Experimental autoimmune thyroiditis (EAT) in mice serves as a prototype for the study of chronic lymphocytic thyroiditis (Hashimoto's disease), as well as other organ-specific autoimmune disorders. The overall goal of this project is to use murine EAT to probe the recognitory and pathogenic mechanisms leading to thyroid dysfunction. As in the human, the autoimmune response is under genetic control. A major thyroid antigen is thyroglobulin (Tg) which can be used to induce EAT in genetically susceptible strains, linked to the major histocompatibility complex (MHC). The recognitory mechanism is under MHC I-A subregion control, but pathogenic mechanisms are influenced by other modifying genes such as the D end of the MHC. We have observed that shared determinants between human and mouse Tg can activate the T lymphocytes of immunized mice to produce thyroid inflammation in vivo and generate cytotoxic T cells in vitro.
Our aims are to: 1) propagate T cell subsets recognizing mouse Tg-specific or shared epitopes by cloning, as well as by fusion to form T cell hybridomas; 2) characterize the T cell lines and their progenies further as to I-subregion restriction and epitope specificity; 3) determine the functional capacities of the T cell lines (and clones) to cause disease in vivo and develop cytotoxicity in vitro, and the effect of D-end genes; 4) examine the kinetics of T cell subsets infiltrating the thyroid and their in situ distribution in immunized animals; and 5) analyze and compare the kinetics of thyroid infiltration of in vitro activated cell lines with those of intact animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK031827-04
Application #
3230368
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1983-01-01
Project End
1990-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Nabozny, G H; Flynn, J C; Kong, Y C (1991) Synergism between mouse thyroglobulin- and vaccination-induced suppressor mechanisms in murine experimental autoimmune thyroiditis. Cell Immunol 136:340-8
Flynn, J C; Kong, Y C (1991) In vivo evidence for CD4+ and CD8+ suppressor T cells in vaccination-induced suppression of murine experimental autoimmune thyroiditis. Clin Immunol Immunopathol 60:484-94
Conaway, D H; Giraldo, A A; David, C S et al. (1990) In situ analysis of T cell subset composition in experimental autoimmune thyroiditis after adoptive transfer of activated spleen cells. Cell Immunol 125:247-53
Krco, C J; Gores, A; David, C S et al. (1990) Immunogenetic aspects of human thyroglobulin-reactive T cell lines and hybridomas. J Immunogenet 17:361-70
Nabozny, G H; Simon, L L; Kong, Y C (1990) Suppression in experimental autoimmune thyroiditis: the role of unique and shared determinants on mouse thyroglobulin in self-tolerance. Cell Immunol 131:140-9
Kong, Y C (1990) Shared thyroglobulin epitopes in autoimmune thyroiditis. Immunol Ser 52:229-40
Conaway, D H; Giraldo, A A; David, C S et al. (1989) In situ kinetic analysis of thyroid lymphocyte infiltrate in mice developing experimental autoimmune thyroiditis. Clin Immunol Immunopathol 53:346-53
Flynn, J C; Conaway, D H; Cobbold, S et al. (1989) Depletion of L3T4+ and Lyt-2+ cells by rat monoclonal antibodies alters the development of adoptively transferred experimental autoimmune thyroiditis. Cell Immunol 122:377-90
Okayasu, I; Hatakeyama, S; Kong, Y C (1989) Long-term observation and effect of age on induction of experimental autoimmune thyroiditis in susceptible and resistant mice. Clin Immunol Immunopathol 53:254-67
Kong, Y M; Giraldo, A A; Waldmann, H et al. (1989) Resistance to experimental autoimmune thyroiditis: L3T4+ cells as mediators of both thyroglobulin-activated and TSH-induced suppression. Clin Immunol Immunopathol 51:38-54

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