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

Abstract

Various approaches have been used to model human Graves’ disease in mice, including transfected fibroblasts, and plasmid or adenoviral immunisations with the extracellular A subunit of the human thyrotropin receptor (TSHR). Some of these models were only observed for a short time period or were self-limiting. A long-term model for human Graves’ disease was established in mice using continuing immunisations (4-weekly injections) with recombinant adenovirus expressing TSHR. Generation of TSHR binding cAMP-stimulatory antibodies, thyroid enlargement and alterations, elevated serum thyroxin levels, tachycardia and cardiac hypertrophy were maintained for at least 9 months in all Ad-TSHR-immunised mice. Here, we show that these mice suffer from orbitopathy, which was detected by serial orbital sectioning and histomorphometry. Attempts to treat established Graves’ disease in preclinical mouse model studies have included small molecule allosteric antagonists and specific antagonist antibodies which were isolated from hypothyroid patients. In addition, novel peptides have been conceived which mimic the cylindrical loops of the TSHR leucine-rich repeat domain, in order to re-establish tolerance toward the antigen. Here, we show preliminary results that one set of these peptides improves or even cures all signs and symptoms of Graves’ disease in mice after six consecutive monthly injections. First beneficial effects were observed 3–4 months after starting these therapies. In immunologically naïve mice, administration of the peptides did not induce any immune response.

Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self-tolerance for a murine model of autoimmune thyroid disease and Graves' orbitopathy

“…Mouse TSHRimmunized animals showed predominantly hyperplastic thyroids characterized by cuboid cylindrical follicular cells with a small amount of colloid (seven of 15 animals), with only one gland with hypothyroidism features characterized by thin follicles (one of 15 animals). S2a), as reported earlier for the adenovirus model [11], while body weights were stable (Supporting information, Fig. 2a).…”

“…Most probably as a consequence of 'hyperthyroidism', the mTSHR-immunized mice showed an increase in heart size (Supporting information, Fig. S2a), as reported earlier for the adenovirus model [11], while body weights were stable (Supporting information, Fig. S2b).…”

“…Another efficient murine model V C 2017 British Society for Immunology, Clinical and Experimental Immunology, 191: 255-267 of Graves' disease uses recombinant adenovirus encoding either the human TSHR holoreceptor or the A-subunit for the induction of autoimmune hyperthyroidism [9,10]. In this model, prolonged regular immunization throughout several months also leads to the development of GO [11]. In the models of autoimmune hyperthyroidism induced by delivery of human TSHR A-subunit cDNA, the induced pathogenic stimulatory antibodies to human TSHR crossreact with endogenous mouse TSHR in vivo to induce disease.…”

Interaction Between CCR6+ Th17 Cells and CD34+ Fibrocytes Promotes Inflammation: Implications in Graves' Orbitopathy in Chinese Population

“…39,40 Although encouraging findings of preclinical murine models for GO have appeared, there exist inconsistent results in different studies and a potentially confounding deviation from GO patients. 39,40 In conclusion, we discovered an elevated level of CCR6 þ Th17 cells in Chinese GO patients, which likely contribute to disease activity. Increased surface expression of IL-17RA, CD80, and CD86 on fibrocytes implies an imbalance in Th17-cell and Treg-cell function during GO.…”

Gut Microbiome in BALB/c and C57BL/6J Mice Undergoing Experimental Thyroid Autoimmunity Associate with Differences in Immunological Responses and Thyroid Function

“…We reported on the induction of orbital manifestations in female BALB/c mice that recapitulate a number of clinical and pathological features present in patients with GO, and showed reproducibility of the model housed in different animal units under variable environments [21,22]. In contrast, genetic predisposition to GO in the mouse model is not known, as only one inbred strain of BALB/c animals with susceptibility to experimental GO has been evaluated [21][22][23], although our earlier preliminary investigations by adenovirus immunisation showed no inflammatory infiltrate in the orbital tissue of C57BL/6 animals [18].…”