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Immunoregulatory mechanisms of IL-33 in heart transplantation

IL-33在心脏移植中的免疫调节机制

基本信息

批准号：
9476343
负责人：
Heth R Turnquist
金额：
$ 37.91万
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9476343
关键词：
Acute Address Adverse effects Alloantigen Allografting Amphiregulin CD8-Positive T-Lymphocytes Cardiac Cell Differentiation process Cells Childhood Chronic Clinical Cytokine Network Pathway Data Dendritic Cells Endothelial Cells Epithelial Cells FOXP3 gene Failure Family member Fibroblasts Fibrosis Functional disorder Funding Gene Targeting Genes Graft Rejection Graft Survival Growth Growth Factor Heart Heart Injuries Heart Transplantation IL2RA gene Immune Immune response Immunosuppression Immunosuppressive Agents Infiltration Inflammation Inflammatory Response Injury Interferon Type II Interleukin Receptor Interleukin-12 Interleukin-13 Interleukin-2 Interleukins Lead Ligands Longevity Lymphoid Maintenance Mediating Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Myocardium Organ Organ failure Outcome Pathogenicity Patients Peripheral Pharmaceutical Preparations Play Prevention Problem Solving Process Production Quality of life Regulatory T-Lymphocyte Reporting Role Sampling Serum Shapes Skeletal muscle injury Solid Survival Rate T cell response T-Cell Proliferation T-Lymphocyte Testing Therapeutic Thinking Thymus Gland Tissues Transgenic Mice Transplant Recipients Transplantation Vascular Diseases Vascular remodeling base cardiac repair coronary fibrosis cytokine effective therapy heart allograft heart cell heart damage heart function immune function immunoregulation improved injured innovation interleukin-23 macrophage novel novel strategies novel therapeutics peripheral tolerance pleiotropism prevent public health relevance receptor repaired response tissue repair transplant model

项目摘要

DESCRIPTION (provided by applicant): Acute heart transplant (HTx) rejection is typically averted by available immunosuppressants, which control recipient CD4+ and CD8+ T cell responses to alloantigens presented by the HTx. Unfortunately, these drugs are unable to prevent chronic rejection, -an immune-driven process of pathogenic fibrotic remodeling of the myocardium and vasculature. Chronic rejection is a significant clinical PROBLEM and leads to the dysfunction and loss the majority of HTx in a little over ten years post transplantation. Approaches regulating chronic rejection-promoting immune responses AND shaping HTx repair are needed to solve this problem. We have discovered a subset of Treg that express ST2, the receptor for interleukin(IL)-33. Our preliminary data suggest that ST2+Treg respond to IL-33 with mechanisms controlling local inflammation and supporting tissue repair. IL-33 is expressed by cells of the HTx and is released in a functional form during tissue damage. In early studies we revealed that IL-33 administration post MHC-mismatched heart transplantation expanded Treg that tripled graft survival in the absence of immunosuppression. Our recent comparisons of ST2+ and ST2- Treg found that, while both are able to control T cell mediated acute HTx rejection, IL-33 stimulation of ST2+Treg is critical for prevention of chronic rejection-associated immune infiltration and myocardial fibrosis. These data support our CENTRAL HYPOTHESIS that ST2+Treg are important for preventing chronic HTx rejection due, not only to their capacity to suppress AlloAg-reactive T cells, but also their ability to facilitate tissue repair and regulat myeloid cells in response to IL-33. The OBJECTIVE of this application is to identify exploitable mechanisms by which ST2+Treg and IL-33 control inflammation and mediate cardiac tissue repair after transplantation. To that end, we will perform HTx and cardiac injury studies utilizing transgenic mice that allow specific gene targeting in Treg and donor and recipient mice lacking IL-33. Our data also suggest that chronic HTx rejection may arises as a result of IL-12 cytokines that suppress ST2+Treg and favor IL-33 stimulation of deleterious CD8+T cell responses. Thus, we will also take advantage of HTx models where ST2 is absent on CD8+ T cells or Treg and IL-33 and IL-12 cytokines targeted in host cells. The requirement of Treg suppression of CD4+ and CD8+ T cell responses for maintenance of peripheral tolerance and induction of Tx tolerance is well established. The concept that local or systemic IL-33 stimulates the reparative capacity of ST2+Treg during tissue injury is novel and untested. The proposed studies are INNOVATIVE because they offer a new way of thinking about the role Treg play in coordinating the cytokine networks controlling HTx outcomes. These studies are also SIGNIFICANT, as they will identify targetable mechanisms controlling the reparative capacity of ST2+Treg in transplantation.

描述（由申请人提供）：急性心脏移植（HTx）排斥通常可以通过可用的免疫抑制剂来避免，免疫抑制剂控制受体 CD4+ 和 CD8+ T 细胞对 HTx 呈递的同种抗原的反应。不幸的是，这些药物无法预防慢性排斥反应，这是一种免疫驱动的心肌和脉管系统致病性纤维化重塑过程。慢性排斥是一个重要的临床问题，在移植后十多年内会导致功能障碍和大部分 HTx 的丢失。解决这个问题需要采取调节慢性排斥促进免疫反应和塑造 HTx 修复的方法。我们发现了表达 ST2（白细胞介素 (IL)-33 受体）的 Treg 子集。我们的初步数据表明，ST2+Treg 通过控制局部炎症和支持组织修复的机制对 IL-33 做出反应。 IL-33 由 HTx 细胞表达，并在组织损伤期间以功能形式释放。在早期研究中，我们发现，MHC 不匹配的心脏移植后给予 IL-33 可以扩大 Treg，在没有免疫抑制的情况下使移植物存活率增加三倍。我们最近对 ST2+ 和 ST2- Treg 的比较发现，虽然两者都能够控制 T 细胞介导的急性 HTx 排斥，但 IL-33 对 ST2+ Treg 的刺激对于预防慢性排斥相关的至关重要。免疫浸润和心肌纤维化。这些数据支持我们的中心假设，即 ST2+Treg 对于预防慢性 HTx 排斥很重要，因为它们不仅能够抑制 AlloAg 反应性 T 细胞，而且还能够促进组织修复和调节骨髓细胞响应 IL-33。本申请的目的是确定 ST2+Treg 和 IL-33 控制炎症并介导移植后心脏组织修复的可利用机制。为此，我们将利用以下方法进行 HTx 和心脏损伤研究：允许在 Treg 以及缺乏 IL-33 的供体和受体小鼠中进行特定基因靶向的转基因小鼠。我们的数据还表明，慢性 HTx 排斥可能是由于 IL-12 细胞因子抑制 ST2+Treg 并有利于 IL-33 刺激有害 CD8+T 细胞反应而引起的。因此，我们还将利用 HTx 模型，其中 CD8+ T 细胞或 Treg 上不存在 ST2，以及宿主细胞中靶向的 IL-33 和 IL-12 细胞因子。 Treg 抑制 CD4+ 和 CD8+ T 细胞反应以维持外周耐受和诱导 Tx 耐受的要求已明确。局部或全身 IL-33 在组织损伤期间刺激 ST2+Treg 的修复能力的概念是新颖且未经测试的。拟议的研究具有创新性，因为它们提供了一种新的方式来思考 Treg 在协调控制 HTx 结果的细胞因子网络中的作用。这些研究也很重要，因为它们将确定控制移植中 ST2+Treg 修复能力的靶向机制。