Studies on the development of a mouse model of Graves' disease

Barrett, Kerry (2003) Studies on the development of a mouse model of Graves' disease. Masters thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (5MB) [English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. (Original Version)

Abstract

Thyroid diseases are commonly caused by an autoimmune response to thyroid antigens. Hashimoto's thyroiditis (HT) is a T-cell mediated disease that ensues when the thyroid gland is destroyed by infiltrating lymphocytes specific antigens such as thyroglobulin (Tg) or thyroid peroxidase (TPO), leading to hypothyroidism. In Graves' disease (GD), autoantibodies against the thyroid-stimulating hormone receptor (TSHR) mimic the action of thyroid-stimulating hormone (TSH) and stimulate thyrocytes to overproduce thyroid hormones resulting in hyperthyroidism. Both spontaneous and experimentally induced animal models of HT exist and have contributed considerably to our understanding of the disease process. In contrast, difficulties in inducing TSHR- specific, stimulating antibodies have delayed the establishment of an animal model for GD. Recently, new strategies including immunization with TSHR-transfected fibroblasts and genetic immunization with eukaryotic expression vectors containing TSHR cDNA have provided promising results in mice, but further studies are required to optimize disease induction. The research described herein focuses on establishing a mouse model of GD through intradermal DNA immunization of BALB/cJ and AKR/J mice with varying doses of plasmid vectors carrying the homologous (murine) or heterologous (human) TSHR cDNA (Chapter 3). By using an algorithm-based approach, we have also identified human TSHR peptides with Aᴷ-binding potential and tested their immunogenicity and pathogenicity in AKR/J mice (Chapter 4). Finally, an alternative method for identifying pathogenic Tg epitopes using DNA immunization was introduced and preliminary data are being presented (Chapter 5).

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