HIGH SUSCEPTIBILITY TO COLLAGEN-INDUCED ARTHRITIS IN MICE LACKING IFN-GAMMA RECEPTORS

Collagen-induced arthritis (CIA), an animal model for rheumatoid arthr itis, is induced in DBA/1 (H-2(q)) mice following immunization with ty pe II collagen (CII) in CFA, Since we have previously shown that IFN-g amma exerts a biphasic effect during the evolution of CIA in DBA/1 mic e, we analyzed the development of this disease in mice with a disrupti on of the IFN-gamma receptor gene (IFN-gamma R-0/0), Mutant mice were interbred with the DBA/1 strain to yield IFN-gamma R-0/0 mice expressi ng the H-2(q) haplotype, In three consecutive experiments, IFN-gamma R -0/0 male mice were found to exhibit severe clinical and histologic ar thritis with an average incidence of 88.5 vs 94.1% for the wild DBA/1 strain, Notably, onset of clinical symptoms occurred significantly ear lier than in DBA/1 mice, Although of a lower magnitude than in males, CIA also developed early in IFN-gamma R-0/0 female mice and with highe r clinical severity than in control DBA/1 females, Immunization of kno ckout mice with CII resulted in the generation of CII-specific T cells belonging to the Th1 phenotype that recognize the same immunodominant peptides as do DBA/1 mice, CIA in IFN-gamma R-0/0 mice was associated with a down-regulation of the CII-specific IgG response, arid this im pairment was essentially due to a strong reduction of Abs of the IgG2a isotype, Taken together, our findings provide evidence that IFN-gamma R deficiency in DBA/1 mice leads to the occurrence of severe CIA with an accelerated onset compared with that in wild-type mice, indicating that the proinflammatory action of IFN-gamma has been bypassed in the IFN-gamma R-0/0 mice.