Animal Models of Graves' Hyperthyroidism

Abstract

Abstract. Graves' disease is a common organ-specific autoimmune disease characterized by overstimulation of the thyroid gland with agonistic anti-thyrotropin (TSH) receptor autoantibodies, which leads to hyperthyroidism and diffuse hyperplasia of the thyroid gland. Several groups including us have recently established several animal models of Graves' hyperthyroidism using novel immunization approaches, such as in vivo expression of the TSH receptor by injecting syngeneic living cells coexpressing the TSH receptor, the major histocompatibility complex (MHC) class II antigen and a costimulatory molecule, or genetic immunization using plasmid or adenovirus vectors coding the TSH receptor. This breakthrough has made it possible for us to study the pathogenesis of Graves' disease in more detail and has provided important insights into our understanding of disease pathogenesis. The important new findings that have emerged include: (i) the shed A subunit being the major autoantigen for TSAb, (ii) the significant role played by dendritic cells (DCs) as professional antigen-presenting cells in initiating disease development, (iii) contribution of MHC and particularly non-MHC genetic backgrounds in disease susceptibility, and (iv) influence of some particular infectious pathogens on disease development. However, the data regarding Th1/Th2 balance of TSH receptor-specific immune response or the association of Graves' hyperthyroidism with intrathyroidal lymphocytic infiltration are rather inconsistent. Future studies with these models will hopefully lead to better understanding of disease pathogenesis and help develop novel strategies for treatment and ultimately prevention of Graves' disease in humans.

Regulatory T cells but not T helper 17 cells are modulated in an animal model of Graves’ hyperthyroidism

“…Further, the animal models of Graves' disease testify that outcomes by immune manipulations to change the balance of Th1/Th2 cytokines are different among distinct models. Th2 immune response seems to be important in the Shimojo and the M12-TSHR models, while Th1 is likely to be crucial in the models involving the DNA-TSHR, Ad-TSHR, and DC-TSHR [7]. Together, these observations suggest that GD cannot be identified as a Th1 or Th2 immune-mediated disease.…”

CXCR3, CCR5, and CRTH2 Chemokine Receptor Expression in Lymphocytes Infiltrating Thyroid Nodules with Coincident Hashimoto’s Thyroiditis Obtained by Fine Needle Aspiration Biopsy

“…The data regarding Th1/Th2 balance of immune response in autoimmune thyroid diseases (AITD) and the relationship between serum cytokine and chemokine concentrations and their intrathyroidal expression are rather inconsistent [1]. Probably, both Th1- and Th2-immune response may be activated during different phases of both Hashimoto's thyroiditis and Graves' disease [2].…”

Hyperthyroid monkeys: a nonhuman primate model of experimental Graves' disease

“…It is well known that adaptive immunity can be differentiated into two distinct subsets: the interferon (IFN)-g-dominated Th1 cell-mediated immune response and the interleukin 4 (IL4)-dominated Th2 antibodymediated immune response (Mosmann & Coffman 1989, Singh et al 1999. There is a concern that the Th2 immune response is likely to be pivotal in the Shimojo and M12-TSHR models, while Th1 seems to be important in the DNA-TSHR, Ad-TSHR, and DC-TSHR models (Nagayama et al 2003, Barrett et al 2004, Nagayama 2005. Furthermore, there are contradictory data about Th1/Th2 balance shift in GD patients (Weetman et al 1990, Latrofa et al 2004).…”