ORAL INSULIN-TREATMENT SUPPRESSES VIRUS-INDUCED ANTIGEN-SPECIFIC DESTRUCTION OF BETA-CELLS AND PREVENTS AUTOIMMUNE DIABETES IN TRANSGENIC MICE

Oral administration of self-antigens has been proposed as a therapy to prevent and treat autoimmune diseases, Here we report that oral treat ment with insulin prevents virus-induced insulin-dependent diabetes me llitus (IDDM) in a transgenic (tg) mouse model, Such mice express the viral nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter in their pancreatic beta cel ls and < 2% spontaneously develop diabetes. However, 2 mo after challe nge with LCMV, IDDM occurs in > 95% of tg mice but not in controls, Or al treatment with 1 mg of insulin twice per week for 2 mo starting eit her 1 wk before or 10 d after initiating LCMV infection prevents IDDM in > 50% of the tg mice (observation time 8 mo), Thus, insulin therapy is effective in preventing progression to overt IDDM in prediabetic t g mice with ongoing islet infiltration. Oral administration of insulin does not affect the generation of LCMV-NP-specific anti-self cytotoxi c T lymphocytes nor the infiltration of lymphocytes into the pancreas, However, less beta cells are destroyed in insulin-treated mice, upreg ulation of MHC class I and II molecules does not occur, and antiviral (self) cytotoxic T lymphocytes are not found in the islets, events pre sent in tg mice developing IDDM. The majority of lymphocytes in the is lets of insulin-treated tg mice without IDDM produces IL-4, IL-10, and TGF-beta. In contrast, lymphocytes from islets of tg mice developing IDDM mainly make gamma-IFN.