期刊
ARTHRITIS RESEARCH & THERAPY
卷 14, 期 3, 页码 -出版社
BMC
DOI: 10.1186/ar3824
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [20592073]
Introduction: The purpose of this study was to determine whether anti-tumour necrosis factor alpha (anti-TNF-alpha) antibody, infliximab, can inhibit T helper 17 (Th17) differentiation in uveitis patients who have Behcet's disease (BD). Methods: To measure inflammatory cytokines, ocular fluid samples from BD patients being treated with infliximab were collected. Cluster of differentiation 4 (CD4)(+) T cells from BD patients with active uveitis were co-cultured with anti-cluster of differentiation 3/cluster of differentiation 28 (CD3/CD28) antibodies in the presence of infliximab. For the induction of Th17 cells, CD4(+) T cells from BD patients were co-cultured with anti-CD3/CD28, anti-interferon-gamma (anti-IFN-gamma), anti-interleukin-4 (anti-IL-4), and recombinant proteins such as interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-23 (IL-23), and TNF-alpha. The BD T cells were co-cultured with infliximab, and the production of interleukin-17 (IL-17) was evaluated by ELISA and flow cytometry, and the expression of retinoid-acid receptor-related orphan receptor gamma t (ROR gamma t) was also evaluated by flow cytometry. In addition, intraocular cells collected from mice with experimental autoimmune uveitis (EAU) were used for the assay with anti-TNF-alpha blocking antibody. Results: Ocular fluids from active uveitis patients who have BD contained significant amounts of inflammatory cytokines such as IFN-gamma, IL-2, TNF-alpha, IL-6, and IL-17, while ocular fluids from infliximab patients did not contain any inflammatory cytokines. Activated CD4(+) T cells from BD patients produced large amounts of TNF-alpha and IL-17, whereas T cells in the presence of infliximab failed to produce these cytokines. Polarized Th17 cell lines from BD patients produced large amounts of IL-17, and Th17 cells exposed to infliximab had significantly reduced IL-17 production. Polarized BD Th17 cells expressed large amounts of transcription factor RORgt. In contrast, in vitro-treated infliximab Th17 cells expressed less ROR gamma t. Moreover, intraocular T cells from EAU mice had a high population of IL-17(+) cells, and retinal antigen-specific T cells from EAU mice produced large amounts of IL-17 in the presence of retinal peptide. However, the EAU T cells produced less IL-17 if the T cells were treated with anti-TNF-alpha antibody. Conclusions: These results indicate that anti-TNF-alpha therapy suppresses effector T-cell differentiation in BD patients with uveitis. Thus, suppression of effector T-cell differentiation by anti-TNF-alpha therapy may provide protection from severe ocular inflammation in BD.
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