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Serpin treatment suppresses inflammatory vascular lesions in temporal artery implants (TAI) from patients with giant cell arteritis.

ABSTRACT: Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models. Serp-1 also reduced markers of myocardial injury in a Phase IIa clinical trial for unstable coronary disease. In recent work, we detected improved survival and decreased arterial inflammation in a mouse Herpesvirus model of IVS. Here we examine Serp-1 treatment of human temporal artery (TA) biopsies from patients with suspected TA GCA arteritis after implant (TAI) into the aorta of immunodeficient SCID (severe combined immunodeficiency) mice. TAI positive for arteritis (GCApos) had significantly increased inflammation and plaque when compared to negative TAI (GCAneg). Serp-1 significantly reduced intimal inflammation and CD11b+ cell infiltrates in TAI, with reduced splenocyte Th1, Th17, and Treg. Splenocytes from mice with GCApos grafts had increased gene expression for interleukin-1 beta (IL-1?), IL-17, and CD25 and decreased Factor II. Serp-1 decreased IL-1? expression. In conclusion, GCApos TAI xenografts in mice provide a viable disease model and have increased intimal inflammation as expected and Serp-1 significantly reduces vascular inflammatory lesions with reduced IL-1?.

SUBMITTER: Chen H

PROVIDER: S-EPMC4319900 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Serpin treatment suppresses inflammatory vascular lesions in temporal artery implants (TAI) from patients with giant cell arteritis.

Chen Hao H Zheng Donghang D Ambadapadi Sriram S Davids Jennifer J Ryden Sally S Samy Hazem H Bartee Mee M Sobel Eric E Dai Erbin E Liu Liying L Macaulay Colin C Yachnis Anthony A Weyand Cornelia C Thoburn Robert R Lucas Alexandra A

PloS one 20150206 2

Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models. Serp-1 also reduced markers of myocardial injury in a Phase IIa clinical trial for unstable coronary disease. In recent work, we d ...[more]

PMID: 25658487

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Project description:ObjectivesThe aim of this study was to quantitatively assess distinct immune cell subsets comprising inflammatory infiltrate in temporal artery biopsies (TABs) from patients with giant cell arteritis (GCA), and to link the obtained histopathological data with expression profiles of immune-related microRNAs (miRNAs).MethodsThe study included 68 formalin-fixed, paraffin-embedded TABs from treatment-naïve patients, including 30 histologically positive GCA and 16 negative GCA TABs, and 22 control non-GCA TABs. Quantitative assessment of histological parameters was performed using histopathological and immunohistochemical techniques. miRNA expression analysis was performed by quantitative real-time PCR.ResultsIntense transmural mononuclear inflammatory infiltrates in TAB-positive GCA arteries were predominantly composed of CD3+, CD4+ and CD8+ T lymphocytes, and CD68+ macrophages, accompanied by a strong nuclear overexpression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATC) in the lymphocyte infiltrate fraction. Furthermore, TAB-positive GCA arteries were characterized by significant overexpression of nine pro-inflammatory miRNAs (miR-132-3p/-142-3p/-142-5p/-155-5p/-210-3p/-212-3p/-326/-342-5p/-511-5p) and a significant under-expression of six regulatory immune-related miRNAs (miR-30a-5p/-30b-5p/-30c-5p/-30d-5p/-30e-5p/-124-3p), whose expression levels significantly associated with most evaluated histopathological parameters. Notably, we revealed miR-132-3p/-142-3p/-142-5p/-155-5p/-212-3p/-511-5p as major promoters of arterial inflammation and miR-30a-5p/-30c-5p/-30d-5p as putative regulators of NFATC signaling in TAB-positive GCA arteries.ConclusionOverall, we demonstrated that an altered arterial tissue-specific pro-inflammatory miRNA signature favors enhanced T cell-driven inflammation and macrophage activity in TAB-positive GCA arteries. Moreover, dysregulation of several immune-related miRNAs seems to contribute crucially to GCA pathogenesis, through impairing their regulatory activity towards T cell-mediated immune responses driven by the calcineurin (CaN)/NFAT signaling pathway, indicating their therapeutic, diagnostic and prognostic potential.

Project description:Background:Giant cell arteritis (GCA) is a common large vessel vasculitis of the elderly, often associated with sight loss. Glucocorticoids (GC remain the mainstay of treatment, although biologic treatments have been approved. Biomarkers predicting disease severity, relapse rates and damage are lacking in GCA.EULAR recommends ultrasound (US) as the first investigation for suspected GCA. The cardinal US finding, a non-compressible halo, is currently categorised as either negative or positive. However, the extent and severity of this finding may vary.In this study, we hypothesise whether the extent and severity of the halo sign [calculated as a single composite Halo score (HS)] of temporal and axillary arteries may be of diagnostic, prognostic and monitoring importance; whether baseline HS is linked to disease outcomes, relapses and damage; whether HS can stratify GCA patients for individual treatment needs; whether HS can function as an objective monitoring tool during follow up. Methods:This is a prospective, observational study. Suspected GCA Participants will be selected from the GCA FTC at the participating centres in the UK. Informed consent will be obtained, and patients managed as part of standard care. Patients with GCA will have HS (temporal and axillary arteries) measured at baseline and months 1,3,6 and 12 long with routine clinical assessments, blood sampling and patient-reported outcomes (EQ5D). Non-GCA patients will be discharged back to the referral team and will have a telephone interview in 6?months.We aim to recruit 272 suspected GCA referrals which should yield 68 patients (25% of referrals) with confirmed GCA. The recruitment will be completed in 1 year with an estimated total study period of 24?months. Discussion:The identification of prognostic factors in GCA is both timely and needed. A prognostic marker, such as the HS, could help to stratify GCA patients for an appropriate treatment regimen. Tocilizumab, an IL-6R blocking agent, switches off the acute phase response (C-Reactive Protein), making it difficult to measure the disease activity. Therefore, an independent HS, and changes in that score during treatment and follow-up, maybe a more objective measure of response compare to patient-reported symptoms and clinical assessment alone.

Dataset Information

Serpin treatment suppresses inflammatory vascular lesions in temporal artery implants (TAI) from patients with giant cell arteritis.

Publications

Serpin treatment suppresses inflammatory vascular lesions in temporal artery implants (TAI) from patients with giant cell arteritis.

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