Dataset Information

Increased Soluble CD137 Levels and CD4+ T-Cell-Associated Expression of CD137 in Acute Atherothrombotic Stroke.

ABSTRACT: As a proinflammatory cytokine, CD137 (4-1BB, TNFRSF9) is present in membrane-bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2.7 pg/ml) and CD137 expression on CD4+ T cells (4.9 ± 3.2%) compared with normal controls (1.1 pg/ml, P < 0.01; 1.3 ± 1.0%, P < 0.01). Alterations in CD137 expression may enhance ischemia-induced inflammatory responses via bidirectional signaling and, consequently, aggravate brain injury in early stages of this disorder.

SUBMITTER: He Y

PROVIDER: S-EPMC6039206 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Increased Soluble CD137 Levels and CD4+ T-Cell-Associated Expression of CD137 in Acute Atherothrombotic Stroke.

He Yang Y Ao Dong-Hui DH Li Xiao-Qing XQ Zhong Shan-Shan SS A Rong R Wang Yang-Yang YY Xiang Ya-Juan YJ Xu Bao-Lei BL Yang Ting-Ting TT Gao Xu-Guang XG Liu Guang-Zhi GZ

Clinical and translational science 20180426 4

As a proinflammatory cytokine, CD137 (4-1BB, TNFRSF9) is present in membrane-bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cy ...[more]

PMID: 29697202

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Project description:BackgroundOn the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic.MethodsWe used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression.ResultsCD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137.ConclusionsCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.

Project description:Background and purposeAtherothrombotic cerebral infarction [atherothrombotic stroke (ATS)] shares common risk factors and pathophysiological mechanisms with coronary artery disease (CAD), and both diseases appear to have common susceptibility loci. The muscle RAS oncogene homolog gene (MRAS) has been identified as a susceptibility locus for CAD and is implicated in atherosclerosis. The aim of this study was to elucidate whether the single-nucleotide polymorphisms (SNPs) and haplotypes of MRAS are associated with increased risk of ATS in a population of Han Chinese.MethodsA case-controlled association study was conducted in which only patients with ATS (identified as a major subtype in the Korean modification of the Trial of Org 10172 in Acute Stroke Treatment classification) were enrolled. Subgroup analyses were carried out to determine whether the effect of the MRAS polymorphism was specific to age and gender among the subjects.ResultsIn total, 194 ATS and 186 control subjects were included in the present study. Two tagging SNPs were identified in MRAS (rs40593 and rs3755751). A multivariate regression analysis revealed a positive association between rs40593 and ATS under dominant and additive models after adjustment for covariates. Subgroup analyses revealed that there were no gender differences with respect to allele or genotype frequencies between the groups. The AG genotype for rs40593 (p=0.028), the CT genotype for rs3755751 (p=0.036), and G-allele carriers (AG plus GG) for rs40593 (p=0.015) exhibited a significant protective effect among those aged ≥45 years. For the haplotype analysis, ATS subjects aged ≥45 years had a higher frequency of the ACAC haplotype (76.0%) than the controls (68.1%; p<0.05); that haplotype was associated with an increased risk of ATS.ConclusionsThe obtained data suggest a positive association between MRAS and ATS among the Han Chinese. Further studies should be performed with larger sample and among different ethnic populations, and gene-gene or gene-environment interactions should be considered.

Dataset Information

Increased Soluble CD137 Levels and CD4+ T-Cell-Associated Expression of CD137 in Acute Atherothrombotic Stroke.

Publications

Increased Soluble CD137 Levels and CD4+ T-Cell-Associated Expression of CD137 in Acute Atherothrombotic Stroke.

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