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：
9096202
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/9096202
关键词：
Acute Address Adverse effects Alloantigen Allografting Amphiregulin CD8B1 gene Cardiac Cell Differentiation process Cells Childhood Chronic Clinical Cytokine Network Pathway Data Dendritic Cells Endothelial Cells Epithelial Cells Failure Family member Fibroblasts Fibrosis Functional disorder Funding Gene Targeting Genes Graft Rejection Graft Survival Growth Health Heart Heart Transplantation IL2RA gene Immune Immune response Immunosuppression Immunosuppressive Agents Infiltration Inflammation Inflammatory Response Injury Interferon Type II Interleukin 2 Receptor Interleukin-12 Interleukin-13 Interleukin-2 Interleukins Lead Ligands Longevity Lymphoid Maintenance Mediating Modeling Mus Myelogenous Myeloid Cells Myocardium Organ Organ failure Outcome Patients Peripheral Pharmaceutical Preparations Play Prevention Problem Solving Process Production Quality of life Regulation Regulatory T-Lymphocyte Reporting Role Sampling Serum Shapes Skeletal muscle injury Solid Suppressor-Effector T-Lymphocytes Survival Rate T cell response T-Cell Proliferation T-Lymphocyte Testing Therapeutic Thinking Thymus Gland Tissues Transgenic Mice Transplantation Vascular Diseases Vascular remodeling base cardiac repair coronary fibrosis cytokine effective therapy heart allograft heart function immune function improved injured innovation interleukin-23 macrophage novel novel strategies novel therapeutics peripheral tolerance pleiotropism prevent receptor repaired response tissue repair

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（由适用提供）：急性心脏移植（HTX）拒绝通常被可用的免疫抑制剂避免，该免疫抑制剂控制受体CD4+和CD8+ T细胞对HTX提出的同种抗原的反应。不幸的是，这些药物无法预防慢性排斥，这是对心肌和脉管系统的致病性纤维化重塑过程的免疫驱动过程。慢性排斥是一个重大的临床问题，导致移植后十多年来大多数HTX的功能障碍和丧失。需要调节慢性拒绝免疫反应和塑造HTX修复的方法来解决此问题。我们发现了一个Treg的子集，该子集表达了ST2，即白介素（IL）-33的接收器。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做出了反应。 IL-33由HTX的细胞表达，并在组织损伤期间以功能形式释放。在早期的研究中，我们透露，MHC匹配后的心脏移植后IL-33在没有免疫抑制的情况下扩大了移植物生存的三倍。我们最近对ST2+和ST2- Treg的比较发现，尽管两者都能够控制T细胞介导的急性HTX排斥反应，但IL-33 ST2+ Treg的模拟对于预防慢性排斥相关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对于防止慢性HTX排斥反应至关重要，不仅是由于它们抑制异触素反应性T细胞的能力，而且还具有促进组织修复和调节IL-33的髓样细胞的能力。并介导移植后心脏组织修复。为此，我们将使用HTX和心脏损伤研究转基因小鼠允许在Treg和供体和缺乏IL-33的受体小鼠中进行特定基因靶向。我们的数据还表明，由于IL-12细胞因子抑制ST2+Treg并有利于IL-33刺激有害CD8+T细胞反应的IL-12细胞因子可能会导致慢性HTX排斥反应。因此，我们还将利用HTX模型，其中CD8+ T细胞不存在ST2，TREG和IL-33和IL-33和IL-12细胞因子靶向宿主细胞中。 TREG抑制CD4+和CD8+ T细胞反应的需求对维持外围耐受性和TX公差的诱导需求已得到很好的确定。局部或全身IL-33刺激组织损伤过程中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思考Treg在协调中扮演的角色的方法，以控制HTX结果的细胞因子网络。这些研究也很重要，因为它们将确定控制ST2+Treg在移植中的修复能力的目标机制。