Current Insights into Animal Models of Graves' Disease and Orbitopathy

Wiesweg, B.; Johnson, Kristian; Eckstein, Anja; Berchner‐Pfannschmidt, Utta

doi:10.1055/s-0033-1343451

Cited by 32 publications

(27 citation statements)

References 31 publications

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“…Animal models of GO also seem to support a role of TSH-R in its pathogenesis. Genetic immunization of mice with TSH-R is followed by a syndrome that to some extent resembles GD [26]. Although in the majority of animal models of GD no eye changes were observed, features of GO were reported by two studies.…”

Section: Thyroid Autoantigens Possibly Involved In the Pathogenesis Omentioning

confidence: 96%

Total thyroid ablation in Graves’ orbitopathy

Menconi

Leo

Vitti

et al. 2015

J Endocrinol Invest

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Graves' orbitopathy (GO) is an autoimmune condition almost always associated with autoimmune thyroid disease, especially Graves' disease (GD). According to the most widely accepted model, the autoantigens responsible for GO would include molecules expressed by thyroid epithelial cells that are present also in orbital tissues. The high likelihood that the etiologies of GO and of the underlying autoimmune thyroid diseases are somehow linked is confirmed by the very close relationship between GO, the onset and the course of Graves' diseases, the size of the thyroid gland, and most importantly, thyroid function and thyroid treatment. Based on these considerations, it has been proposed that complete removal of thyroid antigens and of thyroid infiltrating lymphocytes, the so-called total thyroid ablation (TTA), may be followed by an attenuation of the immune reaction against orbital antigens, and ultimately by an amelioration of GO. The possibility that TTA, achieved by near total thyroidectomy followed by radioiodine, may be beneficial for GO was initially suggested by two retrospective studies and more recently by two prospective, randomized clinical trials conducted in patients with moderate GO treated with intravenous glucocorticoids. Although there seemed to be no difference in the long term, compared with near total thyroidectomy alone TTA was associated with a shorter time required for GO to improve, or anyway to reach its best possible outcome, and with a lesser requirement for additional treatments for GO to improve. Whether this is sufficient to offer ablation to patients remains a matter of discussion. At present, this procedure could be offered only to patients scheduled to thyroidectomy and glucocorticoid treatment.

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Section: Thyroid Autoantigens Possibly Involved In the Pathogenesis Omentioning

confidence: 96%

Total thyroid ablation in Graves’ orbitopathy

Menconi

Leo

Vitti

et al. 2015

J Endocrinol Invest

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“…Although this is an outstanding model for autoimmune thyroid hypertrophy, it does not lead to any orbital manifestations (8,11,19). There are a number of differences in the outcome of the anti-TSHR response between the adenovirus model and the plasmid-in vivo electroporation model described herein.…”

mentioning

confidence: 99%

“…Although a number of mouse models of GD have been developed (7), all singularly lack the complex pathology of orbital remodeling (7,8). Accordingly, other reported mouse models of GO have proved difficult to replicate (9 -11).…”

mentioning

confidence: 99%

“…Presently, the adenovirus model with hTSHR A-subunit immunization in female BALB/c mice is the most widely used experimental model of GD (7,8), due to its high disease incidence and reproducibility in different laboratories, irrespective of housing in germ-free or conventional 'clean' rooms (13,19,20). Although this is an outstanding model for autoimmune thyroid hypertrophy, it does not lead to any orbital manifestations (8,11,19).…”

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confidence: 99%

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Cutting Edge: Retrobulbar Inflammation, Adipogenesis, and Acute Orbital Congestion in a Preclinical Female Mouse Model of Graves' Orbitopathy Induced by Thyrotropin Receptor Plasmid-in Vivo Electroporation

et al. 2013

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Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.

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“…Since there are no spontaneous mouse model of GD and GO available, attempts to increase the expression of TSHR in vivo for the establishment of GD and GO has attracted a lot of attention, but at the same time exhibited various different results [3]. Among these attempts, genetic immunization using adenovirus vectors in female BALB/c mice has been reported to be able to induce the phenotype of GD [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous induction of Graves’ hyperthyroidism and Graves’ ophthalmopathy by TSHR genetic immunization in BALB/c mice

Xia

et al. 2017

PLoS ONE

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BackgroundGraves’ disease is the most common form of autoimmune thyroid disorder, characterized by hyperthyroidism due to circulating autoantibodies. To address the pathological features and establish a therapeutic approach of this disease, an animal model carrying the phenotype of Graves’ disease (GD) in concert with Graves’ Ophthalmopathy (GO) will be very important. However, there are no ideal animal models that are currently available. The aim of the present study is to establish an animal model of GD and GO disease, and its pathological features were further characterized.MethodsA recombinant plasmid pcDNA3.1- T289 was constructed by inserting the TSHR A-subunit gene into the expression vector pcDNA3.1, and genetic immunization was successfully performed by intramuscular injection of the plasmid pcDNA3.1-T289 on female 8-week-old BALB/c mice. Each injection was immediately followed by in vivo electroporation using ECM830 square wave electroporator. Morphological changes of the eyes were examined using 7.0T MRI scanner. Levels of serum T4 and TSHR antibodies (TRAb) were assessed by ELISA. The pathological changes of the thyroid and orbital tissues were examined by histological staining such as H&E staining and Alcian blue staining.ResultsMore than 90% of the immunized mice spontaneously developed goiter, and about 80% of the immunized mice manifested increased serum T4 and TRAb levels, combined with hypertrophy and hyperplasia of thyroid follicles. A significantly increased synthesis of hyaluronic acid was detected in in the immunized mice compared with the control groups.ConclusionWe have successfully established an animal model manifesting Graves’ hyperthyroidism and ophthalmopathy, which provides a useful tool for future study of the pathological features and the development of novel therapies of the diseases.

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Current Insights into Animal Models of Graves' Disease and Orbitopathy

Cited by 32 publications

References 31 publications

Total thyroid ablation in Graves’ orbitopathy

Total thyroid ablation in Graves’ orbitopathy

Cutting Edge: Retrobulbar Inflammation, Adipogenesis, and Acute Orbital Congestion in a Preclinical Female Mouse Model of Graves' Orbitopathy Induced by Thyrotropin Receptor Plasmid-in Vivo Electroporation

Simultaneous induction of Graves’ hyperthyroidism and Graves’ ophthalmopathy by TSHR genetic immunization in BALB/c mice

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