Autologous T-Lymphocytes Stimulate Proliferation of Orbital Fibroblasts Derived from Patients with Graves’ Ophthalmopathy

Feldon, Steven E.; Park, D J John; O’Loughlin, Charles W.; Nguyen, Vu T.; Landskroner-Eiger, Shira; Chang, Donald C.; Thatcher, Thomas H.; Phipps, Richard P.

doi:10.1167/iovs.05-0605

Cited by 99 publications

(108 citation statements)

References 48 publications

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“…9 -11 In patients with severe TED, the initial inflammation subsides, but infiltration of muscle fibers by fibroblasts leads to fibrosis of the extraocular muscles, which limits their motility. 8,10,11 The lung is another organ in which the consequences of scarring are particularly severe. Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic remodeling of lung tissue, including excessive deposition of extracellular matrix components.…”

mentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Lehmann

Xia

Kulkarni

et al. 2011

The American Journal of Pathology

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Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-␤1 (TGF␤1). In this study, we demonstrate that TGF␤1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1=H-indole-3=-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGF␤1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGF␤1-driven myofibroblast differentiation in AhR ؊/؊ fibroblasts: Its ability to inhibit TGF␤1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

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confidence: 99%

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Lehmann

Xia

Kulkarni

et al. 2011

The American Journal of Pathology

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“…25 Progression of GO is due to recruitment of activated T cells that amplifies the B cell response. 26 During the initial stages of GO, orbital infiltration by T cells activate fibroblasts, which produce extracellular matrix, differentiate to adipocytes and proliferate. 26 Fibroblasts, in turn, can initiate the early T cell infiltration of the orbit secondary to IL-16 and RANTES secretion, due to its chemoattractant proprieties, that promote T cell migration.…”

Section: Pathogenesis Graves' Diseasementioning

confidence: 99%

“…26 During the initial stages of GO, orbital infiltration by T cells activate fibroblasts, which produce extracellular matrix, differentiate to adipocytes and proliferate. 26 Fibroblasts, in turn, can initiate the early T cell infiltration of the orbit secondary to IL-16 and RANTES secretion, due to its chemoattractant proprieties, that promote T cell migration. 27 An orbital volume increase is due to fibroblasts proliferation, and adipocyte and GAGs accumulation, whereas fibroblast infiltration of extraocular muscle fibres leads to fibrosis.…”

Section: Pathogenesis Graves' Diseasementioning

confidence: 99%

Radiotherapy for Graves’ disease. The possible role of low-dose radiotherapy

Arenas

Sabater

Jiménez

et al. 2016

Reports of Practical Oncology & Radiotherapy

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Graves' ophthalmopathyRadiotherapy for benign disease a b s t r a c t Immunomodulatory effects of low-dose radiotherapy (LD-RT) have been used for the treatment of several benign diseases, including arthrodegenerative and inflammatory pathologies. Graves' disease is an autoimmune disease and radiotherapy (RT) is a therapeutic option for ocular complications. The dose recommended in the clinical practice is 20 Gy (2 Gy/day). We hypothesized that lower doses (<10 Gy total dose, <1 Gy/day) could results in higher efficacy if we achieved anti-inflammatory and immunomodulatory effects of LD-RT.We review current evidence on the effects of RT in the treatment of Graves' disease and the possible use of LD-RT treatment strategy.

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“…Orbital fibroblasts exposed to IgG from GD patients produce the T cell chemoattractants IL-16 and RANTES due to the presence of autoantibodies towards the IGF-IR (40,41). Orbital fibroblasts from TAO patients proliferate when exposed to autologous T cells; a proliferation which is partly dependent upon CD40 on the fibroblasts interacting with T cell CD40L (61). The production of hyaluronan by orbital fibroblasts has been shown to be induced by autoantibody and CD40 stimulation (42, 62).…”

Section: Possible Interactions Between B Cells and Fibroblastsmentioning

confidence: 99%

The rationale for B lymphocyte depletion in Graves’ disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option

Fassi¹,

Nielsen²,

Hasselbalch³

et al. 2006

eur j endocrinol

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We have reviewed the immunology of thyroid autoimmunity with special reference to the importance of B lymphocytes (B cells) in thyroidal and extrathyroidal Graves' disease (GD), thus providing a framework for the hypothesis that B cell depletion may be beneficial in GD. Additionally, after reviewing the efficacy and safety in other autoimmune diseases, we propose that treatment with the B celldepleting agent Rituximab may become a clinically relevant treatment option in selected cases of GD, particularly when complicated with thyroid-associated ophthalmopathy.European Journal of Endocrinology 154 623-632

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Autologous T-Lymphocytes Stimulate Proliferation of Orbital Fibroblasts Derived from Patients with Graves’ Ophthalmopathy

Cited by 99 publications

References 48 publications

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Radiotherapy for Graves’ disease. The possible role of low-dose radiotherapy

The rationale for B lymphocyte depletion in Graves’ disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option

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