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CD4+ T Cell Proliferation (cd4+ t + cell_proliferation)
Selected AbstractsImpairment of dendritic cell function by excretory-secretory products: A potential mechanism for nematode-induced immunosuppressionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Mariela Segura Abstract To determine whether helminth-derived products modulate dendritic cell (DC) function, we investigated the effects of excretory-secretory products (ES) and adult worm homogenate (AWH) derived from the gastrointestinal nematode Heligmosomoides polygyrus (Hp) on murine bone marrow-derived DC (BMDC). Compared to the TLR9 ligand CpG, Hp-derived products alone failed to induce DC activation. ES, but not AWH, inhibited BMDC cytokine and chemokine production and co-stimulatory molecule expression (CD40, CD86 and MHC class,II) induced by TLR ligation. TLR ligand-independent, PMA-induced DC activation was unaffected by ES. Recipients of ES-treated BMDC pulsed with OVA had suppressed Ab responses in vivo, irrespective of the Th1 or Th2 isotype affiliation, compared to recipients of control OVA-pulsed BMDC. Importantly, suppression occurred even in the presence of the potent type,1 adjuvant CpG. In contrast to untreated OVA-pulsed BMDC, ES-treated BMDC pulsed with OVA had reduced co-stimulatory molecule and cytokine expression. CD4+CD25+Foxp3, T cells, which secreted high IL-10 levels, were generated in co-cultures of OT-II OVA-specific TCR-transgenic CD4+ T cells and ES-treated BMDC. These IL-10-secreting T cells suppressed effector CD4+ T cell proliferation and IFN-, production, the latter effect mediated by an IL-10-dependent mechanism. Together, these results demonstrate that nematode ES impaired DC function and suppressed both Th1 and Th2 adaptive immune responses possibly by inducing regulatory T cells. [source] Patients with Epstein Barr virus-positive lymphomas have decreased CD4+ T-cell responses to the viral nuclear antigen 1INTERNATIONAL JOURNAL OF CANCER, Issue 12 2008Kevin N. Heller Abstract Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4+ T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4+ T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN, expression and proliferation by CD4+ T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8+ T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4+ T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies. © 2008 Wiley-Liss, Inc. [source] In-vitro and in-vivo immunomodulatory effects of syringinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2001Jae Youl Cho Syringin was found to possess immunomodulatory activity by which it inhibited the in-vitro immunohaemolysis of antibody-coated sheep erythrocytes by guinea-pig serum through suppression of C3-convertase of the classical complement. In this study, we examined its in-vitro and in-vivo activity on tumour necrosis factor (TNF)-, and nitric oxide (NO) production, CD4 + T cell and CD8+ cytotoxic T cell (CTLL-2) proliferation, and croton oil-, arachidonic acid- and fluorescein-isothiocynate (FITC)-induced mouse ear oedema model. Syringin significantly inhibited both TNF-, production from lipopolysaccharide (LPS)-stimulated RAW264.7 cells and CD8+ T cell (CTLL-2) proliferation in a dose-dependent manner, whereas neither NO production nor CD4+ T cell proliferation were blocked even by high concentrations of syringin. In the in-vivo experiments, syringin also significantly suppressed FITC-induced ear oedema in mice but not the ear oedema induced by croton or arachidonic acid. These results suggest that syringin may be implicated as an immunomodulator having an anti-allergic effect rather than an antiinflammatory effect. The anti-allergic effect of syringin seems to be due, in part, to inhibition of TNF-, production and cytotoxic T cell proliferation. [source] Overexpression of the growth arrest and DNA damage,induced 45, gene contributes to autoimmunity by promoting DNA demethylation in lupus T cellsARTHRITIS & RHEUMATISM, Issue 5 2010Yaping Li Objective Demethylation of CD11a and CD70 regulatory regions in CD4+ T cells contributes to the development of autoreactivity and overstimulation of autoantibodies. Because growth arrest and DNA damage,induced 45, (GADD45,) reduces epigenetic silencing of genes by removing methylation marks, this study examined whether the gadd45A gene could contribute to autoimmunity by promoting DNA demethylation in T cells from patients with systemic lupus erythematosus (SLE). Methods Levels of GADD45,, CD11a, and CD70 messenger RNA (mRNA) and protein were detected by real-time reverse transcription,polymerase chain reaction and Western blotting or flow cytometry. Global DNA methylation was evaluated using Methylamp global DNA methylation quantification kits. Detection of CD4+ T cell proliferation and autologous B cell IgG antibodies was performed using commercially available kits. CD11a and CD70 promoter methylation was determined with bisulfite sequencing. Results Elevated gadd45A mRNA expression and global DNA hypomethylation were observed in CD4+ T cells from SLE patients. The levels of gadd45A mRNA were inversely proportional to the levels of DNA methylation. Positive correlations were found between gadd45A and CD11a/CD70 mRNA levels. Expression of gadd45A mRNA was increased in CD4+ T cells following ultraviolet B irradiation, and this was accompanied by increased levels of CD11a and CD70 mRNA. Moreover, increased expression of gadd45A, CD11a, and CD70 mRNA was accompanied by increased autoreactivity and excessive B cell stimulation in gadd45A -transfected CD4+ T cells. CD11a promoter methylation was also significantly reduced in transfected cells. Transfection of gadd45A small interfering RNA inhibited the autoreactivity of SLE CD4+ T cells and led to significant increases in the methylation levels of the CD11a and CD70 promoter regions. Conclusion These findings indicate that gadd45A may contribute to lupus-like autoimmunity by promoting DNA demethylation in SLE CD4+ T cells. [source] ANTI-CD3 therapy expands the numbers of CD4+ and CD8+ treg cells and induces sustained amelioration of collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 1 2010Clare A. Notley Objective To assess the therapeutic potential of anti-CD3 monoclonal antibodies (mAb) for rheumatoid arthritis, using collagen-induced arthritis as an animal model. Methods Arthritis was induced in DBA/1 mice by immunization with type II collagen. After disease onset, a single injection of anti-CD3 mAb (20 ,g/mouse) was administered, and arthritis severity was monitored over a 10-day period. Results Anti-CD3 mAb treatment resulted in a sustained reduction in disease activity, which was associated with an increase in the proportion of naturally occurring CD4+CD25+FoxP3+ regulatory T (Treg) cells and the generation of a population of CD8+CD25+FoxP3+ Treg cells. Anti-CD3 mAb treatment did not alter the capacity of CD4+ Treg cells to suppress effector T cell proliferation and interferon-, (IFN,) production in vitro. However, CD4+ Treg cells from both anti-CD3 mAb,treated and control mice were unable to suppress interleukin-17 (IL-17) production. In contrast, CD8+ Treg cells induced by anti-CD3 therapy suppressed IL-17 production as well as CD4+ T cell proliferation and IFN, production. Conclusion These results show that anti-CD3 mAb treatment has important therapeutic potential for rheumatoid arthritis and has the capacity to generate antiarthritic CD8+ Treg cells and expand the relative numbers of CD4+ Treg cells. [source] Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomeraseARTHRITIS & RHEUMATISM, Issue 3 2008Keiichi Iwanami Objective To clarify the glucose-6-phosphate isomerase (GPI),specific CD4+ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease. Methods DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti,interferon-, (anti-IFN,) monoclonal antibody (mAb), anti,interleukin-17 (anti,IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester. Results GPI-specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti,IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFN, mAb exacerbated arthritis. Neither anti,IL-17 mAb nor anti-IFN, mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed. Conclusion IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti,IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase. [source] Pimecrolimus does not affect the differentiation, maturation and function of human monocyte-derived dendritic cells, in contrast to corticosteroidsCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2003F. S. KALTHOFF SUMMARY Clinically, corticosteroids (CS) are among the first line drugs in the therapy of autoimmune and allergic diseases and potently inhibit the activation of immune cells. However, due to their pleiotropic mode of action, the prolonged use of CS is generally associated with a range of undesirable side-effects. In this study, we compared the activity of pimecrolimus, a novel immunomodulatory drug for the treatment of inflammatory skin disorders, and the CS dexamethasone (Dex) and beta-methasone-valerate (, -MSV) in different in vitro assays addressing the cytokine-induced differentiation and maturation of monocyte-derived dendritic cells (M-DC), the susceptibility of M-DC to drug-induced apoptosis and the potency of differentiated M-DC to induce primary T cell activation. In contrast to pimecrolimus, Dex and , -MSV strongly induced apoptosis of M-DC precursors if added at the start of the DC differentiation culture. Flow cytometric analysis of surviving cells on day 6 of culture showed that the expression of several DC-specific antigens such as CD1a, CD40 and CD80 was inhibited by 50% to 80% at concentrations between 1 nm and 10 nm of either Dex or , -MSV. Furthermore, the presence of CS during the final maturation of M-DC inhibited the synthesis of IL-12p70, the expression of critical DC costimulatory molecules, such as CD83 and CD86 and impaired their ability to activate primary CD4+ T cell proliferation. In contrast, pimecrolimus did not inhibit the LPS-induced secretion of IL-12, surface expression of costimulatory molecules or the maturation of M-DC into potent stimulators of T cells. Taken together, these data indicate that pimecrolimus does not interfere with the differentiation and viability of dendritic cells and their precursors or with the function of mature M-DC to prime naïve T lymphocytes, and thus may have a lower potential than CS to interfere with DC-mediated immunosurveillance. [source] | ||||||||||