Prolonged TSH Receptor A Subunit Immunization of Female Mice Leads to a Long-Term Model of Graves' Disease, Tachycardia, and Cardiac Hypertrophy

Holthoff, Hans‐Peter; Goebel, Sylvia; Li, Zhongmin; Faßbender, Julia; Reimann, Andreas; Zeibig, Stefan; Münch, Götz; Ungerer, Martin

doi:10.1210/en.2014-1813

Cited by 42 publications

(54 citation statements)

References 29 publications

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“…Very comparable results were obtained with a second-generation assay using competition against the physiological agonist TSH [15]. …”

Section: Anti-tshr Antibody Titres and Capacity To Stimulate Camp In supporting

confidence: 57%

“…In a recent study [15], we extended these existing models of adenoviral TSH receptor immunisation by using a novel protocol in which regular injections were continued for 9 months, in order to permanently boost antibody production in mice. This protocol was established in parallel to a previous study which successfully introduced a long-term disease model of cardiomyopathy caused by anti-β1 receptor antibodies in rats [16, 17].…”

Section: Animal Models Of Disease—thyroid Alterations and Hyperthyroimentioning

confidence: 99%

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

Ungerer

Faßbender

et al. 2016

Clinic Rev Allerg Immunol

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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.

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“…Very comparable results were obtained with a second-generation assay using competition against the physiological agonist TSH [15]. …”

Section: Anti-tshr Antibody Titres and Capacity To Stimulate Camp In supporting

confidence: 57%

Section: Animal Models Of Disease—thyroid Alterations and Hyperthyroimentioning

confidence: 99%

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

Ungerer

Faßbender

et al. 2016

Clinic Rev Allerg Immunol

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“…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).…”

Section: Figurementioning

confidence: 99%

“…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). …”

Section: Introductionmentioning

confidence: 99%

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

Rapoport

Aliesky

Banuelos

et al. 2015

The Journal of Immunology

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Antibodies that stimulate the thyrotropin receptor (TSHR), the cause of Graves’ hyperthyroidism, only develop in humans. TSHR antibodies can be induced in mice by immunization but studying pathogenesis and therapeutic intervention requires a model without immunization. Spontaneous, iodine-accelerated, thyroid autoimmunity develops in NOD.H2h4 mice associated with thyroglobulin and thyroid-peroxidase, but not TSHR, antibodies. We hypothesized that transferring the human (h)TSHR A-subunit to NOD.H2h4 mice would result in loss of tolerance to this protein. BALB/c hTSHR A-subunit mice were bred to NOD.H2h4 mice and transgenic offspring were repeatedly backcrossed to NOD.H2h4 mice. All offspring developed antibodies to thyroglobulin and thyroid-peroxidase. However, only TSHR-transgenic NOD.H2h4 mice (TSHR/NOD.H2h4) developed pathogenic TSHR antibodies as detected using clinical Graves’ disease assays. As in humans, TSHR/NOD.H2h4 females were more prone than males to developing pathogenic TSHR antibodies. Fortunately, in view of the confounding effect of excess thyroid hormone on immune responses, spontaneously arising pathogenic (h)TSHR antibodies cross-react poorly with the mouse TSHR and do not cause thyrotoxicosis. In summary, the TSHR/NOD.H2h4 mouse strain develops spontaneous, iodine-accelerated, pathogenic TSHR antibodies in females, providing a unique model to investigate disease pathogenesis and test novel TSHR-antigen specific immunotherapies aimed at curing Graves’ disease in humans.

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“…Surprisingly, TSAbs persisted for more than 8 months after the final electroporation immunization (46), which is in contrast to the transient hyperthyroidism induced by intramuscular immunization wherein TSAb activity often began to decline much earlier or even completely disappeared (48). Another recently reported model of long-term Graves’ disease was established by prolonged intramuscular immunization with the ad-TSHR A subunit in female BALB/c mice (49). Long-term Graves’ models would be particularly useful for pharmacological analysis and for monitoring treatment response.…”

Section: Animal Models Of Graves’ Diseasementioning

confidence: 99%

Excessive Cytosolic DNA Fragments as a Potential Trigger of Graves’ Disease: An Encrypted Message Sent by Animal Models

et al. 2016

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Graves’ hyperthyroidism is caused by autoantibodies directed against the thyroid-stimulating hormone receptor (TSHR) that mimic the action of TSH. The establishment of Graves’ hyperthyroidism in experimental animals has proven to be an important approach to dissect the mechanisms of self-tolerance breakdown that lead to the production of thyroid-stimulating TSHR autoantibodies (TSAbs). “Shimojo’s model” was the first successful Graves’ animal model, wherein immunization with fibroblasts cells expressing TSHR and a major histocompatibility complex (MHC) class II molecule, but not either alone, induced TSAb production in AKR/N (H-2k) mice. This model highlights the importance of coincident MHC class II expression on TSHR-expressing cells in the development of Graves’ hyperthyroidism. These data are also in agreement with the observation that Graves’ thyrocytes often aberrantly express MHC class II antigens via mechanisms that remain unclear. Our group demonstrated that cytosolic self-genomic DNA fragments derived from sterile injured cells can induce aberrant MHC class II expression and production of multiple inflammatory cytokines and chemokines in thyrocytes in vitro, suggesting that severe cell injury may initiate immune responses in a way that is relevant to thyroid autoimmunity mediated by cytosolic DNA signaling. Furthermore, more recent successful Graves’ animal models were primarily established by immunizing mice with TSHR-expressing plasmids or adenovirus. In these models, double-stranded DNA vaccine contents presumably exert similar immune-activating effect in cells at inoculation sites and thus might pave the way toward successful Graves’ animal models. This review focuses on evidence suggesting that cell injury-derived self-DNA fragments could act as Graves’ disease triggers.

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Prolonged TSH Receptor A Subunit Immunization of Female Mice Leads to a Long-Term Model of Graves' Disease, Tachycardia, and Cardiac Hypertrophy

Cited by 42 publications

References 29 publications

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

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

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

Excessive Cytosolic DNA Fragments as a Potential Trigger of Graves’ Disease: An Encrypted Message Sent by Animal Models

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