The novel role of beta3 integrin in regulating alloimmunity

β3整合素在调节同种免疫中的新作用

• 批准号: 10573306
• 负责人: Reza Abdi
• 金额: $ 76.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-14 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573306
• 关键词: Acute; Adhesions; Allografting; Antigen Presentation; Biology; Blood Platelets; Blood Vessels; CD8-Positive T-Lymphocytes; Cell Communication; Cell Surface Receptors; Cells; Cellular Immunity; Chronic; Data; Drug Delivery Systems; Encapsulated; Endothelial Cells; Engraftment; Extracellular Matrix; Family; Goals; Graft Rejection; Heart Diseases; Heart Transplantation; ITGB3 gene; Immune; Immune Tolerance; Immunosuppressive Agents; Impairment; Inflammation; Inflammatory Response; Integrins; Interdisciplinary Study; Knockout Mice; Lesion; Mediating; Membrane Proteins; Methods; Mus; Nanodelivery; Natural Immunity; Organ; Organ Transplantation; Organ failure; Outcome; Pathogenesis; Patients; Perfusion; Periodicity; Play; RGD (sequence); Reperfusion Injury; Role; Signal Transduction; Site; T cell infiltration; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Wild Type Mouse; adaptive immunity; allograft rejection; antagonist; cell motility; cell type; conditional knockout; cytokine; heart allograft; improved; inflammatory milieu; inflammatory modulation; innovation; insight; isoimmunity; migration; mouse model; nanoparticle; new therapeutic target; novel; novel strategies; novel therapeutic intervention; optimal treatments; prevent; recruit; response; side effect; targeted delivery; trafficking

Abstract Heart transplantation is the optimal therapy for patients with irreversible, end-stage heart disease. However, a several challenges remain to improve allograft and recipient survival. Immunosuppressive agents used to prevent rejection have improved, but they still cannot consistently eliminate acute and chronic rejection, and they are implicated in the pathogenesis of organ failure. New insights into how innate and adaptive immunity contribute to rejection, identification of new therapeutic targets, and novel approaches to promote immune tolerance are major unmet needs in transplantation. Early innate inflammatory responses in the organs (e.g., due to ischemia-reperfusion injuries) enhance acute and chronic heart allograft rejection. Integrins are heterodimeric cell surface receptors involved in immune cell trafficking and signaling; therefore, they are attractive targets to inhibit inflammation, including transplant rejection. The main goal of this project is to elucidate the novel role of β3 integrin in regulating alloimmune responses via control of platelet- and T cell- mediated immunity. Our ultimate objective is to develop new anti-β3 integrin-based strategies to promote engraftment. Our data indicate that β3 integrin-/- mice (β3-/-) show significantly prolonged heart allograft survival in comparison to wild-type (WT) mice, a finding that is associated with reduced CD8+ T cell infiltration into the grafts. We also show that β3 is expressed by activated CD8+ T cells, and that the trafficking of T cells from β3-/- mice is impaired. Notably, targeting β3 integrin also substantially reduces lesions typical of chronic rejection. The β3 subunit is shared by the two integrin molecules, αVβ3 and αIIbβ3, which are expressed by T cells and platelets, respectively. Based on extensive preliminary data, our specific hypothesis is that β3 on both cell types contributes to rejection. In this proposal, we aim to define the relative roles of β3 integrins expressed on platelets (in early promotion of inflammatory responses) and T cells (in enhancement of alloimmunity) in mediating allograft rejection. Furthermore, our targeted delivery method of therapeutics usingnanoparticles (NPs) has emerged as a promising method that increases efficacy and reduces side effects. Here, we have developed first- in-class NPs for targeted delivery of cyclic RGD tripeptides (cRGD) to suppress β3 integrin- mediated recruitment of platelets and T cells for early reduction of chronic rejection, using a murine model of heart transplantation. In this proposal, we present three main aims to determine the roles of αIIbβ3 on platelets (Aim 1) and T cell- expressed β3 (Aim 2) in regulating alloimmunity. In Aim 3, we will perfuse organs prior to transplantation with NPs carrying cRGD to promote graft acceptance.

抽象的 心脏移植是针对不可逆性，心脏病患者的最佳治疗。但是， 为了改善同种异体移植和接受者的生存仍然存在一些挑战。免疫抑制剂曾经 防止拒绝有所改善，但他们仍然无法始终消除急性和慢性拒绝，他们 在器官衰竭的发病机理中隐含。关于先天和适应性免疫的新见解 有助于拒绝，识别新的治疗靶标以及促进免疫的新方法 公差是移植的主要未满足需求。器官的早期先天炎症反应（例如， 由于缺血 - 灌注损伤）增强了急性和慢性心脏同类排斥。整联蛋白是 涉及免疫细胞运输和信号传导的异二聚体细胞表面受体；因此，它们是 有吸引力的目标抑制注射，包括移植排斥。该项目的主要目标是阐明 β3整联蛋白在通过控制血小板和T细胞介导的同素免疫反应中的新作用 免疫。我们的最终目标是开发新的基于抗β3整合素的策略来促进植入。我们的 数据表明β3整联蛋白 - / - 小鼠（β3 - / - ）与与 野生型（WT）小鼠，这一发现与减少CD8+ T细胞浸润到移植物中有关。我们也是 表明β3由活化的CD8+ T细胞表达，并且从β3 - / - 小鼠的T细胞运输受损。 值得注意的是，靶向β3整联蛋白还大大降低了慢性排斥的典型病变。 β3亚基是 由两个整合素分子共享αVβ3和αIIBβ3，由T细胞和血小板表达 分别。基于广泛的初步数据，我们的具体假设是两种细胞类型的β3 有助于拒绝。在此提案中，我们旨在定义在血小板上表达的β3整合素的相对作用 （早期促进炎症反应）和T细胞（增强同种免疫性） 同种异体移植排斥。此外，我们使用纳米颗粒（NP）的目标递送方法已有 作为一种有望的方法出现，可提高效率并降低副作用。在这里，我们已经开发了首先 在靶向递送环状RGD三肽（CRGD）的阶层NPS抑制β3整联蛋白介导的募集 使用心脏移植的鼠模型，血小板和T细胞可早日减少慢性排斥。在 该提案，我们提出了三个主要目的，以确定αiibβ3在血小板上的作用（AIM 1）和T细胞 - 在调节中表达的β3（目标2）。在AIM 3中，我们将在移植之前灌注器官 NP携带CRGD以促进移植物接受。