ANTI-IL-12 ANTIBODY PREVENTS THE DEVELOPMENT AND PROGRESSION OF COLLAGEN-INDUCED ARTHRITIS IN IFN-GAMMA RECEPTOR-DEFICIENT MICE

In several models of inflammation, including collagen-induced arthriti s (CIA), the disease-promoting effect of IL-12 has been attributed to its well-known ability to produce IFN-gamma. However, IFN-gamma recept or knockout (IFN-gamma R KO) mice of the DBA/1 strain have been report ed to be more susceptible to CIA than corresponding wild-type mice, in dicating the existence of an IFN-gamma-mediated protective pathway in this model. In the present study the development of CIA was found to b e completely prevented by pretreatment with a neutralizing anti-IL-12 antibody, not only in wild-type, but significantly also in IFN-gamma R KO mice. In both strains of mice, the protective effect of anti-IL-12 was associated with lower production of anticollagen type II antibodi es. In vivo stimulation with anti-CD3 antibody in arthritic IFN-gamma R KO mice resulted in production of higher levels of circulating IFN-g amma, TNF and IL-2 than in corresponding control mice that had not rec eived the arthritis-inducing immunization. This was not the case in ar thritis-developing wild-type mice. Furthermore, the protective effect of anti-IL-12 antibody in mutant, but not in wild-type mice, was assoc iated with lower circulating IFN-gamma, TNF and IL-2 and higher IL-4 a nd IL-5 cytokine levels following an anti-CD3 challenge. The data indi cate that IL-12 promotes the development of arthritis independently of its ability to induce or favor production of IFN-gamma. In fact, any IFN-gamma produced in the course of the disease process rather exerts a protective effect. Furthermore, our study suggests that, in the abse nce of a functional IFN-gamma system, endogenous IL-12 exerts its dise ase-promoting effect by favoring production of other Th1-associated cy tokines (IL-2 and TNF), by inhibiting development of IL-4- and IL-5-pr oducing T cells and by stimulating production of anticollagen autoanti bodies.