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，同种异体抗体介导的排斥反应仍然是长期移植生存的限制因素。动物模型显示血小板与炎症内皮的相互作用增强免疫反应，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尚不清楚。我们建议的长期目标是确定血小板介导的移植排斥的机制。具体目标#1：证明血小板在移植免疫反应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和获得性免疫反应的关键。我们将展示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。特异性目的2：证明血小板来源的趋化因子促进移植中的先天免疫反应。血小板还分泌分子，包括趋化因子，具有免疫调节功能并促进白细胞运输。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作为先天同种免疫反应的一部分。特异性目的#3：证明血小板来源的趋化因子促进移植排斥反应的获得性免疫反应。

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.