The investigator has previously focused on the development of new animal models of autoimmune thyroid disease to understand the immunopathology of thyroid antigen self-recognition. Using both intact and the severe combined immunodeficient (scid) mouse, the investigators have characterized the immune response to the receptor for thyroid stimulating hormone (TSHR), a major autoimmune target in the human thyroid gland. For example, patients with Graves' disease have TSHR autoantibodies which act as TSH agonists and induce thyroid hyperfunction. However, the investigators immunization of mice with recombinant human TSHR induced TSHR autoantibodies lacking in TSH agonist activity. They hypothesize that such an immune response was secondary to minor, but immunologically critical, differences in structure and folding of the human immunizing antigen compared to the mouse TSHR. In this competing renewal, they will develop two new animal models for Graves' disease and evaluate their B-cell and T-cell reactivities. The two specific aims are: 1) to prepare recombinant glycosylated mouse TSHR antigen in an insect cell system. Purified receptor will then be used to immunize intact mice, and they will evaluate their immunological and thyroid functional responses in this homologous system; 2) to develop transgenic mice expressing thyroidal human TSHR antigen and to carry out genetic crosses to produce hTSHR mice homozygous for the scid mutation. These scid-hTSHR mice will be injected with intrathyroidal lymphocytes and engrafted with thyroid tissue from patients with Graves' disease. Hence, the human TSHR-Abs will be able to interact with the transgenic human TSHR and induce thyroid overactivity. The construction of both an intact mouse model for Graves' disease as well as the reproduction of the human disease in scid mice will allow a series of intervention procedures to be pursued as potential therapeutic approaches to a common human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045011-05
Application #
2518319
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Akolkar, Beena
Project Start
1993-01-01
Project End
1999-08-31
Budget Start
1997-09-20
Budget End
1998-08-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Ando, Takao; Davies, Terry F (2005) Monoclonal antibodies to the thyrotropin receptor. Clin Dev Immunol 12:137-43
Levin, Lara; Ban, Yoshiyuki; Concepcion, Erlinda et al. (2004) Analysis of HLA genes in families with autoimmune diabetes and thyroiditis. Hum Immunol 65:640-7
Ban, Yoshiyuki; Concepcion, Erlinda S; Villanueva, Ronald et al. (2004) Analysis of immune regulatory genes in familial and sporadic Graves' disease. J Clin Endocrinol Metab 89:4562-8
Ando, Takao; Latif, Rauf; Daniel, Samira et al. (2004) Dissecting linear and conformational epitopes on the native thyrotropin receptor. Endocrinology 145:5185-93
Ando, Takao; Latif, Rauf; Davies, Terry F (2004) Concentration-dependent regulation of thyrotropin receptor function by thyroid-stimulating antibody. J Clin Invest 113:1589-95
Ban, Y; Davies, T F; Greenberg, D A et al. (2004) Arginine at position 74 of the HLA-DR beta1 chain is associated with Graves' disease. Genes Immun 5:203-8
Latif, R; Ando, T; Davies, T F (2004) Monomerization as a prerequisite for intramolecular cleavage and shedding of the thyrotropin receptor. Endocrinology 145:5580-8
Ando, Takao; Davies, Terry F (2004) Self-recognition and the role of fetal microchimerism. Best Pract Res Clin Endocrinol Metab 18:197-211
Ciullo, I; Latif, R; Graves, P et al. (2003) Functional assessment of the thyrotropin receptor-beta subunit. Endocrinology 144:3176-81
Ando, Takao; Davies, Terry F (2003) Clinical Review 160: Postpartum autoimmune thyroid disease: the potential role of fetal microchimerism. J Clin Endocrinol Metab 88:2965-71

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