DEVELOPMENT OF A NOVEL HUMANIZED ANIMAL MODEL OF IDDM

Yale University, New Haven CT

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Abstract

DESCRIPTION (adapted from applicant's abstract): The overall goal of this project is to develop a novel animal model of type 1 diabetes (IDDM) which closely parallels the human disease and to use this "humanized" animal model to identify the molecular basis for the susceptibility to the disease. IDDM is a polygenic disease and studies have confirmed that the main locus defining genetic susceptibility is encoded within the MHC region on chromosome 6. Although the OR locus is thought to be important, current data suggest that the DQ regions are more closely linked to IDDM and the most common haplotype seen in patients with IDDM is the DQ8 haplotype. The recently developed human HLA-DQ8 transgenic mouse lacking murine class II molecules and preliminary studies show that DQ8 molecules can efficiently present glutamic acid decarboxylase (GAD) peptides and elicit humoral and cellular immune responses toward the GAD peptides. T cell lines specific for a GAD peptide (p17), which shares sequence homology with Coxsackie virus protein have also been generated. To study the DQ8 molecules in a spontaneous disease development model, l-A(g7), the non-obese diabetic (NOD) MHC class II is replaced by human HLA-DQ8 without altering any other disease associated genes, such as MHC class I loci. The new "humanized" NOD model will allow us to characterize unique features of DQ8 molecules in presenting potentially etiopathogenic GAD peptides, such as peptide 17 (amino acid 249-268) and its molecular mimic peptide derived from Coxsackie virus protein in a spontaneous diabetes development model. The long-term goal of this project is to generate "humanized" NOD/SCID mice in order to explore the role of human T lymphocytes isolated from newly diagnosed diabetic patients (bearing DQ8) in the pathogenesis of type 1 diabetes. This study will provide a novel means of studying the immunopathogenesis of human IDDM and hopefully will help to develop specific interventions.