INDUCTION OF DIABETES IN STANDARD MICE BY IMMUNIZATION WITH THE P277 PEPTIDE OF A 60-KDA HEAT-SHOCK PROTEIN

We previously reported that immunity to the p277 peptide of the human 60-kDa heat shock protein (hsp60) was a causal factor in the diabetes of non-obese diabetic (NOD) mice, which are genetically prone to devel op spontaneous autoimmune diabetes. The present study was done to test whether immunization with the p277 peptide could cause diabetes in st andard strains of mice. We now report that a single administration of the p277 peptide conjugated to carrier molecules such as bovine serum albumin or ovalbumin can induce diabetes in C57BL/6 mice and in other strains not genetically prone to develop diabetes. The diabetes was ma rked by hyperglycemia, insulitis, insulin autoantibodies, glucose into lerance and low blood levels of insulin. The diabetes could be transfe rred to naive recipients by anti-p277 T cell lines. Similar to other e xperimentally induced autoimmune diseases, the autoimmune diabetes rem itted spontaneously. After recovery, the mice were found to have acqui red resistance to a second induction of diabetes. Susceptibility to in duced diabetes in C57BL/6 mice was influenced by sex (males were much more susceptible than were females) and by class II genes in the major histocompatibility complex (B6.H-2(bm12) mice with a mutation in the MHC-II molecule were relatively resistant). Other strains of mice susc eptible to induced diabetes were C57BL/KSJ, C3HeB/FeJ, and NON/Lt. BAL B/c and C3H/HeJ strains were relatively resistant. Immunization to p27 7-carrier conjugates could also induce transient hyperglycemia in youn g NOD mice, but upon recovery from the induced diabetes, the NOD mice were found to have acquired resistance to later development of spontan eous diabetes. Thus, T cell immunity to the p277 peptide can suffice t o induce diabetes in standard mice, and a short bout of induced diabet es can affect the chronic process that would otherwise lead to spontan eous diabetes in diabetes-prone NOD mice.