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Contains fulltext : 34781.pdf (publisher's version ) (Closed access)

Item does not contain fulltext, OBJECTIVE: Regulatory T cells play an important role in the prevention of autoimmunity and have been shown to be effective in the treatment of experimental colitis, a T cell-mediated and organ-specific disease. We previously demonstrated that intrinsic CD25+ regulatory T cells modulate the severity of collagen-induced arthritis (CIA), which, in contrast to colitis, is a systemic antibody-mediated disease and an accepted model of rheumatoid arthritis. We undertook this study to determine whether regulatory T cells have the potential to be used therapeutically in arthritis. METHODS: We transferred CD4+,CD25+ T cells into mice exhibiting arthritis symptoms, both immunocompetent mice and mice subjected to lethal irradiation and rescued with syngeneic bone marrow transplantation. RESULTS: A single transfer of regulatory T cells markedly slowed disease progression, which could not be attributed to losses of systemic type II collagen-specific T and B cell responses, since these remained unchanged after adoptive transfer. However, regulatory T cells could be found in the inflamed synovium soon after transfer, indicating that regulation may occur locally in the joint. CONCLUSION: Our data indicate that CD25+ regulatory T cells can be used for the treatment of systemic, antibody-mediated autoimmune diseases, such as CIA.

Contains fulltext : 48463.pdf (publisher's version ) (Closed access), Expression of the transcription factor Foxp3 (forkhead box P3) has been implicated as a key element for CD25(+) T regulatory cell function in mice. However, literature over similar involvement of FOXP3 expression in human T regulatory cells is limited. We found that, unlike murine cells, FOXP3 mRNA expression could be induced in human CD25(-) and CD8(+) peripheral blood mononuclear cells, which were both negative for FOXP3 mRNA expression after isolation. Expression of FOXP3 mRNA began as soon as 24-40 hours after stimulation, demonstrating a correlation between activation and FOXP3 mRNA expression in human cells. In order to determine whether FOXP3 expression is confined to CD4(+)CD25(+) T cells with a regulatory phenotype, we analyzed several well-defined T-cell clones and lines with various specificities. Surprisingly, expression of FOXP3 mRNA was detected in all clones and limited to the CD25(hi) populations. Nonetheless, the CD25(hi) fraction did not display regulatory properties because both the CD25(hi) and CD25(low) populations exhibited a similar proliferative- and interferon-gamma-secreting potential after antigenic stimulation. These results indicate that FOXP3 expression in humans, unlike mice, may not be specific for cells with a regulatory phenotype and may be only a consequence of activation status.

Item does not contain fulltext, In the last decade, CD4+CD25+ T regulatory cells have been implicated in the protection against autoimmune diseases. The human DQ8 major histocompatibility complex (MHC) class II molecule is associated with rheumatoid arthritis (RA) and various other autoimmune diseases in humans. The human leukocyte antigen (HLA)-DQ8 transgenic mouse, containing the human DQ8 MHC class II molecule, is predisposed toward collagen-induced arthritis. However, the biologic pathways responsible for DQ8-associated autoimmunity have yet to be defined, including possible defects in the CD4+CD25+ T regulatory cell compartment. To explore this concept, we examined the suppressive capacity of CD4+CD25+ T regulatory cells from DQ8 transgenic mice in vitro and, using CD25-specific depleting antibodies, investigated their influence on collagen-induced arthritis in vivo. CD4+CD25+ T regulatory cells isolated from DQ8 transgenic mice were found to be sufficient suppressors of splenocyte proliferation and interferon (INF)-gamma production. Furthermore, depletion of these cells before immunization led to significant increases in arthritis severity, collagen-specific antibodies, and INF-gamma production. These results indicate that HLA-DQ8 mice contain naturally occurring CD25+ regulatory cells that modulate collagen-induced arthritis and imply that DQ8 expression does not hinder the development of CD25+ T regulatory cells.

Contains fulltext : 58480.pdf (publisher's version ) (Closed access), Objective. The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). Methods. High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. Results. Carriership of the individual alleles HLA-DRBt*0401, DRB1*1001, DQB1*0302, and DQBI*0501 was associated with the presence of antiCCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (11 < 0.001). Conclusion. HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE al

Item does not contain fulltext, OBJECTIVE: CD4+,CD25+ T regulatory cells may offer opportunities to intervene in the course of autoimmune disease. We wished to evaluate their potential for influencing systemic and chronic joint inflammation by investigating their involvement in collagen-induced arthritis (CIA). METHODS: We depleted DBA/1 mice of CD25+ regulatory cells by injection of a depleting monoclonal antibody specific for CD25 14 days before a single immunization with type II collagen (CII) in Freund's complete adjuvant. CD4+,CD25+ T cells were adoptively transferred to some groups of mice during immunization. Mice were then scored for signs of arthritis, and blood was taken periodically to measure the amounts of CII-specific antibodies. Splenocytes of treated mice were examined in vitro to determine the effects of depletion on proliferation to CII and control antigens. RESULTS: CD25+ cell-depleted DBA/1 mice had significantly more severe disease than control mice following collagen immunization. The magnified severity was also accompanied by higher antibody titers against collagen, and in vitro tests showed increased proliferation of collagen-specific T cells. Adoptively transferring CD4+,CD25+ T cells into depleted mice was shown to reverse the heightened severity. Control mice, which were depleted and immunized with the neoantigen keyhole limpet hemocyanin (KLH), had neither an increased antibody response toward KLH nor an augmented proliferative response, indicating that CD25+ cell depletion preferentially affects immunity against self antigen. CONCLUSION: These results establish a link between CD4+,CD25+ regulatory cells and CIA and provide a rationale for investigating CD4+,CD25+ T regulatory cells in the treatment and prevention of arthritis.

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Contains fulltext : 22218.PDF (publisher's version ) (Open Access)

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