Zhao Jinxia, Li Ru, He Jing, Shi Jinxia, Long Li, Li Zhanguo
Department of Rheumatology and Immunology, People's Hospital, Peking University Medical School, 11 Xizhimen South St., Beijing, 100044, China.
Rheumatol Int. 2008 Nov;29(1):9-16. doi: 10.1007/s00296-008-0634-4. Epub 2008 Jul 5.
Rheumatoid arthritis (RA) is a systemic autoimmune disease mediated by T cells. Collagen type II (CII) is one of the autoantigens associated with RA. CII263-272 is a predominant CII antigenic peptide that can induce T-cell activation upon binding to MHC and interaction with the appropriate T-cell receptor (TCR). Altered CII263-272 peptides with substitution of specific amino acids could bind to RA-associated HLA-DR4/1 with no T cell stimulating effects and could inhibit T cell activation in RA. We performed this study to evaluate the effect of mucosal administration and to explore the mechanism of the inhibitory effect of altered CII263-272 peptide (267Q-->A, 270K-->A and 271G-->A) on collagen induced arthritis (CIA). CIA was induced in Lewis rats by immunization with bovine CII. Altered CII263-272 peptide was given intranasally beginning from arthritis onset. Wild CII263-272 peptide or PBS was administered as controls. Therapeutic effects were evaluated by arthritis scores, body weight change, and joint pathologic scores. The anti-CII antibody and its subtypes and the cytokines, IFN-gamma, IL-10, and IL-17 were measured with ELISA. Foxp3+CD4+CD25+ regulatory T cell induction was assessed by FACS analysis. Following treatment with the altered CII263-272 peptide, arthiritis scores were reduced and body weight was increased. The altered CII263-272 peptide could retard the histologic lesion of the joints. The titers of anti-CII antibodies IgG2a in altered CII263-272 peptide treated rats decreased markedly compared to PBS-treated rats. The serum levels of IFN-gamma in rats treated with altered peptide was lower than that of rats treated with wild CII263-272 peptide and PBS. No differences were observed in the levels of serum IL-10 among the three groups. The altered CII263-272 peptide could decrease serum level of IL-17 and increase peripheral Foxp3+CD4+CD25+ T cells at early stage of CIA. Mucosal administration of altered CII263-272 peptide could effectively inhibit the progression of CIA. Altered CII263-272 peptide could suppress Th17 cells and expand regulatory T cells in the early stage of the disease. The IgG2a subtype of anti-CII antibodies and IFN-gamma were reduced and in vivo Th1 responses were inhibited as a result of altered CII peptide treatment. Altered CII peptide is likely therapeutic in RA.
类风湿关节炎（RA）是一种由T细胞介导的全身性自身免疫性疾病。II型胶原蛋白（CII）是与RA相关的自身抗原之一。CII263 - 272是一种主要的CII抗原肽，其与MHC结合并与适当的T细胞受体（TCR）相互作用后可诱导T细胞活化。用特定氨基酸替代的CII263 - 272改变肽可与RA相关的HLA - DR4/1结合，但无T细胞刺激作用，并且可抑制RA中的T细胞活化。我们进行本研究以评估黏膜给药的效果，并探索改变的CII263 - 272肽（267Q→A、270K→A和271G→A）对胶原诱导的关节炎（CIA）的抑制作用机制。通过用牛CII免疫在Lewis大鼠中诱导CIA。从关节炎发作开始经鼻给予改变的CII263 - 272肽。给予野生型CII263 - 272肽或PBS作为对照。通过关节炎评分、体重变化和关节病理评分评估治疗效果。用ELISA法检测抗CII抗体及其亚型以及细胞因子IFN - γ、IL - 10和IL - 17。通过流式细胞术分析评估Foxp3 + CD4 + CD25 +调节性T细胞的诱导情况。用改变的CII263 - 272肽治疗后，关节炎评分降低，体重增加。改变的CII263 - 272肽可延缓关节的组织学损伤。与PBS处理的大鼠相比，改变的CII263 - 272肽处理的大鼠中抗CII抗体IgG2a的滴度明显降低。用改变肽处理的大鼠血清中IFN - γ水平低于用野生型CII263 - 272肽和PBS处理的大鼠。三组之间血清IL - 10水平未观察到差异。改变的CII263 - 272肽可在CIA早期降低血清IL - 17水平并增加外周Foxp3 + CD4 + CD25 + T细胞。经鼻给予改变的CII263 - 272肽可有效抑制CIA的进展。改变的CII263 - 272肽可在疾病早期抑制Th17细胞并扩增调节性T细胞。改变的CII肽治疗导致抗CII抗体的IgG2a亚型和IFN - γ减少，体内Th1反应受到抑制。改变的CII肽可能对RA具有治疗作用。
