Innate Recognition of Allogeneic Non-Self

摘要 尽管急性排斥率显著降低，但同种异体移植的长期存活率仍然存在。 停滞不前，大多数移植器官的半衰期在10年左右。一位校长 移植物长期效果差的原因是持续的宿主免疫激活导致慢性 拒绝。我们在这里提出，持久免疫激活是由先天免疫驱动的 系统，特别是由单核细胞识别同种异体并获得记忆以 它。单核细胞在同种异体组织上检测非MHC和MHC多态并获得 能够针对捐赠者的MHC进行增强的召回反应。此响应将导致 成熟的IL-12+单核细胞来源的DC维持移植物的渗透 炎症Th1反应，是同种异体移植排斥反应的关键。这笔赠款的目的是 应用于目标1研究单核细胞的分子和细胞机制 记忆的产生和对同种异体MHC的特异性，并在目标2中确定 单核细胞记忆在同种异体慢性排斥反应中的作用完成拟议的 研究可能会对器官移植产生重大影响，因为它揭示了新的先天 免疫系统的目标是预防或治疗排斥反应。

Abstract Despite significant reduction in acute rejection rates, long-term allograft survival remains stagnant, hovering at around a half-life of 10 years for most transplanted organs. A principal cause of poor long-term graft outcomes is persistent host immune activation leading to chronic rejection. We propose here that persistent immune activation is driven by the innate immune system, specifically by monocytes which recognize allogeneic non-self and acquire memory to it. Monocytes sense non-MHC and MHC polymorphisms on allogeneic tissues and acquire the ability to mount an enhanced recall response specific to donor MHC. This response results in sustained graft infiltration by mature, IL-12+, monocyte-derived DCs that maintain an inflammatory Th1 response and are critical for allograft rejection. The goal of this grant application is to investigate in Aim 1 the molecular and cellular mechanisms of monocyte memory generation and specificity to allogeneic MHC, and to determine in Aim 2 the contribution of monocyte memory to chronic allograft rejection. Completion of the proposed studies is likely to have a significant impact on organ transplantation by uncovering novel innate immune system targets to prevent or treat rejection.