TACI-Ig对佐剂性关节炎大鼠T细胞反应的调节作用

摘要

目的：研究TACI受体融合蛋白( TACI-Ig)对T细胞介导的免疫性关节炎的调节作用,探讨其调控T细胞反应的部分机制。方法 SD大鼠右后足跖皮内注射完全弗氏佐剂建立大鼠佐剂性关节炎( AA)模型。随机分为8组：正常组,模型组,TACI-Ig(0．7、2．1、6．3 mg/kg,皮下注射,第16~34天)治疗组,阳性对照组：重组人Ⅱ型肿瘤坏死因子受体-Fc融合蛋白(rhTNFR：Fc)(2．8 mg/kg,皮下注射,第16~34天)和甲氨蝶呤(MTX)(0．5 mg/kg,灌胃,第16~34天),阴性对照组：免疫球蛋白G(IgG)-Fc(6．3 mg/kg,皮下注射,第16~34天)。 X线摄片观察四肢关节破坏情况；ELISA法检测外周血和滑膜组织匀浆白细胞介素17( IL-17)的水平；流式细胞仪检测外周血和脾脏总 CD4+ T 细胞( CD3+CD4+)、活化CD4+T细胞( CD4+CD25+)、未致敏CD4+T细胞(CD4+CD62L+)和记忆 CD4+ T 细胞( CD4+ CD44+)比例；免疫组化法检测滑膜组织跨膜激活剂和钙调亲环素配体相互作用分子( TACI)、B细胞成熟抗原( BCMA)和B细胞活化因子受体( BAFF-R )受体蛋白表达。结果 TACI-Ig (6．3 mg/kg)明显减轻 AA 大鼠关节软组织肿胀；TACI-Ig (0．7、2．1、6．3 mg/kg)降低外周血和滑膜组织IL-17含量,升高总CD4+T细胞、活化CD4+T细胞、记忆 CD4+T细胞和未致敏CD4+T细胞比例,下调AA大鼠滑膜组织中TACI和BCMA蛋白表达,上调BAFF-R蛋白表达。结论 TACI-Ig调节免疫性关节炎大鼠异常的T细胞反应,改善关节损伤,发挥其免疫调控作用,可能与其调节TACI、BCMA和BAFF-R受体表达有关。%Objective To investigate the immunoregulatory effects of TACI-Ig, a recombinant fusion protein, on T cell responses in an established adjuvant-induced arthritis ( AA) rat model. Methods Rats with experimental ar-thritis were randomly separated into different groups and then treated with TACI-Ig (0. 7, 2. 1, 6. 3 mg/kg), rhT-NFR-Fc (2. 8 mg/kg), MTX (0. 5 mg/kg) or IgG-Fc (6. 3 mg/kg), from d16 to d34 after immunization. Arthri-tis was evaluated by radiographic examination. Levels of IL-17 were assessed by ELISA. The proportion of total, activated, memory and unactivated CD4 + T cells in peripheral blood and spleens were analysed by FACS. TACI ( transmembrane activator and calciummodulator and cyclophilin ligand interactor) , BCMA ( B-cell maturation anti-gen), and BAFF receptor (BAFF-R) expression were analysed by immunohistochemistry. Results TACI-Ig (6. 3 mg/kg) treatment significantly reduced the severity of established arthritis using the methods of radiographic exami-nation. TACI-Ig (0. 7, 2. 1, 6. 3 mg/kg) treatment decreased IL-17 levels both in serum and synovium homoge-nate in AA rats. TACI-Ig (0. 7, 2. 1, 6. 3 mg/kg) increased the proportion of total, activated, memory and unac-tivated CD4 + T cells in peripheral blood and spleens. TACI-Ig (0. 7, 2. 1, 6. 3 mg/kg) administration downregu-lated TACI and BCMA expression and upregulated BAFF-R expression in synovium tissues of AA rats. Conclusion Data presented here demonstrate that administration of TACI-Ig regulates T cell responses and improves joints damage in rats with AA, which may be related to its immnoregulatory effects on expression of BAFF-R, TACI and BCMA in synovium.