The novel role of beta3 integrin in regulating alloimmunity

摘要 心脏移植是治疗不可逆终末期心脏病的最佳方法。但 提高同种异体移植物和受体存活率仍然存在一些挑战。免疫抑制剂用于 预防排斥反应已经有所改善，但它们仍然不能持续消除急性和慢性排斥反应， 与器官衰竭的发病机制有关。关于先天免疫和适应性免疫如何 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。 耐受性是移植中未满足的主要需求。器官中的早期先天性炎症反应（例如， 由于缺血-再灌注损伤）增强急性和慢性心脏同种异体移植物排斥。整合素是 参与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，以抑制炎症，包括移植排斥。这个项目的主要目标是阐明 β3整合素通过控制血小板和T细胞介导的调节同种免疫反应的新作用 免疫力我们的最终目标是开发新的基于抗β3整合素的策略以促进植入。我们 数据表明β3整联蛋白-/-小鼠（β3-/-）显示出显著延长的心脏移植物存活， 野生型（WT）小鼠，这一发现与移植物中CD 8 + T细胞浸润减少有关。我们也 显示β3由活化的CD 8 + T细胞表达，并且来自β3-/-小鼠的T细胞的运输受损。 值得注意的是，靶向β3整联蛋白还显著减少慢性排斥的典型病变。β3亚基是 由T细胞和血小板表达的两种整合素分子αVβ3和αIIbβ3共享， 分别基于广泛的初步数据，我们的具体假设是，两种细胞类型上的β3 有助于拒绝。在这个建议中，我们的目标是确定血小板上表达的β3整合素的相对作用， (in炎症反应的早期促进）和T细胞（在同种免疫增强中）介导 同种异体移植排斥反应。此外，我们使用纳米颗粒（NPs）的靶向治疗方法， 作为一种有前途的方法出现，增加疗效和减少副作用。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整联蛋白介导的募集的类内NP 血小板和T细胞的早期减少慢性排斥反应，使用小鼠心脏移植模型。在 在这项提议中，我们提出了三个主要目的来确定αIIbβ3对血小板（Aim 1）和T细胞的作用- 表达β3（Aim 2）调节同种免疫。在目标3中，我们将在移植前灌注器官， 携带cRGD的NP促进移植物接受。

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.