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 心脏移植是不可逆的终末期心脏病患者的最佳治疗方法。 提高同种异体移植物和受体存活率仍然存在一些挑战。 预防排斥反应有所改善，但仍不能始终如一地消除急性排斥反应和慢性排斥反应，并且 涉及器官衰竭的发病机制。关于先天性和适应性免疫如何发生的新见解。 有助于排斥反应、识别新的治疗靶点以及促进免疫的新方法 耐受性是器官移植中未满足的主要需求。 由于缺血再灌注损伤），整合素可增强急性和慢性心脏同种异体移植排斥反应。 异二聚体细胞表面受体参与免疫细胞运输和信号传导；因此，它们是 抑制炎症（包括移植排斥）的有吸引力的目标该项目的主要目标是阐明。 β3整合素通过控制血小板和T细胞介导的同种免疫反应的新作用 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。 数据表明，与其他小鼠相比，β3 整合素-/- 小鼠 (β3-/-) 的同种异体心脏移植存活率显着延长 野生型（WT）小鼠，这一发现与移植物中 CD8+ T 细胞浸润减少有关。 显示β3由活化的CD8+ T细胞表达，并且来自β3-/-小鼠的T细胞的运输受到损害。 值得注意的是，靶向β3整合素还可以显着减少慢性排斥反应的典型病变。 由 T 细胞和血小板表达的两个整合素分子 αVβ3 和 αIIbβ3 共享， 基于广泛的初步数据，我们的具体假设是β3 在两种细胞类型上均存在。 在本提案中，我们的目标是定义血小板上表达的 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）介导 此外，我们使用纳米粒子 (NP) 的靶向治疗方法已经实现了同种异体移植排斥。 成为一种有前途的方法，可以提高疗效并减少副作用。在这里，我们首先开发了- 用于靶向递送环状 RGD 三肽 (cRGD) 以抑制 β3 整合素介导的募集的同类 NP 使用小鼠心脏移植模型，利用血小板和 T 细胞早期减少慢性排斥反应。 在该提案中，我们提出了三个主要目标来确定 αIIbβ3 对血小板（目标 1）和 T 细胞的作用 - 表达 β3（目标 2）在调节同种免疫中的作用 在目标 3 中，我们将在移植前灌注器官。 携带 cRGD 的 NP 可促进移植物接受。