Functional Roles of NKp46 in Transplantation

描述（由申请人提供）：自然杀伤（NK）细胞是先天免疫系统的效应细胞，可以在没有事先致敏的情况下溶解靶细胞，在宿主对病原体和转化细胞的防御中起重要作用。NK细胞的功能是由通过种系编码的抑制和激活受体传递的负信号和正信号的平衡控制的。虽然“自我缺失”的概念可能表明NK细胞可以靶向外来同种异体移植物，但普遍的观点是NK细胞在最终导致移植物排斥的机制中并不活跃。然而，最近的研究对这一结论提出了质疑，认为NK细胞参与了急性和慢性同种异体移植排斥反应。相当矛盾的是，NK细胞也被证明促进对同种异体移植物的耐受性。为了调和这些不同的观察结果，我们假设NK细胞通过激活受体的表达和功能，调节免疫系统的其他细胞，特别是树突状细胞（DC）。事实上，我们已经证明DC介导的NK细胞激活依赖于通过NKp46激活受体的信号传导。本探索性/发展性建议的目的是确定NK相互作用如何调节移植后的适应性免疫反应。我们提出了两个综合的特异性目标：1)确定移植后NK细胞的表型和功能特征，2)确定NKp46如何参与移植后NK细胞的功能，以验证我们的假设，即NKp46在移植后调节NK介导的免疫功能中起重要作用。我们的创新研究将对设计预防移植物排斥反应和促进对同种异体移植物的耐受性的策略具有重要意义。

DESCRIPTION (provided by applicant): Natural killer (NK) cells are effector cells of the innate immune system that can lyse target cells without prior sensitization, and have an important role in host defense to pathogens and transformed cells. NK cell function is controlled by a balance of negative and positive signals transmitted via germ-line encoded inhibitory and activating receptors. Although the concept of "missing-self" would suggest NK cells could target foreign allografts, the prevailing dogma has been that NK cells are not active participants in the mechanisms that culminate in graft rejection. Recent studies, however, challenge this conclusion and instead implicate NK cells in both acute and chronic allograft rejection. Quite paradoxically, NK cells have also been shown to facilitate tolerance to an allograft. To reconcile these disparate observations we hypothesized that NK cells, through expression and function of activating receptors, regulate other cells of the immune system especially dendritic cells (DC). Indeed we have demonstrated that DC- mediated activation of NK cells is dependent upon signaling through the NKp46 activation receptor. The goal of this exploratory/developmental proposal is to determine how NK interactions regulate the adaptive immune response after transplantation. We propose two integrated Specific Aims: 1) determine the phenotypic and functional features of NK cells after transplantation and 2) determine how NKp46 contributes to the function of NK cells post-transplant, to test our hypothesis that NKp46 is important in regulating NK-mediated immune functions post-transplant. Our innovative study will have important implications in designing strategies to prevent graft rejection and promote tolerance to an allograft.