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Insulin in Oral Immune "Tolerance": A One-Amino Acid Change in the B Chain Makes the Difference¹

Dirk Homann^2,*, Thomas Dyrberg^2,, Jacob Petersen, Michael B. A. Oldstone^* and Matthias G. von Herrath^3,*

^* Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, La Jolla, CA 92037; and Novo Nordisk, Bagsvaerd, Denmark

Oral administration of self-Ags can dampen or prevent autoimmune processes by induction of bystander suppression. Based on encouraging results from experiments in nonobese diabetic (NOD) mice, clinical trials have been initiated in type 1 diabetes using human insulin as an oral Ag. However, neither the precise antigenic requirements nor the mechanism of bystander suppression are currently understood in detail. Here we report that 1) a 1-aa difference 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 mouse model for type 1 diabetes. In the latter model transgenic mice express the nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under the control of the rat insulin promotor (RIP) in the pancreatic ß cells and develop diabetes only following LCMV infection; and 2) protection could be transferred with insulin B chain-restimulated but not LCMV-restimulated splenocytes from RIP-NP transgenic mice, demonstrating that the mechanism of diabetes prevention in the RIP-NP model is mediated by insulin B chain-specific, IL-4-producing regulatory cells acting as bystander suppressors.

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