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Influence of ST2 and IL-33 on cardiac allograft vasculopathy and outcome

ST2 和 IL-33 对心脏同种异体移植血管病变和结局的影响

基本信息

批准号：
8322657
负责人：
Heth R Turnquist
金额：
$ 24.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-22 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322657
关键词：
Acute Alloantigen Allografting Animal Model Apolipoprotein E Arterial Fatty Streak Atherosclerosis Bioinformatics CD4 Positive T Lymphocytes Cardiac Cardiovascular system Cell Proliferation Cells Chronic Clinical Research Data Dendritic Cells Development Dose Endothelial Cells Environment Etiology Exposure to Failure Family member Gene Activation Gene Expression Heart Diseases Heart Hypertrophy Heart Transplantation Immune Immune response Immune system Immunobiology Immunosuppressive Agents In Vitro Inflammatory Infusion procedures Interferons Interleukin-1 Interleukin-12 Interleukin-4 Knockout Mice Ligands Ligation MAP Kinase Gene Mediating Modeling Molecular Morbidity - disease rate Mus Myelogenous Outcome Pathology Patients Phase Physiologic pulse Population Postoperative Period Prevention Property Proteins Regulation Regulatory T-Lymphocyte Reporting Resistance Signal Pathway Signal Transduction Sirolimus Smooth Muscle Myocytes Staging Stimulus Stress T cell response T-Lymphocyte TNFRSF5 gene Th1 Cells Therapeutic Toll-like receptors Transplant Recipients Transplantation Up-Regulation Vaccines Vascular Diseases allograft rejection base cell motility constriction cytokine graft failure heart allograft improved in vivo insight isoimmunity macrophage migration mortality novel overexpression prevent receptor response

项目摘要

Chronic allograft vasculopathy (CAV), or graft arterial lumen occlusion through intinna expansion, is a major cause of late heart transplant failure and patient morbidity/mortality. CAV etiology is multi-factorial, including promotion by IFN-7 secreting T helper (Th) Type-1 cells (Th1) and the migration/proliferation of smooth muscle cells (SMC) into arterial lumen. The use of rapamycin (RAPA) as an immunosuppressant is associated with reduced CAV, in part through direct inhibition of SMC, but the mechanisms by which RAPA alters the host/graft immunological environment to limit CAV are unclear. We have made the novel observation that prolonged dendritic cell (DC) exposure to RAPA confers DC resistance to pro-inflammatory stimuli by upregulating the transmembrane form of the IL-1R family member ST2 (ST2L). In addition to negatively regulating TLR and CD40 signaling, ST2L is the receptor for IL-33, a cytokine that promotes Th Type-2 (Th2) responses. IL-33 can be produced by a variety of cells, including endothelial cells (EC) and SMC, and may have cardioprotective properties. When the function of IL-33 is blocked, or ST2L is absent, pathology is exacerbated in both atherosclerosis and cardiac hypertrophy models. However, if IL-33 exhorts a Th polarization capacity through direct influence on DC, or can inhibit CAV is not known. Our central hypothesis is that IL-33 promotes DC. especially RAPA-DC expressing increased ST2L, Th2 cell polarization capacity and will prevent CAV bv both inducing Th2 skewing of T cell populations and direct cardioprotective effects on the allograft. In AIM I, we hypothesize that IL-33 induces gene expression arid signaling pathways that mediate a DC capacity to promote Th2 response in vitro and in vivo. In AIM II, we hypothesize that post-operative IL-33 and RAPA alone or, combined with therapeutic DC administration, leads to rejection-free heart allograft survival and prevents CAV by modulating the host immune system towards Th2 and regulatory T cell responses. In AIM III we hypothesize that IL-33 acts via ST2L on both immune cells and cardiac allograft cells to protect cardiac allografts during acute and chronic rejection.

慢性移植物血管病（CAV），或通过内膜扩张导致的移植物动脉管腔闭塞，是一种主要的晚期心脏移植失败的原因和患者发病率/死亡率。CAV病因是多因素的，包括 IFN-7分泌性T辅助细胞（Th）1型细胞（Th 1）的促进作用和平滑肌细胞的迁移/增殖平滑肌细胞（SMC）进入动脉腔。雷帕霉素（RAPA）作为免疫抑制剂的用途是与CAV减少相关，部分通过直接抑制SMC，但RAPA的机制改变宿主/移植物免疫环境以限制CAV尚不清楚。我们把小说观察到树突状细胞（DC）长期暴露于RAPA赋予DC对促炎性细胞因子的抗性。通过上调IL-1 R家族成员ST 2（ST 2L）的跨膜形式刺激。除了负调节TLR和CD 40信号，ST 2L是IL-33的受体，IL-33是一种促进Th细胞增殖的细胞因子， 2型（Th 2）反应。IL-33可以由多种细胞产生，包括内皮细胞（EC）和内皮细胞（EC）。 SMC，并可能具有心脏保护特性。当IL-33的功能被阻断或ST 2L缺失时，病理学在动脉粥样硬化和心脏肥大模型中均加重。但是，如果IL-33 a Th通过直接影响DC的极化能力，或能抑制CAV尚不清楚。我们的中央假设IL-33促进DC。特别是RAPA-DC表达增加了ST 2L、Th 2细胞极化能力，并将通过诱导T细胞群的Th 2偏斜和直接诱导T细胞群的Th 2偏斜来防止CAV。对同种异体移植物的心脏保护作用。在AIM I中，我们假设IL-33诱导基因表达，在体外和体内介导DC促进Th 2应答的能力的信号通路。在AIM II中，我们假设手术后IL-33和RAPA单独或与治疗性DC联合给药，导致无排斥反应的心脏移植物存活，并通过调节宿主免疫系统来预防CAV Th 2和调节性T细胞反应。在AIM III中，我们假设IL-33通过ST 2L作用于免疫细胞和心脏同种异体移植物细胞在急性和慢性排斥反应期间保护心脏同种异体移植物。