained from mating and post-mating season 2003 were compared to test Wingfield et al. [1990. Am Nat 136:829-846] "challenge hypothesis", which predicts a strong positive relationship between male testosterone levels and male-male competition for access to receptive females during breeding season. f T levels and rates of intermale aggression were significantly higher during mating season compared to the post-mating period. Mean f T levels and aggression rates were also higher in the first half of the mating season compared with the second half. Number of males in a group affected rates of intermale agonism, but not mean f T levels. The highest-ranking males in two of the groups exhibited higher mean f T levels than did lower-ranking males, and young males exhibited lower f T levels compared to prime-aged and old males. In the post-mating period, mean male f T levels did not differ between groups, nor were there rank or age effects. Thus, although male testosterone levels rose in relation to mating and heightened male-male aggression, f T levels fell to baseline breeding levels shortly after the early mating period, and to baseline non-breeding levels immediately after mating season had ended, offsetting the high cost of maintaining both high testosterone and high levels of male-male aggression in the early breeding period. PMID:17427976

  11. Implicit cognitive aggression among young male prisoners: Association with dispositional and current aggression.

    PubMed

    Ireland, Jane L; Adams, Christine

    2015-01-01

    The current study explores associations between implicit and explicit aggression in young adult male prisoners, seeking to apply the Reflection-Impulsive Model and indicate parity with elements of the General Aggression Model and social cognition. Implicit cognitive aggressive processing is not an area that has been examined among prisoners. Two hundred and sixty two prisoners completed an implicit cognitive aggression measure (Puzzle Test) and explicit aggression measures, covering current behaviour (DIPC-R) and aggression disposition (AQ). It was predicted that dispositional aggression would be predicted by implicit cognitive aggression, and that implicit cognitive aggression would predict current engagement in aggressive behaviour. It was also predicted that more impulsive implicit cognitive processing would associate with aggressive behaviour whereas cognitively effortful implicit cognitive processing would not. Implicit aggressive cognitive processing was associated with increased dispositional aggression but not current reports of aggressive behaviour. Impulsive implicit cognitive processing of an aggressive nature predicted increased dispositional aggression whereas more cognitively effortful implicit cognitive aggression did not. The article concludes by outlining the importance of accounting for implicit cognitive processing among prisoners and the need to separate such processing into facets (i.e. impulsive vs. cognitively effortful). Implications for future research and practice in this novel area of study are indicated.

  12. Adoptive Immunotherapy using Regulatory T cells and Virus-specific T cells Derived from Cord Blood

    PubMed Central

    Hanley, Patrick J.; Bollard, Catherine M.; Brunstein, Claudio G

    2014-01-01

    Cord blood transplantation, an alternative to traditional stem cell transplants (bone marrow or peripheral blood stem cell transplantation), is an attractive option for patients lacking suitable stem cell transplant donors. Cord blood units have also proven to be a valuable donor source for the development of cellular therapeutics. Virus-specific T cells and regulatory T cells are two cord blood derived products that have shown promise in early phase clinical trials to prevent and/or treat viral infections and graft-versus-host disease (GvHD), respectively. Here we describe how current strategies utilizing cord blood-derived regulatory T cells and virus-specific T cells have been developed to improve outcomes for cord blood transplant recipients. PMID:25632003

  13. Dichotomy between T Cell and B Cell Tolerance to Neonatal Retroviral Infection Permits T Cell Therapy

    PubMed Central

    Mavrommatis, Bettina; Baudino, Lucie; Levy, Prisca; Merkenschlager, Julia; Eksmond, Urszula; Donnarumma, Tiziano; Young, George; Stoye, Jonathan

    2016-01-01

    Elucidation of the immune requirements for control or elimination of retroviral infection remains an important aim. We studied the induction of adaptive immunity to neonatal infection with a murine retrovirus, under conditions leading to immunological tolerance. We found that the absence of either maternal or offspring adaptive immunity permitted efficient vertical transmission of the retrovirus. Maternal immunodeficiency allowed the retrovirus to induce central Th cell tolerance in the infected offspring. In turn, this compromised the offspring’s ability to mount a protective Th cell–dependent B cell response. However, in contrast to T cells, offspring B cells were not centrally tolerized and retained their ability to respond to the infection when provided with T cell help. Thus, escape of retrovirus-specific B cells from deletional tolerance offers the opportunity to induce protective retroviral immunity by restoration of retrovirus-specific T cell help, suggesting similar T cell immunotherapies for persistent viral infections. PMID:27647833

  14. Nature of "memory" in T-cell-mediated antibacterial immunity: anamnestic production of mediator T cells.

    PubMed Central

    North, R J

    1975-01-01

    Mice that survived an immunizing infection with Listeria monocytogenes remained specifically resistant to lethal secondary infection for several months. This acquired, long-lived state of resistance was not dependent on activated macrophages that remained after the primary response. It depended, instead, on an acquired long-lived capacity on the part of immunized mice for generating mediator T cells faster and in larger numbers than normal mice. The number of mediator T cells generated in response to secondary infection was proportional to the level of infection. The results suggest that the accelerated production of mediator T cells that occurs in response to secondary infection represents the expression of a state of immunological T-cell memory. PMID:811558

  15. Aggression in Drosophila.

    PubMed

    Kravitz, Edward A; Fernandez, Maria de la Paz

    2015-10-01

    Aggression is used by essentially all species of animals to gain access to desired resources, including territory, food, and potential mates: Fruit flies are no exception. In Drosophila, both males and females compete in same sex fights for resources, but only males establish hierarchical relationships. Many investigators now study aggression using the fruit fly model, mainly because (a) aggression in fruit flies is a quantifiable well-defined and easily evoked behavior; (b) powerful genetic methods allow investigators to manipulate genes of interest at any place or time during embryonic, larval, pupal or adult life, and while flies are behaving; (c) the growth of the relatively new field of optogenetics makes physiological studies possible at single neuron levels despite the small sizes of neurons and other types of cells in fly brains; and (d) the rearing of fly stocks with their short generation times and limited growth space requirements can easily be performed at relatively low cost in most laboratories. This review begins with an examination of the behavior, both from a historical perspective and then from the birth of the "modern" era of studies of aggression in fruit flies including its quantitative analysis. The review continues with examinations of the roles of genes, neurotransmitters and neurohormones, peptides, nutritional and metabolic status, and surface cuticular hydrocarbons in the initiation and maintenance of aggression. It concludes with suggestions for future studies with this important model system.

  16. Tr1-Like T Cells – An Enigmatic Regulatory T Cell Lineage

    PubMed Central

    White, Anna Malgorzata; Wraith, David C.

    2016-01-01

    The immune system evolved to respond to foreign invaders and prevent autoimmunity to self-antigens. Several types of regulatory T cells facilitate the latter process. These include a subset of Foxp3− CD4+ T cells able to secrete IL-10 in an antigen-specific manner, type 1 regulatory (Tr1) T cells. Although their suppressive function has been confirmed both in vitro and in vivo, their phenotype remains poorly defined. It has been suggested that the surface markers LAG-3 and CD49b are biomarkers for murine and human Tr1 cells. Here, we discuss these findings in the context of our data regarding the expression pattern of inhibitory receptors (IRs) CD49b, TIM-3, PD-1, TIGIT, LAG-3, and ICOS on Tr1-like human T cells generated in vitro from CD4+ memory T cells stimulated with αCD3 and αCD28 antibodies. We found that there were no differences in IR expression between IL-10+ and IL-10− T cells. However, CD4+IL-10+ T cells isolated ex vivo, following a short stimulation and cytokine secretion assay, contained significantly higher proportions of TIM-3+ and PD-1+ cells. They also expressed significantly higher TIGIT mRNA and showed a trend toward increased TIM-3 mRNA levels. These data led us to conclude that large pools of IRs may be stored intracellularly; hence, they may not represent ideal candidates as cell surface biomarkers for Tr1-like T cells. PMID:27683580

  17. Tr1-Like T Cells – An Enigmatic Regulatory T Cell Lineage

    PubMed Central

    White, Anna Malgorzata; Wraith, David C.

    2016-01-01

    The immune system evolved to respond to foreign invaders and prevent autoimmunity to self-antigens. Several types of regulatory T cells facilitate the latter process. These include a subset of Foxp3− CD4+ T cells able to secrete IL-10 in an antigen-specific manner, type 1 regulatory (Tr1) T cells. Although their suppressive function has been confirmed both in vitro and in vivo, their phenotype remains poorly defined. It has been suggested that the surface markers LAG-3 and CD49b are biomarkers for murine and human Tr1 cells. Here, we discuss these findings in the context of our data regarding the expression pattern of inhibitory receptors (IRs) CD49b, TIM-3, PD-1, TIGIT, LAG-3, and ICOS on Tr1-like human T cells generated in vitro from CD4+ memory T cells stimulated with αCD3 and αCD28 antibodies. We found that there were no differences in IR expression between IL-10+ and IL-10− T cells. However, CD4+IL-10+ T cells isolated ex vivo, following a short stimulation and cytokine secretion assay, contained significantly higher proportions of TIM-3+ and PD-1+ cells. They also expressed significantly higher TIGIT mRNA and showed a trend toward increased TIM-3 mRNA levels. These data led us to conclude that large pools of IRs may be stored intracellularly; hence, they may not represent ideal candidates as cell surface biomarkers for Tr1-like T cells.

  18. Tr1-Like T Cells - An Enigmatic Regulatory T Cell Lineage.

    PubMed

    White, Anna Malgorzata; Wraith, David C

    2016-01-01

    The immune system evolved to respond to foreign invaders and prevent autoimmunity to self-antigens. Several types of regulatory T cells facilitate the latter process. These include a subset of Foxp3(-) CD4(+) T cells able to secrete IL-10 in an antigen-specific manner, type 1 regulatory (Tr1) T cells. Although their suppressive function has been confirmed both in vitro and in vivo, their phenotype remains poorly defined. It has been suggested that the surface markers LAG-3 and CD49b are biomarkers for murine and human Tr1 cells. Here, we discuss these findings in the context of our data regarding the expression pattern of inhibitory receptors (IRs) CD49b, TIM-3, PD-1, TIGIT, LAG-3, and ICOS on Tr1-like human T cells generated in vitro from CD4(+) memory T cells stimulated with αCD3 and αCD28 antibodies. We found that there were no differences in IR expression between IL-10(+) and IL-10(-) T cells. However, CD4(+)IL-10(+) T cells isolated ex vivo, following a short stimulation and cytokine secretion assay, contained significantly higher proportions of TIM-3(+) and PD-1(+) cells. They also expressed significantly higher TIGIT mRNA and showed a trend toward increased TIM-3 mRNA levels. These data led us to conclude that large pools of IRs may be stored intracellularly; hence, they may not represent ideal candidates as cell surface biomarkers for Tr1-like T cells. PMID:27683580

  19. T Cell Receptor Signaling in the Control of Regulatory T Cell Differentiation and Function

    PubMed Central

    Li, Ming O.; Rudensky, Alexander Y.

    2016-01-01

    Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self-tolerance and inflammatory responses. Recent studies have revealed a discrete mode of TCR signaling that regulates Treg cell differentiation, maintenance and function and that impacts on gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of Treg cells in the context of their function in health and disease. PMID:27026074

  20. Regulatory T cells and transplantation tolerance.

    PubMed

    Cobbold, S P

    2008-01-01

    Rodent models of transplantation have demonstrated that it is possible to induce specific immunological tolerance of donor antigens and indefinite graft survival in the absence of any continued immunosuppression. If this situation could be achieved clinically it would avoid many of the longer term complications of organ grafting, such as the increased risk of infection and cancer and the nephrotoxicity of many immunosuppressive agents. In this review we shall consider the interplay between regulatory T cells, dendritic cells and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We will discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T cell and antigen-presenting cell activity. The induction and maintenance of tolerance via acquired local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression. PMID:18651537

  1. Regulatory T-cell compartmentalization and trafficking

    PubMed Central

    Wei, Shuang; Kryczek, Ilona; Zou, Weiping

    2006-01-01

    CD4+CD25+FOXP3+ regulatory T cells (CD4+ Treg cells) are thought to differentiate in the thymus and immigrate from the thymus to the periphery. Treg cells can regulate both acquired and innate immunity through multiple modes of suppression. The cross-talk between Treg cells and targeted cells, such as antigen-presenting cells (APCs) and T cells, is crucial for ensuring suppression by Treg cells in the appropriate microenvironment. Emerging evidence suggests that Treg compartmentalization and trafficking may be tissue or/and organ specific and that distinct chemokine receptor and integrin expression may contribute to selective retention and trafficking of Treg cells at sites where regulation is required. In this review, the cellular and molecular signals that control specialized migration and retention of Treg cells are discussed. PMID:16537800

  2. NHL - Extranodal T-cell lymphoma

    PubMed Central

    Devi, Seema; Sinha, Richi; Singh, Rakesh Kumar; Mehta, Gagan

    2015-01-01

    Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a rare lymphoid neoplasm that in the past has been grouped with a variety of granulomatous diseases. ENKL occurs in all age groups. However, it seems to occur more often in people in their 50s and affects more men than women. It is strongly linked to the Epstein-Barr virus (EBV), especially in people of Asian countries. Because this type of lymphoma occurs in organs or tissues other than lymph nodes, it is called ENKL. This is a case report of a 25-year-old female patient who presented with a nonhealing ulcer at the right nasal ala involving the upper lip and cheek for the last 2 months, which had been treated with antitubercular treatment without success. After biopsy and immunohistochemical (IHC) analysis, the patient had been diagnosed a case of extranodal T-cell lymphoma. PMID:26668464

  3. The T Cell Response to Staphylococcus aureus

    PubMed Central

    Bröker, Barbara M.; Mrochen, Daniel; Péton, Vincent

    2016-01-01

    Staphylococcus aureus (S. aureus) is a dangerous pathogen and a leading cause of both nosocomial and community acquired bacterial infection worldwide. However, on the other hand, we are all exposed to this bacterium, often within the first hours of life, and usually manage to establish equilibrium and coexist with it. What does the adaptive immune system contribute toward lifelong control of S. aureus? Will it become possible to raise or enhance protective immune memory by vaccination? While in the past the S. aureus-specific antibody response has dominated this discussion, the research community is now coming to appreciate the role that the cellular arm of adaptive immunity, the T cells, plays. There are numerous T cell subsets, each with differing functions, which together have the ability to orchestrate the immune response to S. aureus and hence to tip the balance between protection and pathology. This review summarizes the state of the art in this dynamic field of research. PMID:26999219

  4. Engineering CAR-T cells: Design concepts.

    PubMed

    Srivastava, Shivani; Riddell, Stanley R

    2015-08-01

    Despite being empirically designed based on a simple understanding of TCR signaling, T cells engineered with chimeric antigen receptors (CARs) have been remarkably successful in treating patients with advanced refractory B cell malignancies. However, many challenges remain in improving the safety and efficacy of this therapy and extending it toward the treatment of epithelial cancers. Other aspects of TCR signaling beyond those directly provided by CD3ζ and CD28 phosphorylation strongly influence a T cell's ability to differentiate and acquire full effector functions. Here, we discuss how the principles of TCR recognition, including spatial constraints, Kon/Koff rates, and synapse formation, along with in-depth analysis of CAR signaling might be applied to develop safer and more effective synthetic tumor targeting receptors.

  5. Modeling T cell responses to antigenic challenge

    PubMed Central

    Wodarz, Dominik

    2014-01-01

    T cell responses are a crucial part of the adaptive immune system in the fight against infections. This article discusses the use of mathematical models for understanding the dynamics of cytotoxic T lymphocyte (CTL) responses against viral infections. Complementing experimental research, mathematical models have been very useful for exploring new hypotheses, interpreting experimental data, and for defining what needs to be measured to improve understanding. This review will start with minimally parameterized models of CTL responses, which have generated some valuable insights into basic dynamics and correlates of control. Subsequently, more biological complexity is incorporated into this modeling framework, examining different mechanisms of CTL expansion, different effector activities, and the influence of T cell help. Models and results are discussed in the context of data from specific infections. PMID:25269610

  6. Accumulation of cytolytic CD8{sup +} T cells in B16-melanoma and proliferation of mature T cells in TIS21-knockout mice after T cell receptor stimulation

    SciTech Connect

    Ryu, Min Sook; Woo, Min-Yeong; Kwon, Daeho; Hong, Allen E.; Song, Kye Yong; Park, Sun; Lim, In Kyoung

    2014-10-01

    In vivo and in vitro effects of TIS21 gene on the mature T cell activation and antitumor activities were explored by employing MO5 melanoma orthograft and splenocytes isolated from the TIS21-knockout (KO) mice. Proliferation and survival of mature T cells were significantly increased in the KO than the wild type (WT) cells, indicating that TIS21 inhibits the rate of mature T cell proliferation and its survival. In MO5 melanoma orthograft model, the KO mice recruited much more CD8{sup +} T cells into the tumors at around day 14 after tumor cell injection along with reduced tumor volumes compared with the WT. The increased frequency of granzyme B{sup +} CD8{sup +} T cells in splenocytes of the KO mice compared with the WT may account for antitumor-immunity of TIS21 gene in the melanoma orthograft. In contrast, reduced frequencies of CD107a{sup +} CD8{sup +} T cells in the splenocytes of KO mice may affect the loss of CD8{sup +} T cell infiltration in the orthograft at around day 19. These results indicate that TIS21 exhibits antiproliferative and proapoptotic effects in mature T cells, and differentially affects the frequencies of granzyme B{sup +} CD8{sup +} T-cells and CD107a{sup +} CD8{sup +} T-cells, thus transiently regulating in vivo anti-tumor immunity. - Highlights: • Constitutive expression of TIS21 in splenocytes and upregulation by TCR stimulation. • Proliferation of mature T-cells in spleen of TIS21KO mice after TCR stimulation. • Inhibition of cell death in mature T-cells of TIS21KO mice compared with the wild type. • Inhibition of melanoma growth in TIS21KO mice and CD8{sup +} T cell infiltration in tumor. • Reduction of CD 107{sup +}CD8{sup +} T cells, but increased granzyme B{sup +} CD8{sup +} T cells in TIS21KO mice.

  7. Inducible T-cell receptor expression in precursor T cells for leukemia control.

    PubMed

    Hoseini, S S; Hapke, M; Herbst, J; Wedekind, D; Baumann, R; Heinz, N; Schiedlmeier, B; Vignali, D A A; van den Brink, M R M; Schambach, A; Blazar, B R; Sauer, M G

    2015-07-01

    Co-transplantation of hematopoietic stem cells with those engineered to express leukemia-reactive T-cell receptors (TCRs) and differentiated ex vivo into precursor T cells (preTs) may reduce the risk of leukemia relapse. As expression of potentially self-(leukemia-) reactive TCRs will lead to negative selection or provoke autoimmunity upon thymic maturation, we investigated a novel concept whereby TCR expression set under the control of an inducible promoter would allow timely controlled TCR expression. After in vivo maturation and gene induction, preTs developed potent anti-leukemia effects. Engineered preTs provided protection even after repeated leukemia challenges by giving rise to effector and central memory cells. Importantly, adoptive transfer of TCR-transduced allogeneic preTs mediated anti-leukemia effect without evoking graft-versus-host disease (GVHD). Earlier transgene induction forced CD8(+) T-cell development was required to obtain a mature T-cell subset of targeted specificity, allowed engineered T cells to efficiently pass positive selection and abrogated the endogenous T-cell repertoire. Later induction favored CD4 differentiation and failed to produce a leukemia-reactive population emphasizing the dominant role of positive selection. Taken together, we provide new functional insights for the employment of TCR-engineered precursor cells as a controllable immunotherapeutic modality with significant anti-leukemia activity.

  8. Inducible T-cell receptor expression in precursor T cells for leukemia control.

    PubMed

    Hoseini, S S; Hapke, M; Herbst, J; Wedekind, D; Baumann, R; Heinz, N; Schiedlmeier, B; Vignali, D A A; van den Brink, M R M; Schambach, A; Blazar, B R; Sauer, M G

    2015-07-01

    Co-transplantation of hematopoietic stem cells with those engineered to express leukemia-reactive T-cell receptors (TCRs) and differentiated ex vivo into precursor T cells (preTs) may reduce the risk of leukemia relapse. As expression of potentially self-(leukemia-) reactive TCRs will lead to negative selection or provoke autoimmunity upon thymic maturation, we investigated a novel concept whereby TCR expression set under the control of an inducible promoter would allow timely controlled TCR expression. After in vivo maturation and gene induction, preTs developed potent anti-leukemia effects. Engineered preTs provided protection even after repeated leukemia challenges by giving rise to effector and central memory cells. Importantly, adoptive transfer of TCR-transduced allogeneic preTs mediated anti-leukemia effect without evoking graft-versus-host disease (GVHD). Earlier transgene induction forced CD8(+) T-cell development was required to obtain a mature T-cell subset of targeted specificity, allowed engineered T cells to efficiently pass positive selection and abrogated the endogenous T-cell repertoire. Later induction favored CD4 differentiation and failed to produce a leukemia-reactive population emphasizing the dominant role of positive selection. Taken together, we provide new functional insights for the employment of TCR-engineered precursor cells as a controllable immunotherapeutic modality with significant anti-leukemia activity. PMID:25652739

  9. Characterization of T cell responses to fragrances.

    PubMed

    Sieben, S; Hertl, M; Al Masaoudi, T; Merk, H F; Blömeke, B

    2001-05-01

    Fragrances are worldwide a major cause of allergic contact dermatitis (ACD), a delayed-type hypersensitivity reaction mediated by T lymphocytes. We investigated T cell responses to fragrances using peripheral blood mononuclear cells (PBMC) and T cells from skin lesions of fragrance-allergic patients. The components of a fragrance mixture (eugenol, isoeugenol, geraniol, oak moss, alpha-amyl cinnamic aldehyde, cinnamic aldehyde, cinnamic alcohol, and hydroxycitronellal) that is commonly used in the patch test were studied in vitro in the lymphocyte transformation test (LTT). PBMC from fragrance-allergic patients (n = 32) showed significant stimulations to all eight fragrances. The calculated stimulation indices (SI) varied between 2.1 and 21.8. The influence of metabolic enzymes on T cell stimulation was studied for two fragrances. Interestingly, stimulation of eugenol and isoeugenol was increased in the presence of antigen-modified human liver microsomes (CYP450) or recombinant CYP1A1 in five of seven cases. Furthermore, we established 18 T cell clones (TCC) from a skin lesion reacting specifically to eugenol. FACS analysis revealed that the majority (n = 15, 83%) of TCC were CD3(+), CD4(+), and HLA-DR(+). Seventeen percent (n = 3) of the clones were CD8(+). TCC (n = 4) released significant amounts of IL-2 and IFN-gamma but no IL-4 and IL-5. In addition, CD4(+) TCC (n = 3) showed antigen-induced cytotoxic activities against autologous B cells. In summary, we demonstrated for the first time that fragrance-specific CD4(+) and CD8(+) T lymphocytes are present in fragrance-allergic individuals. In addition, our results suggest that CYPs can be involved in the formation of the nominative antigen.

  10. T cell epitope-based allergy vaccines.

    PubMed

    Larché, Mark

    2011-01-01

    Specific immunotherapy (SIT) with extracts containing intact allergen molecules is clinically efficacious, but associated with frequent adverse events related to the allergic sensitization of the patient. As a result, treatment is initiated in an incremental dose fashion which ultimately achieves a plateau (maintenance dose) that may be continued for several years. Reduction of allergic adverse events may allow safer and more rapid treatment Thus, many groups have developed and evaluated strategies to reduce allergenicity whilst maintaining immunogenicity, the latter being required to achieve specific modulation of the immune response. Peptide immunotherapy can be used to target T and/or B cells in an antigen-specific manner. To date, only approaches that target T cells have been clinically evaluated. Short, synthetic peptides representing immunodominant T cell epitopes of major allergens are able to modulate allergen-specific T cell responses in the absence of IgE cross linking and activation of effector cells. Here we review clinical and mechanistic studies associated with peptide immunotherapy targeting allergy to cats or to bee venom. 

  11. Functional characterization of prethymic T cells committed to alloreactivity

    SciTech Connect

    Blank, M.; Gronau, C.; Sauer, M.; Wottge, H.U.; Mueller-Ruchholtz, W.

    1986-06-01

    The results of previous experiments on MHC fully allogenic bone marrow transplantation (BMT) in nonthymectomizd recipients indicated that anti-MHC alloreactivity starts to become irreversibly committed at the prethymic level. This is a matter of some controversy. Since it is possible that conflicting results depend on the methods chosen, we reexamined our previous results by applying two new approaches. Adult thymectomized (ATX) Balb/c mice received a syngeneic fetal thymus either 3 weeks before or 3 weeks after lethal irradiation and reconstitution with C57BL/6 BM incubated in antiserum. Since monoclonal antibodies such as anti-Thy 1 are of limited value for investigations of the above type (Thy 1 antigen crosses the prethymic/thymic border), we used two highly selective, excessively cytotoxic xenoantisera for incubation of the donor BM--either a specific anti-T cell serum (SAT) that eliminated only mature T cells, or a specific antilymphocyte serum (SAL) that reacted additionally with a subset of prethymic T cells (PTC). In both experimental approaches the results were similar: Recipients of SAT-BM developed antihost reactivity, in contrast to recipients of SAL-BM. SAT-BM recipients became immunodeficient, whereas SAL-BM chimeras were immunocompetent. Late mortality was observed only following SAT treatment. Preliminary morphological findings in the lymphoid tissue of BM recipients agree fully with the functional observations. We conclude that the data confirm our previous results in nonthymectomized BM recipients--i.e., PTCs initiate antihost reactivity in MHC fully allogeneic BMT--and PTC commitment is thymus/thymus factor independent. These conclusions are discussed with regard to the problems of MHC allogeneic clinical BMT.

  12. Age-associated Failure to Adjust Type I Interferon Receptor Signaling Thresholds after T-cell Activation1

    PubMed Central

    Li, Guangjin; Ju, Jihang; Weyand, Cornelia M.; Goronzy, Jörg J.

    2015-01-01

    With increasing age, naïve CD4 T cells acquire intrinsic defects that compromise their ability to respond and differentiate. Type I IFNs, pervasive constituents of the environment in which adaptive immune responses occur, are known to regulate T cell differentiation and survival. Activated naïve CD4 T cells from older individuals have reduced responses to type I IFN, a defect that develops during activation and is not observed in quiescent naïve CD4 T cells. Naïve CD4 T cells from young adults upregulate the expression of STAT1 and STAT5 after activation, lowering their threshold to respond to type I IFN stimulation. The heightened STAT signaling is critical to maintain the expression of CD69 that regulates lymphocyte egress and the ability to produce IL-2 and to survive. Although activation of T cells from older adults also induces transcription of STAT1 and STAT5, failure to exclude SHP1 to the signaling complex blunts their type I IFN response. In summary, our data show that type I IFN signaling thresholds in naïve CD4 T cells after activation are dynamically regulated to respond environmental cues for clonal expansion and memory cell differentiation. Naïve CD4 T cells from older adults have a defect in this threshold calibration. Restoring their ability to respond to type I IFN emerges as a promising target to restore T cell responses and improve the induction of T cell memory. PMID:26091718

  13. Vorinostat, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Lymphoma or Previously Untreated T-Cell Non-Hodgkin Lymphoma or Mantle Cell Lymphoma

    ClinicalTrials.gov

    2014-09-02

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Waldenström Macroglobulinemia

  14. T Cells and Gene Regulation: The Switching On and Turning Up of Genes after T Cell Receptor Stimulation in CD8 T Cells

    PubMed Central

    Conley, James M.; Gallagher, Michael P.; Berg, Leslie J.

    2016-01-01

    Signaling downstream of the T cell receptor (TCR) is directly regulated by the dose and affinity of peptide antigen. The strength of TCR signaling drives a multitude of T cell functions from development to differentiation. CD8 T cells differentiate into a diverse pool of effector and memory cells after activation, a process that is critical for pathogen clearance and is highly regulated by TCR signal strength. T cells rapidly alter their gene expression upon activation. Multiple signaling pathways downstream of the TCR activate transcription factors, which are critical for this process. The dynamics between proximal TCR signaling, transcription factor activation and CD8 T cell function are discussed here. We propose that inducible T cell kinase (ITK) acts as a rheostat for gene expression. This unique regulation of TCR signaling by ITK provides a possible signaling mechanism for the promotion of a diverse T cell repertoire in response to pathogen. PMID:26973653

  15. Alisertib in Combination With Vorinostat in Treating Patients With Relapsed or Recurrent Hodgkin Lymphoma, B-Cell Non-Hodgkin Lymphoma, or Peripheral T-Cell Lymphoma

    ClinicalTrials.gov

    2016-10-25

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; T-Cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  16. Variable CD52 Expression in Mature T Cell and NK Cell Malignancies: Implications for Alemtuzumab Therapy

    PubMed Central

    Jiang, Liuyan; Yuan, Constance; Hubacheck, Julia; Janik, John E.; Wilson, Wyndham; Morris, John C.; Jasper, Gregory A; Stetler-Stevenson, Maryalice

    2012-01-01

    Summary The anti-CD52 antibody alemtuzumab has been explored as a novel targeted therapy in T-cell malignancies. To assess the suitability of alemtuzumab therapy we carried out a comprehensive study of CD52 expression using flow cytometry (FC) in 78 untreated patients diagnosed with mature T/NK cell neoplasms, including 34 adult T-cell leukemia /lymphomas (ATLL), two anaplastic large cell lymphomas (ALCL), three angioimmunoblastic T-cell lymphomas (AITL), 16 cutaneous T-cell lymphomas (CTCL), four extra-nodal T/NK cell lymphomas (ENT/NKCL), four hepatosplenic T-cell lymphomas (HSTCL), 13 peripheral T-cell lymphomas, unspecified (PTCL-NOS), and two T-prolymphocytic leukemia (T-PLL). The level of CD52 expression was quantitated using QuantiBRITE standard beads. The level of CD52 expression varied widely within each diagnostic category. All AITL, HSTCL, and T-PLL cases were CD52 positive and the frequency of CD52 expression was high in PTCL-NOS (92.3%), ATLL (94.1%) and CTCL (87.5%), implying a rational role for alemtuzumab in the treatment of these diseases; however, CD52 expression was low in ALCL (50%) and ENT/NKCL (25%). FC testing for cell surface expression of CD52 is indicated in patients with T/NK cell malignancies being considered for alemtuzumab therapy. Further studies are necessary to determine if the level of CD52 expression correlates with response to therapy. PMID:19236377

  17. Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms.

    PubMed

    Cobbold, Stephen P; Nolan, Kathleen F; Graca, Luis; Castejon, Raquel; Le Moine, Alain; Frewin, Mark; Humm, Susan; Adams, Elizabeth; Thompson, Sara; Zelenika, Diana; Paterson, Alison; Yates, Stephen; Fairchild, Paul J; Waldmann, Herman

    2003-12-01

    Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells. PMID:14617201

  18. T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma

    PubMed Central

    Singh, Nathan; Kulikovskaya, Irina; Barrett, David M.; Binder-Scholl, Gwendolyn; Jakobsen, Bent; Martinez, Daniel; Pawel, Bruce; June, Carl H.; Kalos, Michael D.; Grupp, Stephan A.

    2016-01-01

    abstract The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro, we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma. PMID:26942053

  19. New cell sources for T cell engineering and adoptive immunotherapy.

    PubMed

    Themeli, Maria; Rivière, Isabelle; Sadelain, Michel

    2015-04-01

    The promising clinical results obtained with engineered T cells, including chimeric antigen receptor (CAR) therapy, call for further advancements to facilitate and broaden their applicability. One potentially beneficial innovation is to exploit new T cell sources that reduce the need for autologous cell manufacturing and enable cell transfer across histocompatibility barriers. Here we review emerging T cell engineering approaches that utilize alternative T cell sources, which include virus-specific or T cell receptor-less allogeneic T cells, expanded lymphoid progenitors, and induced pluripotent stem cell (iPSC)-derived T lymphocytes. The latter offer the prospect for true off-the-shelf, genetically enhanced, histocompatible cell therapy products.

  20. Romidepsin: in the treatment of T-cell lymphoma.

    PubMed

    Yang, Lily P H

    2011-07-30

    Romidepsin is a histone deacetylase inhibitor with high inhibitory activity for class I histone deacetylases. Intravenous romidepsin is indicated in the US for the treatment of adult patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL) who have received at least one prior systemic therapy. The clinical efficacy of romidepsin has been demonstrated in two noncomparative, multicentre, phase II trials in patients with relapsed, refractory or advanced CTCL. In both trials, therapy with intravenous romidepsin was associated with an overall response (i.e. both complete response and partial response) rate of 34% and a complete response rate of 6%. The efficacy of romidepsin was also evaluated in patients with relapsed or refractory PTCL in two noncomparative, multicentre, phase II trials. Intravenous romidepsin therapy was associated with overall response rates of 38% and 26% and a complete response rate of 18% and 13% in these trials. Romidepsin had an acceptable tolerability profile in clinical trials in patients with CTCL or PTCL. The most common adverse events of grade 3 or 4 severity considered at least possibly related to romidepsin were haematological or asthenic in nature, and included leukopenia, lymphopenia, granulocytopenia, thrombocytopenia, fatigue and anaemia.

  1. Type 1 diabetes immunotherapy using polyclonal regulatory T cells.

    PubMed

    Bluestone, Jeffrey A; Buckner, Jane H; Fitch, Mark; Gitelman, Stephen E; Gupta, Shipra; Hellerstein, Marc K; Herold, Kevan C; Lares, Angela; Lee, Michael R; Li, Kelvin; Liu, Weihong; Long, S Alice; Masiello, Lisa M; Nguyen, Vinh; Putnam, Amy L; Rieck, Mary; Sayre, Peter H; Tang, Qizhi

    2015-11-25

    Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing β cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo-expanded autologous CD4(+)CD127(lo/-)CD25(+) polyclonal Tregs (0.05 × 10(8) to 26 × 10(8) cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3(+)CD4(+)CD25(hi)CD127(lo) phenotype long-term. There were no infusion reactions or cell therapy-related high-grade adverse events. C-peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy. PMID:26606968

  2. Lactose inhibits regulatory T-cell-mediated suppression of effector T-cell interferon-γ and IL-17 production.

    PubMed

    Paasela, Monika; Kolho, Kaija-Leena; Vaarala, Outi; Honkanen, Jarno

    2014-12-14

    Our interest in lactose as an immunomodulatory molecule results from studies showing that lactose binds to galectin-9, which has been shown to have various regulatory functions in the immune system including regulation of T-cell responses. Impaired regulation of T helper (Th)1 and Th17 type immune responses and dysfunction of regulatory T cells (Treg) have been implicated in many human immune-mediated diseases. In the present study, we investigated the effects of lactose on immune regulation using co-cultures of human peripheral blood mononuclear cell (PBMC)-derived Treg and effector T cells (Teff) obtained from twenty healthy adults. Treg, i.e. CD4+CD25+CD127-, were isolated from PBMC by immunomagnetic separation. The fraction of CD4+CD127- cells that was depleted of CD25+ cells was used as Teff. Treg and Teff at a ratio 1:5 were activated and the effects of lactose on the secretion of interferon-γ (IFN-γ) and IL-17 were analysed using ELISA for protein and quantitative RT-PCR for mRNA. Treg down-regulated the secretion of both IFN-γ (8.8-3.9 ng/ml, n 20, P= 0.003) and IL-17 (0.83-0.64 ng/ml, n 15, P= 0.04) in co-cultures, while in the presence of lactose the levels of secreted IFN-γ and IL-17 remained high and no down-regulation was observed (16.4 v. 3.99 ng/ml, n 20, P< 0.0001, and 0.74 v. 0.64 ng/ml, n 15, P= 0.005, respectively). We showed that lactose inhibits human Treg-mediated suppression of Th1 and Th17 immune responses in vitro.

  3. Cord Blood Derived CD4+CD25high T Cells Become Functional Regulatory T Cells upon Antigen Encounter

    PubMed Central

    Mayer, Elisabeth; Bannert, Christina; Gruber, Saskia; Klunker, Sven; Spittler, Andreas; Akdis, Cezmi A.

    2012-01-01

    Background: Upon antigen exposure, cord blood derived T cells respond to ubiquitous environmental antigens by high proliferation. To date it remains unclear whether these “excessive” responses relate to different regulatory properties of the putative T regulatory cell (Treg) compartment or even expansion of the Treg compartment itself. Methods: Cord blood (>37 week of gestation) and peripheral blood (healthy controls) were obtained and different Treg cell subsets were isolated. The suppressive potential of Treg populations after antigen exposure was evaluated via functional inhibition assays ([3H]thymidine incorporation assay and CFSE staining) with or without allergen stimulation. The frequency and markers of CD4+CD25highFoxP3+ T cells were characterized by mRNA analysis and flow cytometry. Results: Cord blood derived CD4+CD25high cells did not show substantial suppressor capacity upon TCR activation, in contrast to CD4+CD25high cells freshly purified from adult blood. This could not be explained by a lower frequency of FoxP3+CD4+CD25highcells or FOXP3 mRNA expression. However, after antigen-specific stimulation in vitro, these cells showed strong proliferation and expansion and gained potent suppressive properties. The efficiency of their suppressive capacity can be enhanced in the presence of endotoxins. If T-cells were sorted according to their CD127 expression, a tiny subset of Treg cells (CD4+CD25+CD127low) is highly suppressive even without prior antigen exposure. Conclusion: Cord blood harbors a very small subset of CD4+CD25high Treg cells that requires antigen-stimulation to show expansion and become functional suppressive Tregs. PMID:22272233

  4. WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells.

    PubMed

    Stauss, Hans J; Thomas, Sharyn; Cesco-Gaspere, Michela; Hart, Daniel P; Xue, Shao-An; Holler, Angelika; King, Judy; Wright, Graham; Perro, Mario; Pospori, Constantina; Morris, Emma

    2008-01-01

    Adoptive transfer of antigen-specific T lymphocytes is an attractive form of immunotherapy for haematological malignancies and cancer. The difficulty of isolating antigen-specific T lymphocytes for individual patients limits the more widespread use of adoptive T cell therapy. The demonstration that cloned T cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy. The first trial in humans demonstrated that TCR gene-modified T cells persisted for an extended time period and reduced tumor burden in some patients. The WT1 protein is an attractive target for immunotherapy of leukemia and solid cancer since elevated expression has been demonstrated in AML, CML, MDS and in breast, colon and ovarian cancer. In the past, we have isolated high avidity CTL specific for a WT1-derived peptide presented by HLA-A2 and cloned the TCR alpha and beta genes of a WT1-specific CTL line. The genes were inserted into retroviral vectors for transduction of human peripheral blood T lymphocytes of leukemia patients and normal donors. The treatment of leukemia-bearing NOD/SCID mice with T cells transduced with the WT1-specific TCR eliminated leukemia cells in the bone marrow of most mice, while treatment with T cells transduced with a TCR of irrelevant specificity did not diminish the leukemia burden. In order to improve the safety and efficacy of TCR gene therapy, we have developed lentiviral TCR gene transfer. In addition, we employed strategies to enhance TCR expression while avoiding TCR mis-pairing. It may be possible to generate dominant TCR constructs that can suppress the expression of the endogenous TCR on the surface of transduced T cells. The development of new TCR gene constructs holds great promise for the safe and effective delivery of TCR gene therapy for the treatment of malignancies.

  5. WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells.

    PubMed

    Stauss, Hans J; Thomas, Sharyn; Cesco-Gaspere, Michela; Hart, Daniel P; Xue, Shao-An; Holler, Angelika; King, Judy; Wright, Graham; Perro, Mario; Pospori, Constantina; Morris, Emma

    2008-01-01

    Adoptive transfer of antigen-specific T lymphocytes is an attractive form of immunotherapy for haematological malignancies and cancer. The difficulty of isolating antigen-specific T lymphocytes for individual patients limits the more widespread use of adoptive T cell therapy. The demonstration that cloned T cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy. The first trial in humans demonstrated that TCR gene-modified T cells persisted for an extended time period and reduced tumor burden in some patients. The WT1 protein is an attractive target for immunotherapy of leukemia and solid cancer since elevated expression has been demonstrated in AML, CML, MDS and in breast, colon and ovarian cancer. In the past, we have isolated high avidity CTL specific for a WT1-derived peptide presented by HLA-A2 and cloned the TCR alpha and beta genes of a WT1-specific CTL line. The genes were inserted into retroviral vectors for transduction of human peripheral blood T lymphocytes of leukemia patients and normal donors. The treatment of leukemia-bearing NOD/SCID mice with T cells transduced with the WT1-specific TCR eliminated leukemia cells in the bone marrow of most mice, while treatment with T cells transduced with a TCR of irrelevant specificity did not diminish the leukemia burden. In order to improve the safety and efficacy of TCR gene therapy, we have developed lentiviral TCR gene transfer. In addition, we employed strategies to enhance TCR expression while avoiding TCR mis-pairing. It may be possible to generate dominant TCR constructs that can suppress the expression of the endogenous TCR on the surface of transduced T cells. The development of new TCR gene constructs holds great promise for the safe and effective delivery of TCR gene therapy for the treatment of malignancies. PMID:17855129

  6. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity

    PubMed Central

    Paterson, Alison M.; Lovitch, Scott B.; Sage, Peter T.; Juneja, Vikram R.; Lee, Youjin; Trombley, Justin D.; Arancibia-Cárcamo, Carolina V.; Sobel, Raymond A.; Rudensky, Alexander Y.; Kuchroo, Vijay K.; Freeman, Gordon J.

    2015-01-01

    Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of T cell responses. Germline Ctla4 deficiency is lethal, making investigation of the function of CTLA-4 on mature T cells challenging. To elucidate the function of CTLA-4 on mature T cells, we have conditionally ablated Ctla4 in adult mice. We show that, in contrast to germline knockout mice, deletion of Ctla4 during adulthood does not precipitate systemic autoimmunity, but surprisingly confers protection from experimental autoimmune encephalomyelitis (EAE) and does not lead to increased resistance to MC38 tumors. Deletion of Ctla4 during adulthood was accompanied by activation and expansion of both conventional CD4+Foxp3− (T conv) and regulatory Foxp3+ (T reg cells) T cell subsets; however, deletion of CTLA-4 on T reg cells was necessary and sufficient for protection from EAE. CTLA-4 deleted T reg cells remained functionally suppressive. Deletion of Ctla4 on T reg cells alone or on all adult T cells led to major changes in the Ctla4 sufficient T conv cell compartment, including up-regulation of immunoinhibitory molecules IL-10, LAG-3 and PD-1, thereby providing a compensatory immunosuppressive mechanism. Collectively, our findings point to a profound role for CTLA-4 on T reg cells in limiting their peripheral expansion and activation, thereby regulating the phenotype and function of T conv cells. PMID:26371185

  7. Survival of mature T cells depends on signaling through HOIP

    PubMed Central

    Okamura, Kazumi; Kitamura, Akiko; Sasaki, Yoshiteru; Chung, Doo Hyun; Kagami, Shoji; Iwai, Kazuhiro; Yasutomo, Koji

    2016-01-01

    T cell development in the thymus is controlled by a multistep process. The NF-κB pathway regulates T cell development as well as T cell activation at multiple differentiation stages. The linear ubiquitin chain assembly complex (LUBAC) is composed of Sharpin, HOIL-1L and HOIP, and it is crucial for regulating the NF-κB and cell death pathways. However, little is known about the roles of LUBAC in T-cell development and activation. Here, we show that in T-HOIPΔlinear mice lacking the ubiquitin ligase activity of LUBAC, thymic CD4+ or CD8+ T cell numbers were markedly reduced with severe defects in NKT cell development. HOIPΔlinear CD4+ T cells failed to phosphorylate IκBα and JNK through T cell receptor-mediated stimulation. Mature CD4+ and CD8+ T cells in T-HOIPΔlinear mice underwent apoptosis more rapidly than control T cells, and it was accompanied by lower CD127 expression on CD4+CD24low and CD8+CD24low T cells in the thymus. The enforced expression of CD127 in T-HOIPΔlinear thymocytes rescued the development of mature CD8+ T cells. Collectively, our results showed that LUBAC ligase activity is key for the survival of mature T cells, and suggest multiple roles of the NF-κB and cell death pathways in activating or maintaining T cell-mediated adaptive immune responses. PMID:27786304

  8. Neoantigen landscape dynamics during human melanoma-T cell interactions.

    PubMed

    Verdegaal, Els M E; de Miranda, Noel F C C; Visser, Marten; Harryvan, Tom; van Buuren, Marit M; Andersen, Rikke S; Hadrup, Sine R; van der Minne, Caroline E; Schotte, Remko; Spits, Hergen; Haanen, John B A G; Kapiteijn, Ellen H W; Schumacher, Ton N; van der Burg, Sjoerd H

    2016-08-01

    Recognition of neoantigens that are formed as a consequence of DNA damage is likely to form a major driving force behind the clinical activity of cancer immunotherapies such as T-cell checkpoint blockade and adoptive T-cell therapy. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens are currently under development. In mouse models, T-cell pressure can sculpt the antigenicity of tumours, resulting in the emergence of tumours that lack defined mutant antigens. However, whether the T-cell-recognized neoantigen repertoire in human cancers is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer cells and T cells, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance. PMID:27350335

  9. Immune homeostasis enforced by co-localized effector and regulatory T cells

    PubMed Central

    Liu, Zhiduo; Gerner, Michael Y.; Van Panhuys, Nicholas; Levine, Andrew G.; Rudensky, Alexander Y.; Germain, Ronald N.

    2015-01-01

    Foxp3+ regulatory T cells (Tregs) play a critical role in preventing autoimmune disease by limiting the effector activity of conventional T cells that have escaped thymic negative selection or cell-autonomous peripheral inactivation1–3. However, despite the substantial information available about the molecular players mediating Treg functional interference with auto-aggressive effector responses4,5, the relevant cellular events in intact tissues remain largely unexplored and the issues of whether Tregs prevent activation of self-specific T cells or function primarily to limit damage from such cells have not been addressed6. Here we have employed multiplex, high-resolution, quantitative imaging to reveal that within most secondary lymphoid tissues, Tregs expressing phosphorylated STAT5 (pSTAT5) and high amounts of the suppressive molecules CD73 and CTLA-4 exist in discrete clusters with rare IL-2 producing effector T cells activated by self-antigens. This local IL-2 production induces the STAT5 phosphorylation in the Tregs and is part of a feedback circuit that augments the suppressive properties of the Tregs to limit further autoimmune responses. Inducible ablation of TCR expression by Tregs reduces their regulatory capacity and disrupts their localization in such clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells reach a state of activation and cytokine gene induction on a regular basis, with physically co-clustering, TCR-stimulated Tregs responding to this activation in a feedback manner to suppress incipient autoimmunity and maintain immune homeostasis. PMID:26605524

  10. Naive CD8+ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics

    PubMed Central

    Neller, Michelle A; Ladell, Kristin; McLaren, James E; Matthews, Katherine K; Gostick, Emma; Pentier, Johanne M; Dolton, Garry; Schauenburg, Andrea JA; Koning, Dan; Fontaine Costa, Ana Isabel CA; Watkins, Thomas S; Venturi, Vanessa; Smith, Corey; Khanna, Rajiv; Miners, Kelly; Clement, Mathew; Wooldridge, Linda; Cole, David K; van Baarle, Debbie; Sewell, Andrew K; Burrows, Scott R; Price, David A; Miles, John J

    2015-01-01

    Basic parameters of the naive antigen (Ag)-specific T-cell repertoire in humans remain poorly defined. Systematic characterization of this ‘ground state' immunity in comparison with memory will allow a better understanding of clonal selection during immune challenge. Here, we used high-definition cell isolation from umbilical cord blood samples to establish the baseline frequency, phenotype and T-cell antigen receptor (TCR) repertoire of CD8+ T-cell precursor populations specific for a range of viral and self-derived Ags. Across the board, these precursor populations were phenotypically naive and occurred with hierarchical frequencies clustered by Ag specificity. The corresponding patterns of TCR architecture were highly ordered and displayed partial overlap with adult memory, indicating biased structuring of the T-cell repertoire during Ag-driven selection. Collectively, these results provide new insights into the complex nature and dynamics of the naive T-cell compartment. PMID:25801351

  11. Recovery from T cell depletion during murine listeriosis and effect on a T-dependent antibody response.

    PubMed Central

    Chan, Y Y; Cheers, C

    1982-01-01

    During the infection of mice with Listeria monocytogenes, there is a profound depletion of T (Thy-1+ Ig-) lymphocytes between days 1 and 4, followed by an increase in T cells to three times normal levels by day 9. The recovery of T cell numbers required cell proliferation, being sensitive to vinblastin and cyclophosphamide. Adult thymectomy 6 months before infection had no effect on recovery. The repopulating cells were no more sensitive than normal T cells to hydrocortisone. B lymphocytes (Ig+ cells) and null (Thy-1-Ig-) cells increased from day 1 after the injection of either live or (in contrast to T cells) killed Listeria organisms. Their increase was inhibited by vinblastin and cyclophosphamide. Despite T cell depletion, no depression of the antibody response to the T-dependent antigen, sheep erythrocytes, occurred during infection or when spleen cells were adoptively transferred from infected mice to irradiated recipients. PMID:6982870

  12. Enhanced pathogenicity of diabetogenic T cells escaping a non-MHC gene-controlled near death experience.

    PubMed

    Choisy-Rossi, Caroline-Morgane; Holl, Thomas M; Pierce, Melissa A; Chapman, Harold D; Serreze, David V

    2004-09-15

    For unknown reasons, the common MHC class I variants encoded by the H2g7 haplotype (Kd, Db) aberrantly elicit autoreactive CD8 T cell responses essential to type 1 diabetes development when expressed in NOD mice, but not other strains. In this study, we show that interactive non-MHC genes allow a NOD-derived diabetogenic CD8 T cell clonotype (AI4) to be negatively selected at far greater efficiency in C57BL/6 mice congenically expressing H2g7 (B6.H2g7). However, the few AI4 T cells escaping negative selection in B6.H2g7 mice are exported from the thymus more efficiently, and are more functionally aggressive than those of NOD origin. This provides mechanistic insight to previous findings that resistant mouse strains carry some genes conferring greater diabetes susceptibility than the corresponding NOD allele. In the B6.H2g7 stock, non-MHC gene-controlled elevations in TCR expression are associated with both enhanced negative selection of diabetogenic CD8 T cells and increased aggressiveness of those escaping this process. An implication of this finding is that the same phenotype, in this case relatively high TCR expression levels, could have double-edged sword effects, contributing to type 1 diabetes resistance at one level of T cell development, but at another actually promoting pathogenesis.

  13. Understanding Aggression.

    ERIC Educational Resources Information Center

    Scott, J. P.

    Research in many fields of the social and biological sciences indicates that there are ecological, cultural, social, psychological, physiological, and genetic causes of aggression. The agonistic behavior system, which adapts to situations of social conflict, includes several patterns of conduct ranging from overt fighting to complete passivity. In…

  14. Clustering of T cell ligands on artificial APC membranes influences T cell activation and protein kinase C theta translocation to the T cell plasma membrane.

    PubMed

    Giannoni, Francesca; Barnett, Joellen; Bi, Kun; Samodal, Rodrigo; Lanza, Paola; Marchese, Patrizia; Billetta, Rosario; Vita, Randi; Klein, Mark R; Prakken, Berent; Kwok, William W; Sercarz, Eli; Altman, Amnon; Albani, Salvatore

    2005-03-15

    T cell activation is associated with active clustering of relevant molecules in membrane microdomains defined as the supramolecular activation cluster. The contact area between these regions on the surface of T cells and APC is defined as the immunological synapse. It has been recently shown that preclustering of MHC-peptide complexes in membrane microdomains on the APC surface affects the efficiency of immune synapse formation and the related T cell activation. Disruption of such clusters may reduce the efficiency of stimulation. We describe here an entirely artificial system for Ag-specific, ex vivo stimulation of human polyclonal T cells (artificial APC (aAPC)). aAPC are based on artificial membrane bilayers containing discrete membrane microdomains encompassing T cell ligands (i.e., appropriate MHC-peptide complexes in association with costimulatory molecules). We show here that preclustering of T cell ligands triggered a degree of T cell activation significantly higher than the one achieved when we used either soluble tetramers or aAPC in which MHC-peptide complexes were uniformly distributed within artificial bilayer membranes. This increased efficiency in stimulation was mirrored by increased translocation from the cytoplasm to the membrane of protein kinase theta, a T cell signaling molecule that colocalizes with the TCR within the supramolecular activation cluster, thus indicating efficient engagement of T cell activation pathways. Engineered aAPC may have immediate application for basic and clinical immunology studies pertaining to modulation of T cells ex vivo.

  15. Transcriptional regulator Id2 mediates CD8+ T cell immunity.

    PubMed

    Cannarile, Michael A; Lind, Nicholas A; Rivera, Richard; Sheridan, Alison D; Camfield, Kristin A; Wu, Bei Bei; Cheung, Kitty P; Ding, Zhaoqing; Goldrath, Ananda W

    2006-12-01

    Transcriptional programs that initiate and sustain the proliferation, differentiation and survival of CD8(+) T cells during immune responses are not completely understood. Here we show that inhibitor of DNA binding 2 (Id2), an antagonist of E protein transcription factors, was upregulated in CD8(+) T cells during infection and that expression of Id2 was maintained in memory CD8(+) T cells. Although Id2-deficient naive CD8(+) T cells recognized antigen and proliferated normally early after infection, effector CD8(+) T cells did not accumulate because the cells were highly susceptible to apoptosis. Id2-deficient CD8(+) T cells responding to infection had changes in the expression of genes that influence survival and had altered memory formation. Our data emphasize the importance of Id2 in regulating gene expression by CD8(+) T cells and the magnitude of effector responses, suggesting a mechanism involving Id protein- and E protein-mediated survival and differentiation of mature T cells.

  16. Cytokines and T-Cell Homeostasis in HIV Infection.

    PubMed

    Freeman, Michael L; Shive, Carey L; Nguyen, Thao P; Younes, Souheil-Antoine; Panigrahi, Soumya; Lederman, Michael M

    2016-10-01

    Untreated human immunodeficiency virus (HIV) infection is characterized by progressive CD4(+) T-cell depletion and CD8(+) T-cell expansion, and CD4(+) T-cell depletion is linked directly to the risk for opportunistic infections and infection-associated mortality. With suppression of HIV replication by antiretroviral therapy, circulating CD4(+) Tcell numbers typically improve while CD8(+) T-cell expansion persists, and both CD4(+) T-cell cytopenia and CD8(+) T-cell expansion are associated with morbidity and mortality. In this brief review, we report on the role that selected homeostatic and inflammatory cytokines may play both in the failure of CD4(+) T-cell restoration and the CD8(+) T-cell expansion that characterize HIV infection. PMID:27625431

  17. Advances in T-cell therapy for ALL

    PubMed Central

    Grupp, Stephan A.

    2014-01-01

    CD19-directed chimeric antigen receptor T cells (CART19 or CTL019) have been used with success in pediatric and adult acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL) patients. While this therapy has caused toxicities, including cytokine release syndrome and macrophage activation syndrome, these conditions are reversible with IL-6 blockade using the monoclonal antibody tocilizumab. Furthermore, 90% of the very high-risk patients who underwent infusion with CTL019 achieved a complete response, despite the fact that they previously failed multiple therapies and/or transplant. With improved cell persistence, this immunotherapy may one day prove to be more than a bridge to transplant and may in fact be a transplant alternative. PMID:25455270

  18. Regulatory T cells: balancing protection versus pathology.

    PubMed

    Rakebrandt, Nikolas; Littringer, Katharina; Joller, Nicole

    2016-01-01

    Foxp3+ regulatory T cells (Tregs) maintain immune tolerance, prevent autoimmunity and modulate immune responses during infection and cancer. Recent studies have revealed considerable heterogeneity and plasticity within the Treg compartment, depending on the immunological context, which may result in Tregs losing their suppressive function in inflammatory environments. We review how dysfunctional Tregs contribute to disease pathogenesis in inflammatory conditions and how inappropriate regulatory responses may hamper protective immunity in the context of infection and cancer. We also discuss how Tregs might be targeted therapeutically to re-establish a proper balance between regulatory and effector responses in autoimmunity, infections, and cancer. PMID:27497235

  19. [Angiogenesis and lymphangiogenesis in primary cutaneous T-cell lymphomas].

    PubMed

    Jankowska-Konsur, Alina; Kobierzycki, Christopher; Dzięgiel, Piotr

    2015-01-01

    Primary cutaneous T-cell lymphomas are a group of rare hematologic malignancies, derived from mature T lymphocytes and initially developing only in the skin. The most common lymphomas representing this group are mycosis fungoides and Sezary syndrome. Mycosis fungoides is an indolent disease with a chronic course and characteristic evolution of the skin lesions from erythematous patches, through plaques to tumors. Sezary syndrome is characterized by an aggressive course and a triad of symptoms (erythroderma, generalized lymphadenopathy, and the presence of atypical cells in the skin, lymph nodes and peripheral blood). The etiopathogenesis of cutaneous lymphomas is not fully understood, but a few studies on angiogenesis and lymphangiogenesis in these malignancies indicate a significant role in their development and progression. Angiogenesis is a process of formation of new blood vessels from existing ones. Lymphangiogenesis is a similar process concerning lymphatic vasculature. Development of new vessels is a complex process composed of several successive stages: migration, proliferation, and differentiation of endothelial cells, extracellular matrix degradation and formation and stabilization of new vessels, regulated by growth factors, cytokines and other proteins. Both phenomena are essential in the development and progression of solid tumors and hematological malignancies. Therapeutic strategies involving the inhibition of tumor angiogenesis and lymphangiogenesis are a promising new direction of studies in antitumor therapy, requiring further experiments. PMID:26561847

  20. Foxp3+ T cells inhibit antitumor immune memory modulated by mTOR inhibition.

    PubMed

    Wang, Yanping; Sparwasser, Tim; Figlin, Robert; Kim, Hyung L

    2014-04-15

    Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3(+) T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3(+) T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients.

  1. Neurotropic Gamma-Delta T-Cell Lymphoma With CD30-Positive Lymphoid Infiltrates.

    PubMed

    Gammon, Bryan; Gammon, Benjamin R; Kim, Youn H; Kim, Jinah

    2016-09-01

    Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a clonal proliferation of gamma-delta T cells with a cytotoxic phenotype that is typically characterized by an aggressive clinical course with ulcerative plaques or subcutaneous nodules. In this report, the authors describe a patient who developed an ulcerated tumor on the left upper extremity and painful papules and nodules on the right lower extremity. Interestingly, several of the papulonodules on the right lower extremity underwent spontaneous involution. A skin biopsy of the papulonodular lesion demonstrated a superficial and deep perivascular interstitial infiltrate with a population of pleomorphic enlarged CD30-positive T cells. These enlarged lymphocytes lacked expression of TCR beta, CD4, CD8, and the pan T-cell antigen CD7, but were positive for TCR gamma, supporting the diagnosis of PCGD-TCL. The patient rapidly developed pain and severe weakness in the left upper limb and MRI revealed extensive neurolymphomatosis of the left brachial plexus. The patient was treated with chemotherapy with complete remission achieved. Unfortunately, her response was transient and the patient relapsed and ultimately died due to her disease. In this article, the authors describe an extraordinary case of a CD30-positive PCGD-TCL to expand the histopathological spectrum of CD30-positive and gamma-delta-positive lymphoproliferative disorders. PMID:27391454

  2. TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

    PubMed Central

    Kotsiou, Eleni; Okosun, Jessica; Besley, Caroline; Iqbal, Sameena; Matthews, Janet; Fitzgibbon, Jude; Gribben, John G.

    2016-01-01

    Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. PMID:27103745

  3. Effector and Central Memory Poly-Functional CD4+ and CD8+ T Cells are Boosted upon ZOSTAVAX® Vaccination

    PubMed Central

    Sei, Janet J.; Cox, Kara S.; Dubey, Sheri A.; Antonello, Joseph M.; Krah, David L.; Casimiro, Danilo R.; Vora, Kalpit A.

    2015-01-01

    ZOSTAVAX® is a live attenuated varicella-zoster virus (VZV) vaccine that is licensed for the protection of individuals ≥50 years against shingles and its most common complication, postherpetic neuralgia. While IFNγ responses increase upon vaccination, the quality of the T cell response has not been elucidated. By using polychromatic flow cytometry, we characterized the breadth, magnitude, and quality of ex vivo CD4+ and CD8+ T cell responses induced 3–4 weeks after ZOSTAVAX vaccination of healthy adults. We show, for the first time that the highest frequencies of VZV-specific CD4+ T cells were poly-functional CD154+IFNγ+IL-2+TNFα+ cells, which were boosted upon vaccination. The CD4+ T cells were broadly reactive to several VZV proteins, with immediate early (IE) 63 ranking the highest among them in the fold rise of poly-functional cells, followed by IE62, gB, open reading frame (ORF) 9, and gE. We identified a novel poly-functional ORF9-specific CD8+ T cell population in 62% of the subjects, and these were boosted upon vaccination. Poly-functional CD4+ and CD8+ T cells produced significantly higher levels of IFNγ, IL-2, and TNFα compared to mono-functional cells. After vaccination, a boost in the expression of IFNγ by poly-functional IE63- and ORF9-specific CD4+ T cells and IFNγ, IL-2, and TNFα by ORF9-specific poly-functional CD8+ T cells was observed. Responding poly-functional T cells exhibited both effector (CCR7−CD45RA−CD45RO+), and central (CCR7+CD45RA−CD45RO+) memory phenotypes, which expressed comparable levels of cytokines. Altogether, our studies demonstrate that a boost in memory poly-functional CD4+ T cells and ORF9-specific CD8+ T cells may contribute toward ZOSTAVAX efficacy. PMID:26579128

  4. CD4+CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses

    PubMed Central

    Wing, Kajsa; Larsson, Pia; Sandström, Kerstin; Lundin, Samuel B; Suri-Payer, Elisabeth; Rudin, Anna

    2005-01-01

    Activation of self-reactive T cells in healthy adults is prevented by the presence of autoantigen-specific CD4+CD25+ regulatory T cells (CD25+ Treg). To explore the functional development of autoantigen-reactive CD25+ Treg in humans we investigated if thymic CD25+ Treg from children aged 2 months to 11 years and cord blood CD25+ Treg are able to suppress proliferation and cytokine production induced by specific antigens. While CD4+CD25− thymocytes proliferated in response to myelin oligodendrocyte glycoprotein (MOG), tetanus toxoid and beta-lactoglobulin, suppression of proliferation was not detected after the addition of thymic CD25+ Treg. However, CD25+ Treg inhibited interferon (IFN)-γ production induced by MOG, which indicates that MOG-reactive CD25+ Treg are present in the thymus. In contrast, cord blood CD25+ Treg suppressed both proliferation and cytokine production induced by MOG. Both cord blood and thymic CD25+ Treg expressed FOXP3 mRNA. However, FOXP3 expression was lower in cord blood than in thymic CD25+ T cells. Further characterization of cord blood CD25+ T cells revealed that FOXP3 was highly expressed by CD25+CD45RA+ cells while CD25+CD45RA− cells contained twofold less FOXP3, which may explain the lower expression level of FOXP3 in cord blood CD25+ T cells compared to thymic CD25+ T cells. In conclusion, our data demonstrate that low numbers of MOG-reactive functional CD25+ Treg are present in normal thymus, but that the suppressive ability of the cells is broader in cord blood. This suggests that the CD25+ Treg may be further matured in the periphery after being exported from the thymus. PMID:16011520

  5. Antiapoptotic Role for Lifeguard in T Cell Mediated Immune Response

    PubMed Central

    Verma, Inder M.

    2015-01-01

    Anti-apoptotic protein Lifeguard (LFG) is upregulated on T cells upon in vitro activation. To investigate its role in T cell immunity we infected wild type and LFG knockout bone marrow chimaeras mice with LCMV. We observed a decreased number of LFG KO activated CD8 and CD4 T cells throughout the infection and a marked decrease in LFG KO LCMV specific memory T cells. WT and KO T cells proliferated at the same rate, however, LFG KO CD44hi T cells showed increased cell death during the initial phase of the immune response. LFG KO and WT T cells were equally sensitive to the FAS antibody Jo-2 in ex vivo cultures, and blocking extrinsic pathways of cell death in vivo with Fas L or caspase 8 inhibitors did not rescue the increased apoptosis in LFG KO T cells. Our data suggest that LFG plays a role in T cell survival during the initial phase of anti-viral immune response by protecting pre-existing memory T cells and possibly newly activated T cells resulting in a diminished immune response and a decreased number of LCMV specific memory T cells. PMID:26565411

  6. Differential Responses of Human Regulatory T Cells (Treg) and Effector T Cells to Rapamycin

    PubMed Central

    Strauss, Laura; Czystowska, Malgorzata; Szajnik, Marta; Mandapathil, Magis; Whiteside, Theresa L.

    2009-01-01

    Background The immunosuppressive drug rapamycin (RAPA) promotes the expansion of CD4+ CD25highFoxp3+ regulatory T cells via mechanisms that remain unknown. Here, we studied expansion, IL-2R-γ chain signaling, survival pathways and resistance to apoptosis in human Treg responding to RAPA. Methodology/Principal Findings CD4+CD25+ and CD4+CD25neg T cells were isolated from PBMC of normal controls (n = 21) using AutoMACS. These T cell subsets were cultured in the presence of anti-CD3/CD28 antibodies and 1000 IU/mL IL-2 for 3 to 6 weeks. RAPA (1–100 nM) was added to half of the cultures. After harvest, the cell phenotype, signaling via the PI3K/mTOR and STAT pathways, expression of survival proteins and Annexin V binding were determined and compared to values obtained with freshly-separated CD4+CD25high and CD4+CD25neg T cells. Suppressor function was tested in co-cultures with autologous CFSE-labeled CD4+CD25neg or CD8+CD25neg T-cell responders. The frequency and suppressor activity of Treg were increased after culture of CD4+CD25+ T cells in the presence of 1–100 nM RAPA (p<0.001). RAPA-expanded Treg were largely CD4+CD25highFoxp3+ cells and were resistant to apoptosis, while CD4+CD25neg T cells were sensitive. Only Treg upregulated anti-apoptotic and down-regulated pro-apoptotic proteins. Treg expressed higher levels of the PTEN protein than CD4+CD25neg cells. Activated Treg±RAPA preferentially phosphorylated STAT5 and STAT3 and did not utilize the PI3K/mTOR pathway. Conclusions/Significance RAPA favors Treg expansion and survival by differentially regulating signaling, proliferation and sensitivity to apoptosis of human effector T cells and Treg after TCR/IL-2 activation. PMID:19543393

  7. Primary central nervous system T-cell lymphoma in a common dolphin (Delphinus delphis).

    PubMed

    Arbelo, M; Espinosa de los Monteros, A; Herráez, P; Suárez-Bonnet, A; Andrada, M; Rivero, M; Grau-Bassas, E R; Fernández, A

    2014-01-01

    This report describes the pathological findings in an adult female short-beaked common dolphin (Delphinus delphis) stranded alive in the Canary Islands. Necropsy examination revealed the presence of a nodular neoplastic growth in the central nervous system (CNS) at the level of the thalamus. Microscopical examination revealed the mass to be a lymphoma and immunohistochemical labelling demonstrated a T-cell origin. No significant lesions were observed in other organs, including lymphoid organs. This is the first report of a primary T-cell lymphoma in the CNS in cetaceans. PMID:24650893

  8. Clinical experience in T cell deficient patients

    PubMed Central

    2010-01-01

    T cell disorders have been poorly understood until recently. Lack of knowledge of underlying molecular mechanisms together with incomplete data on long term outcome have made it difficult to assess prognosis and give the most effective treatment. Rapid progress in defining molecular defects, improved supportive care and much improved results from hematopoietic stem cell transplantation (HSCT) now mean that curative treatment is possible for many patients. However, this depends on prompt recognition, accurate diagnosis and careful treatment planning. This review will discuss recent progress in our clinical and molecular understanding of a variety of disorders including: severe combined immunodeficiency, specific T cell immunodeficiencies, signaling defects, DNA repair defects, immune-osseous dysplasias, thymic disorders and abnormalities of apoptosis. There is still much to discover in this area and some conditions which are as yet very poorly understood. However, with increased knowledge about how these disorders can present and the particular problems each group may face it is hoped that these patients can be recognized early and managed appropriately, so providing them with the best possible outcome. PMID:20465788

  9. Elevated T cell subpopulations in dental students

    SciTech Connect

    Eedy, D.J.; Burrows, D.; Clifford, T.; Fay, A. )

    1990-05-01

    The absolute numbers of circulating white cells and lymphocyte subpopulations were studied in 25 final-year dental students and compared with a control group of 28 medical students. The total lymphocyte count, total T cell numbers (CD3), T helper/inducer (CD4), and T suppressor/cytotoxic (CD8) numbers were significantly elevated in the dental students as compared with the control group. There was no significant difference in the T helper/inducer to T suppressor/cytotoxic cell ratios or the circulating B cell (CD21) and natural killer cell (CD16) numbers between the study and control groups. Patch testing to mercury and mercuric compounds in both the study and control groups showed no evidence of cutaneous hypersensitivity to mercury. The reason for the observed elevations in T cell subpopulations in dental students is not clear. However, one possible explanation is the dental student's occupational exposure to mercury. Further work is underway to examine this possible relationship and it is suggested that dental personnel take adequate measures to reduce their exposure to mercury until the results of these studies are available.

  10. Co-infection with Mycobacterium tuberculosis impairs HIV-Specific CD8+ and CD4+ T cell functionality.

    PubMed

    Chetty, Shivan; Govender, Pamla; Zupkosky, Jennifer; Pillay, Mona; Ghebremichael, Musie; Moosa, Mahomed-Yunus S; Ndung'u, Thumbi; Porichis, Filippos; Kasprowicz, Victoria O

    2015-01-01

    The ability of antigen-specific T cells to simultaneously produce multiple cytokines is thought to correlate with the functional capacity and efficacy of T cells. These 'polyfunctional' T cells have been associated with control of HIV. We aimed to assess the impact of co-infection with Mycobacterium tuberculosis (MTB) on HIV-specific CD8+ and CD4+ T cell function. We assessed T cell functionality in 34 South African adults by investigating the IFN-y, IL-2, TNF-α, IL-21 and IL-17 cytokine secretion capacity, using polychromatic flow cytometry, following HIV Gag-specific stimulation of peripheral blood mononuclear cells. We show that MTB is associated with lower HIV-specific T cell function in co-infected as compared to HIV mono-infected individuals. This decline in function was greatest in co-infection with active Tuberculosis (TB) compared to co-infection with latent MTB (LTBI), suggesting that mycobacterial load may contribute to this loss of function. The described impact of MTB on HIV-specific T cell function may be a mechanism for increased HIV disease progression in co-infected subjects as functionally impaired T cells may be less able to control HIV.

  11. Primary and secondary T-cell lymphomas of the breast: clinico-pathologic features of 11 cases.

    PubMed

    Gualco, Gabriela; Chioato, Lucimara; Harrington, William J; Weiss, Lawrence M; Bacchi, Carlos E

    2009-07-01

    Breast involvement by non-Hodgkin lymphomas is rare, and exceptional for T-cell lymphomas; we studied the morphologic, immunophenotypic, and clinical features of 11 patients with T-cell non-Hodgkin lymphomas involving the breast. Four cases fulfilled the definition criteria for primary breast lymphomas, 3 females and 1 male, with a median age of 51 years. One primary breast lymphomas was T-cell lymphoma unspecified, other was subcutaneous panniculitis-like T-cell lymphoma, and 2 cases were anaplastic large cell lymphomas. One of the anaplastic large cell lymphoma cases was found surrounding a silicone breast implant and presented as clinically as mastitis; whereas the other case occurred in a man. T-cell lymphoma secondarily involved the breast in 7 patients, all women and 1 bilateral, with a median age of 29 years. These secondary breast lymphomas occurred as part of widespread nodal or leukemic disease. Three patients had adult T-cell leukemia/lymphoma, including the patient with bilateral lesions, 3 others had precursor T-lymphoblastic lymphoma/leukemia, and the other presented with a peripheral-T-cell lymphoma non otherwise specified type. Breast T-cell lymphomas are very infrequent and are morphologically and clinically heterogeneous.

  12. Intergenerational Transmission of Relationship Aggression: A Prospective Longitudinal Study

    PubMed Central

    Cui, Ming; Durtschi, Jared A.; Donnellan, M. Brent; Lorenz, Frederick O.; Conger, Rand D.

    2012-01-01

    The present study examined whether physical and verbal aggression in the family of origin were associated with similar patterns of aggression in young adult couples. Hypotheses were tested using a sample of 213 focal individuals who were followed from adolescence to adulthood. Results suggested that aggression in the family when focal participants were adolescents predicted aggression with romantic partners when participants were adults. The association between interparental aggression and later aggression in adult romantic unions was partially mediated through parents’ aggression to focal participants when they were adolescents. Both physical and verbal aggression revealed the same pattern of findings. All together, these findings are consistent with a developmental-interactional perspective (Capaldi & Gorman-Smith, 2003) concerning the developmental origins of aggression in intimate relationships. PMID:21171767

  13. An update on the management of peripheral T-cell lymphoma and emerging treatment options

    PubMed Central

    Phillips, Adrienne A; Owens, Colette; Lee, Sangmin; Bhagat, Govind

    2011-01-01

    Peripheral T-cell lymphomas (PTCLs) comprise a rare and heterogeneous subset of non-Hodgkin’s lymphomas (NHLs) that arise from post-thymic T-cells or natural killer (NK)-cells at nodal or extranodal sites. Worldwide, PTCLs represent approximately 12% of all NHLs and the 2008 World Health Organization (WHO) classification includes over 20 biologically and clinically distinct T/NK-cell neoplasms that differ significantly in presentation, pathology, and response to therapy. Because of the rarity and heterogeneity of these diseases, large clinical trials have not been conducted and optimal therapy is not well defined. Most subtypes are treated with similar combination chemotherapy regimens as used for aggressive B-cell NHL, but with poorer outcomes. New treatment combinations and novel agents are currently being explored for PTCLs and this review highlights a number of options that appear promising. PMID:22287871

  14. Aggression on inpatient units: Clinical characteristics and consequences.

    PubMed

    Renwick, Laoise; Stewart, Duncan; Richardson, Michelle; Lavelle, Mary; James, Karen; Hardy, Claire; Price, Owen; Bowers, Len

    2016-08-01

    Aggression and violence are widespread in UK Mental Health Trusts, and are accompanied by negative psychological and physiological consequences for both staff and other patients. Patients who are younger, male, and have a history of substance use and psychosis diagnoses are more likely to display aggression; however, patient factors are not solely responsible for violence, and there are complex circumstances that lead to aggression. Indeed, patient-staff interactions lead to a sizeable portion of aggression and violence on inpatient units, thus they cannot be viewed without considering other forms of conflict and containment that occur before, during, and after the aggressive incident. For this reason, we examined sequences of aggressive incidents in conjunction with other conflict and containment methods used to explore whether there were particular profiles to aggressive incidents. In the present study, 522 adult psychiatric inpatients from 84 acute wards were recruited, and there were 1422 incidents of aggression (verbal, physical against objects, and physical). Cluster analysis revealed that aggressive incident sequences could be classified into four separate groups: solo aggression, aggression-rule breaking, aggression-medication, and aggression-containment. Contrary to our expectations, we did not find physical aggression dominant in the aggression-containment cluster, and while verbal aggression occurred primarily in solo aggression, physical aggression also occurred here. This indicates that the management of aggression is variable, and although some patient factors are linked with different clusters, these do not entirely explain the variation.

  15. Aggression on inpatient units: Clinical characteristics and consequences.

    PubMed

    Renwick, Laoise; Stewart, Duncan; Richardson, Michelle; Lavelle, Mary; James, Karen; Hardy, Claire; Price, Owen; Bowers, Len

    2016-08-01

    Aggression and violence are widespread in UK Mental Health Trusts, and are accompanied by negative psychological and physiological consequences for both staff and other patients. Patients who are younger, male, and have a history of substance use and psychosis diagnoses are more likely to display aggression; however, patient factors are not solely responsible for violence, and there are complex circumstances that lead to aggression. Indeed, patient-staff interactions lead to a sizeable portion of aggression and violence on inpatient units, thus they cannot be viewed without considering other forms of conflict and containment that occur before, during, and after the aggressive incident. For this reason, we examined sequences of aggressive incidents in conjunction with other conflict and containment methods used to explore whether there were particular profiles to aggressive incidents. In the present study, 522 adult psychiatric inpatients from 84 acute wards were recruited, and there were 1422 incidents of aggression (verbal, physical against objects, and physical). Cluster analysis revealed that aggressive incident sequences could be classified into four separate groups: solo aggression, aggression-rule breaking, aggression-medication, and aggression-containment. Contrary to our expectations, we did not find physical aggression dominant in the aggression-containment cluster, and while verbal aggression occurred primarily in solo aggression, physical aggression also occurred here. This indicates that the management of aggression is variable, and although some patient factors are linked with different clusters, these do not entirely explain the variation. PMID:26892149

  16. Auto-reactive T cells revised. Overestimation based on methodology?

    PubMed

    Thorlacius-Ussing, Gorm; Sørensen, Jesper F; Wandall, Hans H; Pedersen, Anders Elm

    2015-05-01

    Autoreactive T cells have been identified in most autoimmune diseases and recently even in healthy individuals. Similar, T cells that recognize either wild-type or tumorspecific tumor antigens have been increasingly reported to develop spontaneously in cancer patients. This insight has become possible mainly due to novel immunoassays which have revolutionized the discovery of rare antigen specific T cells. At present, the major dogma that explains this increasing number of reports of autoreactive T cells is that autoreactive T cells are counteracted by CD4+CD25+ regulatory T (Treg) cells in vivo, in particular in healthy individuals, whereas dysfunction in Tregs or Treg responsiveness may unmask the autoreactive T cell responses in patients with autoimmune diseases. However, studies that identify autoreactive T cells are usually performed by culturing T cells with antigen presenting cells loaded with E. coli produced recombinant protein or unmodified synthetic HLA binding peptides. Our concern is that this approach may ignore the presence of natural genetic variation and post-translational modifications such as e.g. the complex nature of N- and O-linked glycosylation of mammalian proteins. Thus, T cell antigen reactivities identified with unmodified antigens in vitro may in part represent in vitro T cell activation against neo-epitopes and not true in vivo autoreactivity as postulated. This methodological problem may have implications for the interpretation of the frequent reporting of autoreactive T cells in autoimmunity, T cell responses to wild-type tumor antigens in cancer patients and most important for the increasing reports on naïve T cells with specificity against self-antigens in healthy individuals. Here, we discuss and provide examples for the possibility that the experimental methodology applied to document T cell reactivity against unmodified protein or peptide may lead to overinterpretation of the reported frequencies of autoreactive CD4+ and CD8+ T

  17. The Social Information Processing Model as a Framework for Explaining Frequent Aggression in Adults with Mild to Moderate Intellectual Disabilities: A Systematic Review of the Evidence

    ERIC Educational Resources Information Center

    Larkin, Peter; Jahoda, Andrew; MacMahon, Ken

    2013-01-01

    Background: There is an established evidence base concerning the use of anger management interventions with violent offenders who have intellectual disabilities. However, there has been limited research investigating the role of social cognitive factors underpinning problems of aggression. Psychosocial sources of aggression in the non-disabled…

  18. Comparison of a Cognitive Re-Appraisal Approach and a Problem-Solving Approach to Improve Social Cognition in Adults with Intellectual Disabilities Who Exhibit Aggressive Behavior

    ERIC Educational Resources Information Center

    Collado-Castillo, Carmen J.

    2010-01-01

    It has been established in the literature that aggressive behaviors in individuals with intellectual disabilities (ID) represents a high percentage of referrals to mental health services (Davidson, Cain, Sloane-Reeves, Speybroech, Segel, et al., 1994). The results of several studies conducted with children with ID and aggressive behaviors indicate…

  19. Indolent Small Intestinal CD4+ T-cell Lymphoma Is a Distinct Entity with Unique Biologic and Clinical Features

    PubMed Central

    Margolskee, Elizabeth; Jobanputra, Vaidehi; Lewis, Suzanne K.; Alobeid, Bachir; Green, Peter H. R.; Bhagat, Govind

    2013-01-01

    Enteropathy-associated T-cell lymphomas (EATL) are rare and generally aggressive types of peripheral T-cell lymphomas. Rare cases of primary, small intestinal CD4+ T-cell lymphomas with indolent behavior have been described, but are not well characterized. We describe morphologic, phenotypic, genomic and clinical features of 3 cases of indolent primary small intestinal CD4+ T-cell lymphomas. All patients presented with diarrhea and weight loss and were diagnosed with celiac disease refractory to a gluten free diet at referring institutions. Small intestinal biopsies showed crypt hyperplasia, villous atrophy and a dense lamina propria infiltrate of small-sized CD4+ T-cells often with CD7 downregulation or loss. Gastric and colonic involvement was also detected (n = 2 each). Persistent, clonal TCRβ gene rearrangement products were detected at multiple sites. SNP array analysis showed relative genomic stability, early in disease course, and non-recurrent genetic abnormalities, but complex changes were seen at disease transformation (n = 1). Two patients are alive with persistent disease (4.6 and 2.5 years post-diagnosis), despite immunomodulatory therapy; one died due to bowel perforation related to large cell transformation 11 years post-diagnosis. Unique pathobiologic features warrant designation of indolent small intestinal CD4+ T-cell lymphoma as a distinct entity, greater awareness of which would avoid misdiagnosis as EATL or an inflammatory disorder, especially celiac disease. PMID:23861889

  20. The potential of human regulatory T cells generated ex vivo as a treatment for lupus and other chronic inflammatory diseases

    PubMed Central

    Horwitz, David A; Gray, J Dixon; Zheng, Song Guo

    2002-01-01

    Regulatory T cells prevent autoimmunity by suppressing the reactivity of potentially aggressive self-reactive T cells. Contact-dependent CD4+ CD25+ 'professional' suppressor cells and other cytokine-producing CD4+ and CD8+ T-cell subsets mediate this protective function. Evidence will be reviewed that T cells primed with transforming growth factor (TGF)-β expand rapidly following restimulation. Certain CD4+ T cells become contact-dependent suppressor cells and other CD4+ and CD8+ cells become cytokine-producing regulatory cells. This effect is dependent upon a sufficient amount of IL-2 in the microenvironment to overcome the suppressive effects of TGF-β. The adoptive transfer of these suppressor cells generated ex vivo can protect mice from developing chronic graft-versus-host disease with a lupus-like syndrome and alter the course of established disease. These data suggest that autologous T cells primed and expanded with TGF-β have the potential to be used as a therapy for patients with systemic lupus erythematosus and other chronic inflammatory diseases. This novel adoptive immunotherapy also has the potential to prevent the rejection of allogeneic transplants. PMID:12106494

  1. High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity.

    PubMed

    Lynn, R C; Feng, Y; Schutsky, K; Poussin, M; Kalota, A; Dimitrov, D S; Powell, D J

    2016-06-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here we isolated a high-affinity (HA) folate receptor beta (FRβ)-specific single-chain variable fragment (2.48 nm KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ(+) AML in vitro and in vivo compared with a low-affinity FRβ CAR (54.3 nm KD). Using the HA-FRβ immunoglobulin G, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34(+) hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T cells lysed mature CD14(+) monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T cells retained effective antitumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T cells is highly effective against AML and reduces the risk for long-term myeloid toxicity.

  2. Environmental and Metabolic Sensors That Control T Cell Biology

    PubMed Central

    Ramsay, George; Cantrell, Doreen

    2015-01-01

    The T lymphocyte response to pathogens is shaped by the microenvironment. Environmental sensors in T cells include the nutrient-sensing serine/threonine kinases, adenosine monophosphate-activated protein kinase and mammalian target of rapamycin complex 1. Other environmental sensors are transcription factors such as hypoxia-inducible factor-1 and the aryl hydrocarbon receptor. The present review explores the molecular basis for the impact of environmental signals on the differentiation of conventional T cell receptor αβ T cells and how the T cell response to immune stimuli can coordinate the T cell response to environmental cues. PMID:25852681

  3. Apoptosis and T-cell depletion during feline infectious peritonitis.

    PubMed

    Haagmans, B L; Egberink, H F; Horzinek, M C

    1996-12-01

    Cats that have succumbed to feline infectious peritonitis, an immune-mediated disease caused by variants of feline coronaviruses, show apoptosis and T-cell depletion in their lymphoid organs. The ascitic fluid that develops in the course of the condition causes apoptosis in vitro but only in activated T cells. Since feline infectious