The Role of Platelets in Alloantibody Mediated Transplant Rejection

描述(申请人提供)：目前的免疫抑制方案已经大大延长了普通移植和移植受者的寿命，同种抗体介导的排斥反应仍然是移植长期存活的限制因素。动物模型已经表明，血小板与炎症的内皮细胞相互作用会放大免疫反应，增加白细胞的粘附性，并加剧动脉粥样硬化。然而，血小板在移植排斥反应中的作用还不是很清楚。我们建议的长期目标是确定血小板介导的移植排斥反应的机制。具体目标#1：证明在移植免疫反应中，血小板促进白细胞的运输和内皮细胞的炎症。白细胞和内皮细胞的相互作用对先天性和获得性免疫反应都是至关重要的。我们将展示血小板衍生的黏附分子在促进移植的同种异体免疫反应中的白细胞定位和运输方面的作用。特殊目的#2：证明血小板衍生的趋化因子促进移植中的先天免疫反应。血小板还分泌包括趋化因子在内的分子，这些分子具有免疫调节功能，并促进白细胞的运输。我们将证明，血小板衍生的趋化因子增加中性粒细胞(PMN)和单核细胞的激活和运输，这是天然同种免疫反应的一部分。具体目标#3：证明血小板衍生的趋化因子促进移植排斥反应中的获得性免疫反应。 公共卫生相关性：为了进一步探讨血小板衍生的趋化因子在移植排斥反应中的重要作用，我们将证明血小板也能增加移植导向的T细胞的激活和募集。仅在2005年，就有近27,000名美国人接受了器官移植。抗体介导的移植排斥反应仍然是移植失败的一个难以控制的原因，其机制尚不清楚。

DESCRIPTION (provided by applicant): Current immune suppression protocols have greatly prolonged the life span of the average transplant and transplant recipient, alloantibody mediated rejection remains a limiting factor in long-term transplant survival. Animal models have shown platelet interactions with an inflamed endothelium amplify the immune response, increase leukocyte adhesion, and exacerbate atherosclerosis. However, the role of platelets in transplant rejection is not well understood. The long-term objective of our proposal is to define mechanisms of platelet mediated transplant rejection. Specific Aim #1: To demonstrate that platelets promote leukocyte trafficking and endothelial cell inflammation in immune responses to transplants. Leukocyte and endothelial cell interactions are pivotal for both the innate and acquired immune responses. We will demonstrate the role of platelet derived adhesion molecules in promoting leukocyte localization and trafficking in alloimmune responses to transplants. Specific Aim #2: To demonstrate that platelet derived chemokines promote an innate immune response in transplantation. Platelets also secrete molecules, including chemokines, that have immuno-regulatory functions and promote leukocyte trafficking. We will demonstrate that platelet derived chemokines increase neutrophil (PMN) and monocyte activation and trafficking as part of innate alloimmune responses. Specific Aim #3: To demonstrate that platelet derived chemokines promote an acquired immune response in transplant rejection. PUBLIC HEALTH RELEVANCE: To further explore the important role of platelet derived chemokines in transplant rejection we will demonstrate that platelets also increase transplant directed T-cell activation and recruitment. In 2005 alone almost 27,000 Americans received an organ transplant. Antibody mediated transplant rejection remains a difficult to control cause of transplant loss and its mechanisms are poorly understood.