ACCELERATED COLLAGEN-INDUCED ARTHRITIS IN IFN-GAMMA RECEPTOR-DEFICIENT MICE

Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis, Here, we describe experiments showing that IFN-gamma receptor knockout (IFN-gamma R alpha KO) mice of the DBA/1 strain develop CIA more read ily than their wild-type counterparts, Symptoms of disease started 10 days earlier and the cumulative incidence of arthritis was significant ly higher in the mutant mice than in wild-type mice, Similarly, accele rated onset of the disease was also found in wild-type DBA/1 mice trea ted with neutralizing mAbs against IFN-gamma, Histologic examination o f the joints revealed a massive infiltration of the synovium with mono nuclear cells and neutrophils, hyperplasia, and severe pannus formatio n in IFN-gamma R alpha KO mice when such inflammatory lesions were not yet detectable in wild-type mice, Serum levels of anti-collagen type II Abs, including total IgG and IgM, as well as IgG1, IgG2a, and IgG2b isotypes were found to be lower in the mutant mice, IL-2 and IL-4 rem ained undetectable in sera of both groups of mice, but did appear in t he circulation after anti-CD3 Ab challenge, Significantly higher IL-2 and lower IL-4 serum levels were found in anti-CD3-challenged IFN-gamm a R alpha KO mice than in wild-type counterparts, both at an early and at a later stage of the disease, These observations indicate that end ogenous IFN-gamma counteracts development of collagen-induced arthriti s and suggest that IFN-gamma does so by up-regulating IL-4 production and/or down-regulating IL-2 production. The data are in line with the concept of a pathogenic role of Th1-type cellular immunity in CIA in s pite of a decreased Ab response to collagen type II.