Insulin in oral immune "tolerance": a one-amino acid change in the B chain makes the difference.
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 beta 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.
Homann
D
D
Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, La Jolla, CA 92037.
Dyrberg
T
T
Petersen
J
J
Oldstone
M B
MB
von Herrath
M G
MG
D000284:Administration, Oral; D019264:Adoptive Transfer / Q000379:methods; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000276:immunology*; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D017710:Lymphocyte Transfusion; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009698:Nucleoproteins / Q000276:immunology; D009928:Organ Specificity / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D013552:Swine
D007328:Insulin; D009698:Nucleoproteins; D010446:Peptide Fragments; C094246:nucleoprotein peptide 118-126, lymphocytic choriomeningitis virus