Induction of diabetes in standard mice by immunization with the p277 peptide of a 60‐kDa heat shock protein

Abstract

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 develop spontaneous autoimmune diabetes. The present study was done to test whether immunization with the p277 peptide could cause diabetes in standard 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 marked by hyperglycemia, insulitis, insulin autoantibodies, glucose intolerance and low blood levels of insulin. The diabetes could be transferred to naive recipients by anti-p277 T cell lines. Similar to other experimentally induced autoimmune diseases, the autoimmune diabetes remitted spontaneously. After recovery, the mice were found to have acquired resistance to a second induction of diabetes. Susceptibility to induced 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-2bm12 mice with a mutation in the MHC-II molecule were relatively resistant). Other strains of mice susceptible to induced diabetes were C57BL/KSJ, C3HeB/FeJ, and NON/Lt. BALB/c and C3H/HeJ strains were relatively resistant. Immunization to p277-carrier conjugates could also induce transient hyperglycemia in young NOD mice, but upon recovery from the induced diabetes, the NOD mice were found to have acquired resistance to later development of spontaneous diabetes. Thus, T cell immunity to the p277 peptide can suffice to induce diabetes in standard mice, and a short bout of induced diabetes can affect the chronic process that would otherwise lead to spontaneous diabetes in diabetes-prone NOD mice.

The specificity of T cell regulation that enables self-nonself discrimination in the periphery

“…Although 1-9NacMBP is a self-peptide responsible for pathogenic autoimmune EAE in B10PL mice (27) and p277 can induce T1D in certain mouse strains (21) and therefore may be involved in T1D in NOD mice, there is no evidence that p277 can induce EAE in B10PL mice or that 1-9NacMBP can induce T1D in NOD mice. Interestingly, both peptides are equally capable of Fig.…”

The Regulatory C-Terminal Determinants within Mycobacterial Heat Shock Protein 65 Are Cryptic and Cross-Reactive with the Dominant Self Homologs: Implications for the Pathogenesis of Autoimmune Arthritis

“…In addition, Abs to Bhsp65 (5), and one or more of the mechanisms underlying epitope spreading in other models of autoimmunity (13, 14, 39 -41) might also contribute to induction of T cell response to BCTD during AA. The spontaneous or deliberate priming of T cell response to previously cryptic/subdominant antigenic determinants (22,30) has generally been associated with induction and/or propagation of autoimmunity (pathogenic cryptic/subdominant epitopes) (13,14,(42)(43)(44)(45). However, our results described above show that T cell responses to cryptic BCTD are AA protective in nature (regulatory cryptic epitopes) (4,46).…”

Clinical Potential of Antigen-Specific Therapies in Type 1 Diabetes

“…HSP60 has long been known as an autoantigen in the NOD mouse [78]. Specifically, a HSP60-derived peptide (p277) harbors the potential to protect mice from diabetes [79,80], and has the ability to induce disease in non-susceptible strains after vaccination [81]. The protein appears to be a relatively unimportant autoantigen in patients, although some evidence exists that autoreactivity arises during the natural course of T1D [82].…”