The overall goal is to use murine experimental autoimmune thyroiditis (EAT) as a model to probe the recognitory, pathogenic, and regulatory mechanisms, both promoting and inhibiting thyroid damage in Hashimoto's thyroiditis (HT), the hypothyroid syndrome. A major thrust in this renewal application is the emphasis on the use of specific HLA single and double class II transgenic mice and major human thyroid antigens and a novel H2E transgenic model because of new findings in the previous years. These include: 1) Identification of HLA-DRB1 and DQ transgenes responsible for susceptibility and resistance to EAT induced with either human thyroglobulin (hTg) or mouse (m) Tg, thereby demonstrating polymorphism in EAT susceptibility and resistance. 2) In the presence of resistant class II alleles, EAT development is down-modulated; an example is DQ8 transgene moderating DR3-mediated susceptibility. 3) The unusual H2E model is permissive only for hTg, but not mTg, induction, unlike conventional, susceptible strains. 4) For both HLA and H2E transgenic models, specific Tg epitopes derived from computer modeling have proven thyroiditogenic, revealing hTg-unique epitopes. The recent success in genetic immunization with DNA has provided renewed impetus to extend our models to two other major thyroid antigens. We propose to: 1. Characterize the novel H2AE+ transgenic model with distinct permissiveness for hTg. 2. Examine the response of HLA-DR3 transgenic mice to Tg and thyroiditogenic epitopes under the influence of protective class II alleles and environmental factors. 3. Determine if HLA association with Tg correlates with other major thyroid antigens-genetic immunization with thyroid peroxidase (hTPO) and thyroid-stimulating hormone receptor (hTSHR). 4. Characterize the mechanisms of T cell regulation in mTg-induced resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045960-12
Application #
6757997
Study Section
Endocrinology Study Section (END)
Program Officer
Spain, Lisa M
Project Start
1992-09-30
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
12
Fiscal Year
2004
Total Cost
$240,599
Indirect Cost
Name
Wayne State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kong, Yi-chi M; Brown, Nicholas K; Flynn, Jeffrey C et al. (2011) Efficacy of HLA-DRB1ýýý03:01 and H2E transgenic mouse strains to correlate pathogenic thyroglobulin epitopes for autoimmune thyroiditis. J Autoimmun 37:63-70
Kong, Yi-chi M; Wei, Wei-Zen; Tomer, Yaron (2010) Opportunistic autoimmune disorders: from immunotherapy to immune dysregulation. Ann N Y Acad Sci 1183:222-36
Morris, Gerald P; Brown, Nicholas K; Kong, Yi-chi M (2009) Naturally-existing CD4(+)CD25(+)Foxp3(+) regulatory T cells are required for tolerance to experimental autoimmune thyroiditis induced by either exogenous or endogenous autoantigen. J Autoimmun 33:68-76
Kong, Yi-chi M; Jacob, Jennifer B; Flynn, Jeffrey C et al. (2009) Autoimmune thyroiditis as an indicator of autoimmune sequelae during cancer immunotherapy. Autoimmun Rev 9:28-33
Kong, Yi-Chi M; Morris, Gerald P; Brown, Nicholas K et al. (2009) Autoimmune thyroiditis: a model uniquely suited to probe regulatory T cell function. J Autoimmun 33:239-46
Jacob, Jennifer B; Kong, Yi-chi M; Nalbantoglu, Ilke et al. (2009) Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity. J Immunol 182:5873-81
Brown, Nicholas K; McCormick, Daniel J; David, Chella S et al. (2008) H2E-derived Ealpha52-68 peptide presented by H2Ab interferes with clonal deletion of autoreactive T cells in autoimmune thyroiditis. J Immunol 180:7039-46
Brown, Nicholas K; McCormick, Daniel J; Brusic, Vladimir et al. (2008) A novel H2A-E+ transgenic model susceptible to human but not mouse thyroglobulin-induced autoimmune thyroiditis: identification of mouse pathogenic epitopes. Cell Immunol 251:1-7
Flynn, Jeffrey C; Gilbert, Jacqueline A; Meroueh, Chady et al. (2007) Chronic exposure in vivo to thyrotropin receptor stimulating monoclonal antibodies sustains high thyroxine levels and thyroid hyperplasia in thyroid autoimmunity-prone HLA-DRB1*0301 transgenic mice. Immunology 122:261-7
Kong, Yi-Chi M; Flynn, Jeffrey C; Banga, J Paul et al. (2007) Application of HLA class II transgenic mice to study autoimmune regulation. Thyroid 17:995-1003

Showing the most recent 10 out of 45 publications