Autoantigen Specific CD4+ T Cell Responses in Children with Type 1 Diabetes Mellitus and Healthy Controls

Abstract 551 Endocrinology & Diabetes III Platform, Sunday, 5/2

Type 1 diabetes mellitus is an autoimmune disease characterized by destruction of the insulin producing beta cells of the pancreas. Autoreactive T cells specific for the beta islet cell proteins, preproinsulin (PPI) and glutamic acid decarboxylase (GAD)65 are thought to play a major role in beta cell destruction. About 50% of the genetic risk for developing type 1 diabetes is associated with the major histocompatibility complex (MHC) class II genes (Human Leukocyte Antigens or HLA, in humans). HLA-DR and DQ are most closely associated with type 1 diabetes, and the HLA-DR4-DQ8 haplotype is especially common. In particular, disease-susceptibility is associated with the DR4 subtype: (Table) Because it is difficult to obtain sufficient numbers of lymphocytes from diabetic patients to study these large islet cell proteins, a panel of HLA-DR or DQ transgenic mice have been created with a knock out of the murine MHC class II genes and the insertion of a fully functional human CD4 transgene. These mice serve as a substitute for the human immune system. Following immunization of HLA-DR4 susceptible or non-susceptible transgenic mice with human GAD65 or PPI, the immunogenic peptide epitopes of GAD65 and PPI were defined using large panels of T cell hybridomas. T cell proliferation assays were then performed on a number of diabetic patients, their relatives, and healthy control subjects using the panel of immunogenic peptide epitopes from GAD65 and PPI determined in the transgenic mice. We confirmed that the immunodominant epitopes found in the transgenic mice were also reactive in patients with type 1 diabetes as well as relatives and healthy controls with disease-susceptible HLA alleles. In general, however, relatives and controls with non-susceptible HLA alleles did not respond to the epitopes identified in the mice. Autoreactive CD4+ T cell responses are, therefore, commonly found in healthy individuals but rarely cause disease.

Table 1 No caption available.