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: 10467425
• 负责人: Reza Abdi
• 金额: $ 77.71万
• 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/10467425
• 关键词: Acute; Adhesions; Allografting; Antigen Presentation; Biology; Blood Platelets; 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; Integrin alpha Chains; Integrins; Interdisciplinary Study; Knockout Mice; Lesion; Mediating; Membrane Proteins; Methods; Mus; Nano delivery; Natural Immunity; Organ; Organ Transplantation; Organ failure; Outcome; Pathogenesis; Patients; Perfusion; Periodicity; Play; RGD (sequence); Reperfusion Injury; Role; Signal Transduction; Site; T-Lymphocyte; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Tumor-infiltrating immune cells; Wild Type Mouse; adaptive immunity; allograft rejection; antagonist; base; cell motility; cell type; conditional knockout; cytokine; heart allograft; improved; inflammatory milieu; 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.

摘要 心脏移植是治疗不可逆的终末期心脏病的最佳方法。然而，a 在提高同种异体移植和受体存活率方面仍存在一些挑战。用于治疗的免疫抑制剂 预防排斥已经有所改善，但仍然不能始终如一地消除急性和慢性排斥，而且他们 与器官衰竭的发病机制有关。对先天免疫和获得性免疫如何 有助于排斥反应、确定新的治疗靶点和促进免疫的新方法 耐受性是移植中未得到满足的主要需求。器官中的早期先天炎症反应(例如， 由于缺血-再灌流损伤)增加了心脏移植的急性和慢性排斥反应。整合素是 异二聚体细胞表面受体参与免疫细胞的运输和信号传递；因此，它们是 有吸引力的靶点，以抑制炎症，包括移植排斥反应。这个项目的主要目标是阐明 β-3整合素通过调节血小板和T细胞介导的同种异体免疫反应的新作用 豁免权。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 数据显示，β3整合素/-小鼠(β3-/-)的移植心脏存活时间显著延长 野生型(WT)小鼠，这一发现与CD8+T细胞在移植物中的渗透减少有关。我们也 结果表明，β3是由活化的CD8+T细胞表达的，来自β3-/-小鼠的T细胞的转运受到损害。 值得注意的是，靶向β3整合素也大大减少了慢性排斥反应的典型损害。β3亚单位是 由T细胞和血小板表达的两个整合素分子αVβ3和αIIbβ3所共有的， 分别进行了分析。基于大量的初步数据，我们的具体假设是β3在这两种细胞类型上 会导致拒绝。在这个方案中，我们的目标是确定在血小板上表达的β3整合素的相对作用 (早期促进炎症反应)和T细胞(增强同种异体免疫) 同种异体排斥反应。此外，我们使用纳米颗粒(NPs)的靶向治疗方法已经 作为一种有希望的方法，它可以提高疗效并减少副作用。在这里，我们首先开发了- 类内NPs靶向递送环状RGD三肽抑制β3整合素介导的募集 利用小鼠心脏移植模型，研究了用于早期减少慢性排斥反应的血小板和T细胞。在……里面 在这个提议中，我们提出了三个主要目的来确定αIIbβ3在血小板(目标1)和T细胞上的作用。 在同种异体免疫调节中表达β3(Aim 2)。在目标3中，我们将在移植前用 携带cRGD的NPS可促进移植物的接受。