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 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 II 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.
Knoerzer
D B
DB
Department of Immunology, G.D. Searle and Co., St Louis, Missouri 63198, USA.
Karr
R W
RW
Schwartz
B D
BD
Mengle-Gaw
L J
LJ
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018122:B7-1 Antigen / Q000502:physiology*; D001483:Base Sequence; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D002358:Cartilage, Articular / Q000473:pathology; D002417:Cattle; D003094:Collagen / Q000633:toxicity*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006968:Hypersensitivity, Delayed / Q000209:etiology; D018796:Immunoconjugates / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008211:Lymphocyte Cooperation; D008969:Molecular Sequence Data; D051381:Rats; D011913:Rats, Inbred BB; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept; D003094:Collagen