Enhancement of experimental Graves' disease by intranasal administration of a T cell epitope of the thyrotropin receptor

Arima, Takayasu; Shimojo, Naoki; Yamaguchi, Kensei; Tomiita, Minako; Kohn, Leonard D.; Kohno, Yoichi

doi:10.1016/j.clim.2007.11.007

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…For several years, studies in Ad-TSHR-immunised mice have been used to investigate antigen-specific immune therapies as novel interventions: An early specific immune therapy approach in mouse models of Graves’ disease relied on intranasal administration of linear peptides as T cell epitopes which however did not prove successful [ 65 ]. Alternatively, a soluble form of the TSHR A domain (expressed as his-tagged protein in CHO cells) was shown to induce tolerance in mice when given before subsequent Ad-TSHR immunisations [ 66 ].…”

Section: Antigen-specific Immunotherapy For Thyroid Disease In Animalmentioning

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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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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Section: Antigen-specific Immunotherapy For Thyroid Disease In Animalmentioning

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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“…Preliminary results indicate that C10 has potential for autoimmune diseases regardless of thyroid function. Indeed, using Shimojo’s mouse model of Graves’-like disease (Arima et al 2008), we have found that the administration of C10 can prevent the onset of the disease in the majority of the mice without causing hypothyroidism (Cerrone et al . 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of aberrant MHC class-II gene expression in the development of autoimmune thyroid disease has been supported by several clinical and experimental observations. For example, mice immunized with fibroblasts expressing both human TSH receptor (TSHR) and an MHC class-II molecule develop pathological features of Graves’ disease (Shimojo et al 1996, Arima et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Regulation of major histocompatibility complex gene expression in thyroid epithelial cells by methimazole and phenylmethimazole

Giuliani

Bucci²,

Montani³

et al. 2009

Journal of Endocrinology

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Increased expression of major histocompatibility complex (MHC) class-I genes and aberrant expression of MHC class-II genes in thyroid epithelial cells (TECs) are associated with autoimmune thyroid diseases. Previous studies have shown that methimazole (MMI) reduces MHC class-I expression and inhibits interferon-g (IFN-g or IFNG as listed in the MGI Database)-induced expression of the MHC class-II genes in TECs. The action of MMI on the MHC class-I genes is transcriptional, but its mechanism has not been investigated previously. In the present study, we show that in Fisher rat thyroid cell line 5 cells, the ability of MMI and its novel derivative phenylmethimazole (C10) to decrease MHC class-I promoter activity is similar to TSH/cAMP suppression of MHC class-I and TSH receptor genes, and involves a 39 bp silencer containing a cAMP response element (CRE)-like site. Furthermore, we show that C10 decreases MHC class-I gene expression to a greater extent than MMI and at 10-to 50-fold lower concentrations. C10 also reduces the IFN-ginduced increase in the expression of MHC class-I and MHC class-II genes more effectively than MMI. Finally, we show that in comparison to MMI, C10 is a better inhibitor of specific protein-DNA complexes that are formed with a CRE-like element on the MHC class-II promoter. These data support the conclusion that the immunosuppressive mechanism by which MMI and C10 inhibit MHC gene expression mimics 'normal' hormonal suppression by TSH/cAMP.

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The VDR gene confers a genetic predisposition to Graves’ disease and Graves’ ophthalmopathy in the Southwest Chinese Han population

Zhou

Liang

Wang

et al. 2021

Gene

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Enhancement of experimental Graves' disease by intranasal administration of a T cell epitope of the thyrotropin receptor

Cited by 6 publications

References 24 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

Regulation of major histocompatibility complex gene expression in thyroid epithelial cells by methimazole and phenylmethimazole

The VDR gene confers a genetic predisposition to Graves’ disease and Graves’ ophthalmopathy in the Southwest Chinese Han population

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