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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044427-02
Application #
2887917
Study Section
Special Emphasis Panel (ZAI1-PTM-I (S1))
Program Officer
Collier, Elaine S
Project Start
1998-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wen, Li; Green, Elizabeth A; Stratmann, Thomas et al. (2011) In vivo diabetogenic action of CD4+ T lymphocytes requires Fas expression and is independent of IL-1 and IL-18. Eur J Immunol 41:1344-51
Wong, F S; Wen, L (2004) What can the HLA transgenic mouse tell us about autoimmune diabetes? Diabetologia 47:1476-87
Chakrabarty, S; Nagata, M; Yasuda, H et al. (2003) Critical roles of CD30/CD30L interactions in murine autoimmune diabetes. Clin Exp Immunol 133:318-25
Wen, Li; Wong, F Susan; Sherwin, Robert et al. (2002) Human DQ8 can substitute for murine I-Ag7 in the selection of diabetogenic T cells restricted to I-Ag7. J Immunol 168:3635-40
Wen, L; Chen, N Y; Tang, J et al. (2001) The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model. J Clin Invest 107:871-80
Wen, L; Wong, F S; Tang, J et al. (2000) In vivo evidence for the contribution of human histocompatibility leukocyte antigen (HLA)-DQ molecules to the development of diabetes. J Exp Med 191:97-104