PREVENTION OF SPONTANEOUS AUTOIMMUNE DIABETES IN DIABETES-PRONE BB RATS BY PROPHYLACTIC TREATMENT WITH ANTIRAT INTERFERON-GAMMA ANTIBODY

The role of endogenous interferon-gamma (IFN gamma) in the development of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone BE ra ts was evaluated. Several groups of these animals were treated under d ifferent experimental conditions with a purified polyclonal antibody ( Ab), antirat IFN gamma. The results show that when administered at dos es of 100 or 200 mu g/week from the 30/33th until the 105th day of age , the anti-IFN gamma Ab reversibly reduced the incidence of IDDM compa red 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 o f anti-IFN gamma 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, u nder none of the above experimental conditions did larger doses of ant i-IFN gamma Ab (500 mu g or 1 mg/week) exert antidiabetogenic effects in the BE rats. Apparently, this was due to the exuberant production o f neutralizing Abs elicited by the large amount of the xenogeneic Ab i njected. At histoimmunological analyses, the BE rats treated with 200 mu g/ week anti-IFN gamma Abs from 30-80 days of age exhibited a milde r insulitic process along with diminished spleen frequency of activate d lymphoid cells (MHC class II and interleukin-2 receptor positive). T aken together, these results provide further in vivo evidence for the central pathogenic role of IFN gamma in BE rat IDDM and anticipate the usefulness of specific IFN gamma inhibitors in the prevention of the disease in the clinical setting. Defining novel and less immunogenic f orms of specific IFN gamma inhibitors than xenogeneic Abs is important for improving the efficiency of anti-IFN gamma-oriented approaches.