Fingolimod Improves the Outcome of Experimental Graves' Disease and Associated Orbitopathy by Modulating the Autoimmune Response to the Thyroid-Stimulating Hormone Receptor

Plöhn, Svenja; Hose, Matthias; Schlüter, A; Michel, Lars; Díaz‐Cano, Salvador; Hendgen‐Cotta, Ulrike B.; Banga, J. Paul; Bechrakis, Nikolaos E.; Hansen, Wiebke; Eckstein, Anja; Berchner‐Pfannschmidt, Utta

doi:10.1089/thy.2018.0754

Cited by 15 publications

(13 citation statements)

References 63 publications

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“…Studies in GO murine models also supported T cell-mediated inflammation in the orbit in vivo . CD3 + total T cells were found to infiltrate into the orbital muscles and periorbital tissues of human (h) TSHR-A subunit plasmid-immunized BALB/c mice ( 35 , 46 ). The same phenomenon was found in mouse TSHR-A subunit plasmid-immunized BALB/c mice ( 47 ).…”

Section: Cd4 + and Cd8 + T Cellmentioning

confidence: 99%

Mechanisms That Underly T Cell Immunity in Graves’ Orbitopathy

et al. 2021

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Graves’ orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is the most common ocular abnormality of Graves’ disease. It is a disfiguring, invalidating, and potentially blinding orbital disease mediated by an interlocking and complicated immune network. Self-reactive T cells directly against thyroid-stimulating hormone receptor-bearing orbital fibroblasts contribute to autoimmune inflammation and tissue remodeling in GO orbital connective tissues. To date, T helper (Th) 1 (cytotoxic leaning) and Th2 (antibody leaning) cell subsets and an emerging role of Th17 (fibrotic leaning) cells have been implicated in GO pathogenesis. The potential feedback loops between orbital native residential CD34- fibroblasts, CD34+ infiltrating fibrocytes, and effector T cells may affect the T cell subset bias and the skewed pattern of cytokine production in the orbit, thereby determining the outcomes of GO autoimmune reactions. Characterization of the T cell subsets that drive GO and the cytokines they express may significantly advance our understanding of orbital autoimmunity and the development of promising therapeutic strategies against pathological T cells.

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Section: Cd4 + and Cd8 + T Cellmentioning

confidence: 99%

Mechanisms That Underly T Cell Immunity in Graves’ Orbitopathy

et al. 2021

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“…In the future thyroid specialists should consider immunosuppressive/immunomodulatory therapy not only for patients with severe GO but possibly also for patients which reach the cut off for relapse to improve the prognosis for ATD therapy, because it has been shown with the serial evaluation that once a patient reaches the relapse zone the probability to switch in the remission group is almost zero. Immunotherapeutic options have been recently tested to be effective in treating autoimmune hyperthyroidism as well in a GD mouse model [33].…”

Section: Cut Off Levels For Predictions Of Relapse During the Course mentioning

confidence: 99%

Predicting the Relapse of Hyperthyroidism in Treated Graves’ Disease with Orbitopathy by Serial Measurements of TSH-Receptor Autoantibodies

Stöhr

Oeverhaus

Lytton³

et al. 2021

Horm Metab Res

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The aim of this study was to investigate the potential of the new TSH-receptor antibody (TRAb) assays to predict remission or relapse of hyperthyroidism in patients with Graves’ disease (GD) and Graves’ orbitopathy (GO). TRAbs were measured retrospectively in sera from a cohort of GD patients with GO (n=117; remission n=38 and relapse n=79–Essen GO biobank) with automated binding immunoassays: TRAb Elecsys (Cobas Roche) and TRAb bridge assay (IMMULITE, Siemens), and the TSAb (thyroid stimulating Ab) cell-based bioassay (Thyretain, Quidel Corp.). To identify relapse risk/remission of hyperthyroidism patients were followed up at least 10 months after the end of antithyroid drug therapy (ATD) therapy. ROC plot analysis was performed to calculate cut-off levels of TRAb and TSAb for prediction of relapse and remission of hyperthyroidism. Cut-off serum levels are provided for timepoints around 3, 6, 10, and 15 months after the beginning of ATD. Repeated measurements of TRAb increase the rate of relapses predictions to 60% (Elecsys), 70% (IMMULITE), and 55% (Thyretain). Patients with remission have consistently TRAb levels below the cut off for relapse in repeated measurements. The cell-based bioassay was the most sensitive – and continued to be positive during follow up [at 15 months: 90% vs. 70% (IMMULITE) and 65% (Elecsys)]. Identification of relapsing hyperthyroidism is possible with automated immunoassays and cell-based bioassay especially with serial TRAb measurements during the course of ATD therapy. Patient who need eye surgery may profit from an early decision towards definitive treatment.

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“…With respect to this, our study is limited since it did not investigate Treg populations expressing Foxp3 which could have been differently affected by the antibiotic treatment. A few studies addressed the role of Treg expressing FoxP3 in GD/GO mouse models [33][34][35][36]. In a GD mouse model induced by adenovirus Ad-TSHR289, the frequencies of CD4+CD25+Foxp3+ Treg cells were decreased [34,36].…”

Section: • Fibroblastsmentioning

confidence: 99%

“…Another recent in vitro study suggested that sphingosine-1-phosphate (S1P) signaling is involved in orbitopathy [13]. In a follow-up study the immune modulatory potential of S1P receptor antagonist fingolimod (FTY720) was explored in a murine model for Graves' disease [33]. In the model TSHR autoimmunity was induced by immunization with a plasmid encoding for the A-subunit of the TSHR.…”

Section: Treatment Studies With In Vivo Models Of Go-translation Intomentioning

confidence: 99%

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Lessons from mouse models of Graves’ disease

et al. 2020

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Graves' disease (GD) is an autoimmune condition with the appearance of anti-TSH receptor (TSHR) autoantibodies in the serum. The consequence is the development of hyperthyroidism in most of the patients. In addition, in the most severe cases, patients can develop orbitopathy (GO), achropachy and dermopathy. The central role of the TSHR for the disease pathology has been well accepted. Therefore immunization against the TSHR is pivotal for the creation of in vivo models for the disease. However, TSHR is well preserved among the species and therefore the immune system is highly tolerant. Many differing attempts have been performed to break tolerance and to create a proper animal model in the last decades. The most successful have been achieved by introducing the human TSHR extracellular domain into the body, either by injection of plasmid or adenoviruses. Currently available models develop the whole spectrum of Graves' disease-autoimmune thyroid disease and orbitopathy and are suitable to study disease pathogenesis and to perform treatment studies. In recent publications new immunomodulatory therapies have been assessed and also diseaseprevention by inducing tolerance using small cyclic peptides from the antigenic region of the extracellular subunit of the TSHR.

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Fingolimod Improves the Outcome of Experimental Graves' Disease and Associated Orbitopathy by Modulating the Autoimmune Response to the Thyroid-Stimulating Hormone Receptor

Cited by 15 publications

References 63 publications

Mechanisms That Underly T Cell Immunity in Graves’ Orbitopathy

Mechanisms That Underly T Cell Immunity in Graves’ Orbitopathy

Predicting the Relapse of Hyperthyroidism in Treated Graves’ Disease with Orbitopathy by Serial Measurements of TSH-Receptor Autoantibodies

Lessons from mouse models of Graves’ disease

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