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

Abstract

Graves' disease (GD) is a common organ-specific autoimmune disease with the prevalence between 0.5 and 2% in women. Several lines of evidence indicate that the shed A-subunit rather than the full-length thyrotropin receptor (TSHR) is the autoantigen that triggers autoimmunity and leads to hyperthyroidism. We have for the first time induced GD in female rhesus monkeys, which exhibit greater similarity to patients with GD than previous rodent models. After final immunization, the monkeys injected with adenovirus expressing the A-subunit of TSHR (A-sub-Ad) showed some characteristics of GD. When compared with controls, all the test monkeys had significantly higher TSHR antibody levels, half of them had increased total thyroxine (T 4 ) and free T 4 , and 50% developed goiter. To better understand the underlying mechanisms, quantitative studies on subpopulations of CD4CT helper cells were carried out. The data indicated that this GD model involved a mixed Th1 and Th2 response. Declined Treg proportions and increased Th17:Treg ratio are also observed. Our rhesus monkey model successfully mimicked GD in humans in many aspects. It would be a useful tool for furthering our understanding of the pathogenesis of GD and would potentially shorten the distance toward the prevention and treatment of this disease in human.

The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis

“…Subgroup analysis based on different types of AITD indicated that the proportion of circulating Tregs was lower in untreated GDs than in HCs, which is in accordance with previous studies that revealed a significantly lower percentage of Tregs in female rhesus monkeys with GD [32]. When Tregs were depleted, both disease incidence in resistant C57BL/6 mice and disease severity in susceptible BALB/c mice were enhanced [33].…”

A Unique Mouse Strain That Develops Spontaneous, Iodine-Accelerated, Pathogenic Antibodies to the Human Thyrotrophin Receptor

“…H2 h4 mice is the restoration of tolerance to the TSHR. Methods used to induce hyperthyroidism in mice, unsuitable for inducing self-tolerance to the TSHR, include: TSH injection (for example 48), TSAb mAb injection (45), hamster TSAb mAb hybridoma injection (44), TSHR immunization approaches to express TSHR in mice (5–9), hamsters (10) and rhesus monkeys (11), and expressing TSAb (B6B7) in a transgenic mouse (42,43). Confounding effects of hyperthyroidism on the immune system include altering the phenotype and function of antigen-presenting dendritic cells (46) and polarizing dendritic cells leading to impaired function of regulatory T-cells (Treg), a major change that may influence the emergence of pathogenic autoantibodies (47).…”

“…In 1996, a breakthrough occurred with the demonstration that in vivo expression of the TSHR was necessary to induce thyroid stimulating antibodies (TSAb) in mice, with resultant hyperthyroidism (4). Subsequently, different vectors and immunization approaches have been used to express TSHR in vivo leading to TSAb induction and hyperthyroidism, for example in some mouse strains (5–9), hamsters (10) and rhesus monkeys (11). …”

Review of Mouse Models of Graves’ Disease and Orbitopathy—Novel Treatment by Induction of Tolerance

“…Effects of Ad-TSHR immunisation were reported in three rhesus macaque monkeys which were successfully treated with seven consecutive injections over 20 weeks [29]. Clinical investigation of these three animals also indicated increased heart rate (no details on method were given).…”