Cai Li, Xu Haiyan, Zhang Han, Zhang Lili, Wang Guojue, Nie Hong
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Department of Allergy and Immunology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Mol Immunol. 2016 Nov;79:83-91. doi: 10.1016/j.molimm.2016.09.017. Epub 2016 Oct 11.
T cell response is crucial to the pathogenesis and progression of rheumatoid arthritis (RA). IL-7/IL-7R axis has significant effect on CD4 T cell response, including proliferation, differentiation, survival and migration. However, whether blockade of IL-7/IL-7R axis signaling can relieve RA and what is the potential treatment mechanisms are still remaining unclear. In this paper, we established collagen-induced arthritis (CIA) model and observed the effect of IL-7Rα antibody in the treatment of CIA mice. It is demonstrated that IL-7Rα antibody significantly alleviated clinical symptoms of CIA mice, accompanied with reduced CD4 T cell number in both spleen and joints. Decreased CII-specific CD4 T cell proliferation and reduced mRNA expression of inflammatory cytokines in IL-7Rα antibody-treated mice were observed. Subsequently, IL-7Rα antibody treatment in vivo downregulated the percentages of Th1 and Th17 cells and the mRNA expression of T-bet and RORγt gene. Moreover, it was found that IL-7 promoted Th1 cell differentiation in vitro, while having no effect on Th17 cell differentiation. In addition, administration of IL-7Rα antibody reduced the mRNA expression of chemokine receptors (CCR7, CXCR3, CXCR6 and XCR1) on CD4 T cells and chemokine CXCL2 in joints. The results suggested that IL-7Rα antibody treated CIA mice via the inhibition of CII-specific CD4 T cell proliferation, the reduction of Th1 cell differentiation and the restrain of CD4 T cell migration to joint lesion site. This investigation indicates that IL-7Rα is a potential therapeutic target for RA.
T细胞反应对类风湿性关节炎（RA）的发病机制和病情进展至关重要。IL-7/IL-7R轴对CD4 T细胞反应有显著影响，包括增殖、分化、存活和迁移。然而，阻断IL-7/IL-7R轴信号是否能缓解RA以及潜在的治疗机制仍不清楚。在本文中，我们建立了胶原诱导性关节炎（CIA）模型，并观察了IL-7Rα抗体对CIA小鼠的治疗效果。结果表明，IL-7Rα抗体显著减轻了CIA小鼠的临床症状，同时脾脏和关节中的CD4 T细胞数量减少。观察到在IL-7Rα抗体治疗的小鼠中，CII特异性CD4 T细胞增殖减少，炎症细胞因子的mRNA表达降低。随后，体内给予IL-7Rα抗体下调了Th1和Th17细胞的百分比以及T-bet和RORγt基因的mRNA表达。此外，发现IL-7在体外促进Th1细胞分化，而对Th17细胞分化没有影响。另外，给予IL-7Rα抗体降低了CD4 T细胞上趋化因子受体（CCR7、CXCR3、CXCR6和XCR1）的mRNA表达以及关节中趋化因子CXCL2的表达。结果提示，IL-7Rα抗体通过抑制CII特异性CD4 T细胞增殖、减少Th1细胞分化以及抑制CD4 T细胞向关节病变部位迁移来治疗CIA小鼠。这项研究表明IL-7Rα是RA的一个潜在治疗靶点。
