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

Ferdinando Nicoletti, Paola Zaccone, Roberto Di Marco, Maurizio Di Mauro, Gaetano Magro, Sebastiano Grasso, Lanfranco Mughini, Pierluigi Meroni, Gianni Garotta

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Previous studies have shown that in vivo treatment with antiinterferon- γ (anti-IFNγ) monoclonal antibodies (mAbs) prevents the development of autoimmune diabetes in NOD mice. Although these findings anticipate that specific anti-IFNγ therapies may be useful for the prevention/treatment of human insulin-dependent diabetes mellitus, there are several reasons why the use of anti-IFNγ mAb may be difficult in the clinical setting. With the aim to develop alternative forms of specific anti-IFNγ therapies, we recently produced a nonimmunogenic form of the soluble IFNγ receptor (sIFNγR) that binds and neutralizes murine IFNγ with an affinity higher than that of anti- IFNγ mAb. In this study we compared the efficacy of sIFNγR to that of two anti-IFNγ 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, sIFNγR could prevent histological and clinical signs of autoimmune diabetes as efficiently as the two mAbs. Under ex vivo conditions, sIFNγR 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 IgG, sIFNγR did not induce antibody formation. Unexpectedly, in the cyclophosphamide- induced model, sIFNγR turned out to be less effective than either of the two anti-IFNγ mAbs. Taken together, these data support the role of IFNγ in the pathogenesis of NOD mice, but, more importantly, suggest that a nonimmunogenic approach is possible to the diminution of the effects of IFNγ in this model.

Original languageEnglish
Pages (from-to)5567-5575
Number of pages9
Issue number12
Publication statusPublished - 1996

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism


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