The effects of a nonimmunogenic form of murine soluble interferon-gamma receptor on the development of autoimmune diabetes in the NOD mouse

Previous studies have shown that in vivo treatment with antiinterferon-gamma (anti-IFN gamma) monoclonal antibodies (mAbs) prevents the development of autoimmune diabetes in NOD mice. Although these findings anticipate that specific anti-IFN gamma therapies may be useful for the prevention/treatment of human insulin-dependent diabetes mellitus, there are several reasons why the use of anti-IFN gamma mAb may be difficult in the clinical setting. With the aim to develop alternative forms of specific anti-IFN gamma therapies, we recently produced a nonimmunogenic form of the soluble IFN gamma receptor (sIFN gamma R) that binds and neutralizes murine IFN gamma with an affinity higher than that of anti-IFN gamma mAb. In this study we compared the efficacy of sIFN gamma R to that of two anti-IFN gamma mAbs (XMG 1.2 and AN-18) in the prevention of spontaneous and accelerated (cyclophosphamide-induced) forms of autoimmune diabetes in NOD mice. The results show that in the spontaneous model, sIFN gamma R could prevent histological and clinical Signs of autoimmune diabetes as efficiently as the two mAbs. Under ex vivo conditions, sIFN gamma R exhibited a more powerful modulatory effect than XMG1.2 mAb on cytokine secretion from splenic lymphoid cells, which resulted in a significant reduction of Concanavalin A-induced IL-2 secretion and an augmented release of both unstimulated and lipopolysaccharide-induced IL-6. Moreover, although both mAbs were immunogenic and elicited formation of high titers of anti-rat Igd, sIFN gamma R did not induce antibody formation. Unexpectedly, in the cyclophosphamide-induced model, sIFN gamma R turned out to be less effective than either of the two anti-IFN gamma mAbs. Taken together, these data support the role of IFN gamma in the pathogenesis of NOD mice, but, more importantly, suggest that a nonimmunogenic approach is possible to the diminution of the effects of IFN gamma in this model.