Immunoregulatory mechanisms of IL-33 in heart transplantation

 描述(由申请人提供)：急性心脏移植(HTX)排斥反应通常可以通过可用的免疫抑制剂来避免，这种免疫抑制剂控制受者CD4+和CD8+T细胞对HTX呈递的同种异体抗原的反应。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血管系统病理性纤维化重塑过程。慢性排斥反应是一个重要的临床问题，在移植后10年多一点的时间内会导致大部分HTX的功能障碍和丢失。要解决这一问题，需要通过调节慢性排斥反应、促进免疫反应和塑造HTX修复来解决这个问题。我们已经发现了Treg的一个子集，它表达白介素33的受体ST2。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的细胞表达，在组织损伤时以功能性形式释放。在早期的研究中，我们发现在没有免疫抑制的情况下，在MHC不相合的心脏移植后应用IL-33可以扩大Treg，使移植物存活率增加两倍。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排斥反应，但IL-33刺激ST2+Treg对于预防慢性排斥反应至关重要 免疫渗出与心肌纤维化。这些数据支持我们的中心假设，即ST2+Treg对于预防慢性HTX排斥反应非常重要，这不仅是因为它们能够抑制异体抗原反应性T细胞，而且它们还能够促进组织修复和调节髓系细胞对IL-33的反应。这项应用的目的是确定ST2+Treg和IL-33控制炎症和介导移植后心脏组织修复的可用机制。为此，我们将利用HTX和心脏损伤研究 允许在Treg中进行特定基因打靶的转基因小鼠，以及缺乏IL-33的供体和受体小鼠。我们的数据还表明，慢性HTX排斥反应的发生可能是由于IL-12细胞因子抑制ST2+Treg，而有利于IL-33刺激有害的CD8+T细胞反应。因此，我们还将利用HTX模型，其中CD8+T细胞上缺少ST2，或者宿主细胞中靶向Treg和IL-33和IL-12细胞因子。抑制CD4+和CD8+T细胞反应的Treg对维持外周耐受和诱导TX耐受的要求已经得到很好的确立。局部或全身IL-33刺激ST2+Treg在组织损伤中的修复能力的概念是新的和未经检验的。提出的研究是创新的，因为他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所起的作用。这些研究也具有重要意义，因为它们将确定在移植中控制ST2+Treg修复能力的有针对性的机制。

 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.