COLLAGEN-INDUCED ARTHRITIS IN THE BB-RAT - PREVENTION OF DISEASE BY TREATMENT WITH CTLA-4-IG

Antigen-specific T cell activation requires two independent signalling events, one mediated through T cell receptor engagement by the antige n-presenting cell-expressed peptide/class II major histocompatibility complex, and the second through the cognate interactions of costimulat ory molecules expressed on the T cell and antigen-presenting cell, The re is evidence from in vitro and in vivo experimental systems suggesti ng 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 his tological manifestations of disease in a collagen-induced arthritis mo del 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 ra ts compared to diseased control animals, Histologically, joints from C TLA-4-Ig-treated animals show no histological abnormalities, in contra st to control antibody-treated animals, which show complete erosion of the articular cartilage and bone, Despite the efficacy of CTLA-4-Ig i n preventing clinical and histological signs of arthritis and reducing antibody responses to BIIC, delayed type hypersensitivity responses t o 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 di sease suppression observed does not result from induction of T cell an ergy.