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：
8522216
负责人：
Heth R Turnquist
金额：
$ 22.92万
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/8522216
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.

慢性同种异体血管病（CAV）或通过Intinna膨胀的移植动脉腔闭塞是主要的心脏移植晚期失败和患者发病率/死亡率的原因。 Cav病因是多因素的，包括通过IFN-7分泌T助手（Th）1型细胞（TH1）的促进和光滑的迁移/增殖肌肉细胞（SMC）进入动脉腔。使用雷帕霉素（RAPA）作为免疫抑制剂是与CAV减少相关，部分通过直接抑制SMC，但RAPA的机制不清楚宿主/移植免疫环境以限制CAV。我们做了小说观察到长时间的树突状细胞（DC）暴露于RAPA会赋予直流对促炎的抗药性通过上调IL-1R家族成员ST2（ST2L）的跨膜形式来刺激。此外负调控TLR和CD40信号传导，ST2L是IL-33的受体，IL-33是一种促进TH的细胞因子类型2（TH2）响应。 IL-33可以由多种细胞产生，包括内皮细胞（EC）和 SMC，并且可能具有心脏保护特性。当IL-33的功能被阻止或不存在ST2L时，在动脉粥样硬化和心脏肥大模型中，病理均恶化。但是，如果IL-33劝诫通过直接影响DC或可以抑制CAV的TH极化能力是不知道的。我们的中心假设是IL-33促进了直流。特别是表达ST2L的RAPA-DC Th2细胞增加极化能力，将防止CAV BV均诱导T细胞种群的Th2偏斜和直接对同种异体移植的心脏保护作用。在目标I中，我们假设IL-33诱导基因表达干旱信号传导途径介导DC在体外和体内促进Th2反应的能力。在AIM II中，我们假设单独的术后IL-33和RAPA，或者与治疗DC给药相结合导致无排斥的心脏同种异体移植存活，并通过调节宿主免疫系统来防止CAV 朝向Th2和调节性T细胞反应。在AIM III中，我们假设IL-33通过ST2L对免疫细胞和心脏同种异体移植细胞在急性和慢性排斥期间保护心脏同种异体移植物。