The role of endogenous interferon-γ (IFNγ) in the development of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone BB rats was evaluated. Several groups of these animals were treated under different experimental conditions with a purified polyclonal antibody (AB), antirat IFNγ. The results show that when administered at doses of 100 or 200 μg/week from the 30/33th until the 105th day of age, the anti-IFNγ Ab reversibly reduced the incidence of IDDM compared to that in control rats treated with either irrelevant rabbit IgG or PBS. Moreover, when given up to the 105th day of age, these doses of anti-IFNγ Abs exerted comparable preventive effects regardless of whether application started as early as within 24 h after birth or at the end of the prediabetic period (e.g. 70/75 days). In contrast, under none of the above experimental conditions did larger doses of anti-IFNγ Ab (500 μg or1 mg/week) exert antidiabetogenic effects in the BB rats. Apparently, this was due to the exuberant production of neutralizing Abs elicited by the large amount of the xenogeneic Ab injected. At histoimmunological analyses, the BB rats treated with 200 μg/week anti-IFNγ Abs from 30-80 days of age exhibited a milder insulitic process along with diminished spleen frequency of activated lymphoid cells (MHC class II and interleukin-2 receptor positive). Taken together, these results provide further in vivo evidence for the central pathogenic role of IFNγ in BB rat IDDM and anticipate the usefulness of specific IFNγ inhibitors in the prevention of the disease in the clinical setting. Defining novel and less immunogenic forms of specific IFNγ inhibitors than xenogeneic Abs is important for improving the efficiency of anti-IFNγ-oriented approaches.
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