Insulin in oral immune "tolerance": A one-amino acid change in the B chainmakes the difference

Oral administration of self-Ags can dampen or prevent autoimmune processes by induction of bystander suppression. Based on encouraging results from ex periments in nonobese diabetic (NOD) mice, clinical trials have been initia ted in type 1 diabetes using human insulin as an oral Ag, However, neither the precise antigenic requirements nor the mechanism of bystander suppressi on are currently understood in detail. Here we report that 1) a 1-aa differ ence in position 30 of the insulin B chain abrogated the ability of insulin to confer protection in both NOD as well as a virus-induced transgenic mou se model for type 1 diabetes. In the latter model transgenic mice express t he nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under th e control of the rat insulin promotor (RIP) in the pancreatic beta cells an d develop diabetes only following LCMV infection; and 2) protection could b e transferred with insulin B chain-restimulated but not LCMV-restimulated s plenocytes from RIP-NP transgenic mice, demonstrating that the mechanism of diabetes prevention in the RIP-NP model is mediated by insulin B chain-spe cific, IL-4-producing regulatory cells acting as bystander suppressors.