COLLAGEN-INDUCED ARTHRITIS IN THE BB-RAT - PREVENTION OF DISEASE BY TREATMENT WITH CTLA-4-IG
COLLAGEN-INDUCED ARTHRITIS IN THE BB-RAT - PREVENTION OF DISEASE BY TREATMENT WITH CTLA-4-IG
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DOI：
10.1172/jci118146
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发表时间：
1995-08-01
影响因子：
15.9
通讯作者：
MENGLEGAW, LJ
中科院分区：
文献类型：
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作者：
KNOERZER, DB;KARR, RW;MENGLEGAW, LJ
抗原特异性T细胞活化需要两个独立的信号传导事件，一个是通过抗原呈递细胞表达的肽/II类主要组织相容性复合体介导的T细胞受体接合，第二个是通过T细胞和抗原呈递细胞上表达的共刺激分子的同源相互作用，来自体外和体内实验系统的证据表明，CD 28/B7共刺激途径对于诱导最大T细胞增殖和T辅助细胞增殖是至关重要的。B细胞协作产生IgG。该途径可以被CTLA-4-IG阻断，CTLA-4是以高亲合力结合CD 28配体B7-1和B7-2的可溶形式。我们表明CTLA-4-IG治疗可预防胶原蛋白-在糖尿病抗性BB/Wor大鼠的类风湿性关节炎的诱导关节炎模型中，当在用牛IP型胶原（BIIC）免疫之前开始治疗时，与患病对照动物相比，CTLA-4-Ig处理的大鼠中的抗BIIC抗体滴度降低。组织学上，CTLA-4-Ig-处理的动物的关节没有显示组织学异常，与对照抗体处理的动物相反，对照抗体处理的动物显示关节软骨和骨的完全侵蚀。尽管CTLA-4-IG在预防关节炎的临床和组织学体征和减少对BIIC的抗体应答方面有效，CTLA-4-IG治疗结束后18天或更长时间对胶原蛋白的迟发型超敏反应在CTLA-4-Ig治疗的和未治疗的大鼠中是相似的，这表明观察到的延长的疾病抑制不是由T细胞无反应性的诱导引起的。
Antigen-specific T cell activation requires two independent signalling events, one mediated through T cell receptor engagement by the antigen-presenting cell-expressed peptide/class II major histocompatibility complex, and the second through the cognate interactions of costimulatory molecules expressed on the T cell and antigen-presenting cell, There is evidence from in vitro and in vivo experimental systems suggesting that the CD28/B7 costimulatory pathway is crucial for induction of maximal T cell proliferation and T helper-B cell collaboration for IgG production, This pathway can be blocked by CTLA-4-Ig, a soluble form of CTLA-4 which binds with high avidity to the CD28 ligands, B7-1 and B7-2, Here, we show that CTLA-4-Ig treatment prevents clinical and histological manifestations of disease in a collagen-induced arthritis model of rheumatoid arthritis in the diabetes resistant BB/Wor rat, when therapy is initiated before immunization with bovine type IP collagen (BIIC), Anti-BIIC antibody titers are reduced in CTLA-4-Ig-treated rats compared to diseased control animals, Histologically, joints from CTLA-4-Ig-treated animals show no histological abnormalities, in contrast to control antibody-treated animals, which show complete erosion of the articular cartilage and bone, Despite the efficacy of CTLA-4-Ig in preventing clinical and histological signs of arthritis and reducing antibody responses to BIIC, delayed type hypersensitivity responses to collagen 18 d or more after CTLA-4-Ig treatment ends are similar in CTLA-4-Ig-treated and untreated rats, suggesting that the prolonged disease suppression observed does not result from induction of T cell anergy.