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：
7714818
负责人：
Heth R Turnquist
金额：
$ 8.69万
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：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7714818
关键词：
Acute Alloantigen Allografting Animal Model ApoE knockout mouse 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 Expression Heart Hypertrophy Heart Transplantation Immune Immune response Immune system Immunobiology Immunosuppressive Agents In Vitro Inflammatory Infusion procedures Interleukin-1 Interleukin-1 Receptors Interleukin-12 Interleukin-4 Ligands Ligation MAP Kinase Gene Mediating Modeling Molecular Morbidity - disease rate Mus Myelogenous Outcome Pathology Patients Phase Physiologic pulse Population Postoperative Period Prevention Principal Investigator Property Proteins Regulation Reporting Resistance Signal Pathway Signal Transduction Sirolimus Smooth Muscle Myocytes Stimulus Stress T-Lymphocyte TNFRSF5 gene Th1 Cells Th2 Cells Therapeutic Toll-like receptors Transplant Recipients Up-Regulation Vaccines Vascular Diseases base cell motility constriction cytokine graft failure heart allograft in vivo insight isoimmunity macrophage migration mortality novel overexpression prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): 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 The 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 The 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.

描述（由申请人提供）：慢性同种异体血管病（CAV）或通过Intinna膨胀的移植动脉腔闭塞，是晚期心脏移植衰竭和患者发病率/死亡率的主要原因。 CAV病因是多因素的，包括通过IFN-7分泌T助手（Th）型1细胞（TH1）的促进以及平滑肌细胞（SMC）（SMC）迁移/增殖到动脉腔。使用雷帕霉素（RAPA）作为免疫抑制剂与CAV的减少有关，部分是通过直接抑制SMC的，但是RAPA改变宿主/移植物免疫环境以限制CAV的机制尚不清楚。我们已经进行了新的观察结果，即延长了树突状细胞（DC）暴露于RAPA，通过上调IL-1R家族成员ST2（ST2L）的跨膜形式来赋予DC对促炎性刺激的抗性。除了负调控TLR和CD40信号传导外，ST2L是IL-33的受体，IL-33是一种促进类型2（TH2）反应的细胞因子。 IL-33可以由包括内皮细胞（EC）和SMC在内的多种细胞产生，并且可能具有心脏保护特性。当IL-33的功能被阻断或不存在ST2L的功能时，在动脉粥样硬化和心脏肥大模型中都会加剧病理。但是，如果IL-33通过直接影响DC劝诫A极化能力，或者可以抑制CAV。我们的中心假设是IL-33促进了DC。尤其是表达ST2L，Th2细胞极化能力增加的RapA-DC，并且将防止CAV BV既诱导T细胞群体的Th2偏斜，又可以对同种异体移植物进行直接的心脏保护作用。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，我们假设单独使用后IL-33和RAPA，或者与治疗性直流给药相结合，导致无排斥的心脏同种异体移植物存活，并通过调节宿主免疫系统对TH2和调节性T细胞反应来防止CAV。在AIM III中，我们假设IL-33在免疫细胞和心脏同种异体移植细胞上都通过ST2L起作用，以保护急性和慢性排斥期间的心脏同种异体移植物。