The Role of Platelets in Alloantibody Mediated Transplant Rejection

描述（由申请人提供）：目前的免疫抑制方案大大延长了平均移植和移植受体的寿命，同种抗体介导的排斥反应仍然是长期移植存活的限制因素。动物模型已经显示血小板与发炎的内皮的相互作用放大免疫应答，增加白细胞粘附，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：证明血小板在对移植物的免疫应答中促进白细胞运输和内皮细胞炎症。白细胞和内皮细胞的相互作用是先天性和获得性免疫应答的关键。我们将证明血小板衍生的粘附分子在促进白细胞定位和移植物同种免疫反应中的作用。具体目标#2：证明血小板衍生趋化因子促进移植中的先天免疫应答。血小板还分泌具有免疫调节功能并促进白细胞运输的分子，包括趋化因子。我们将证明，血小板衍生的趋化因子增加中性粒细胞（PMN）和单核细胞活化和运输的一部分，先天性同种免疫反应。具体目标#3：证明血小板衍生的趋化因子促进移植排斥中的获得性免疫应答。 公共卫生相关性：为了进一步探讨血小板衍生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细胞活化和募集。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难以控制的移植失败原因，其机制知之甚少。

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.