B. Manouryschwartz et al., HIGH SUSCEPTIBILITY TO COLLAGEN-INDUCED ARTHRITIS IN MICE LACKING IFN-GAMMA RECEPTORS, The Journal of immunology, 158(11), 1997, pp. 5501-5506
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.