Functional Roles of NKp46 in Transplantation

NKp46 在移植中的功能作用

• 批准号: 8460369
• 负责人: Sheri M. Krams
• 金额: $ 22.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-09 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460369
• 关键词: Acute; Alloantigen; Allografting; Cell Communication; Cell physiology; Cells; Chronic; Cytolysis; Dendritic Cells; Development; Down-Regulation; Effector Cell; Equilibrium; Family; Germ Lines; Goals; Graft Rejection; Graft Tolerance; Host Defense; Immune; Immune response; Immune system; Immunologic Monitoring; Influenza; Injection of therapeutic agent; Lead; Ligands; Lymphocyte; Mediating; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Organ Transplantation; Outcome; Participant; Population; Predisposition; Protein Isoforms; Receptor Activation; Regulation; Role; Sequence Analysis; Signal Transduction; Site; Solid; Testing; Transplantation; allograft rejection; cell transformation; cytotoxic; cytotoxicity; design; immune function; immunological synapse; improved; innovation; member; natural killer cell protein 44-kDa; pathogen; prevent; public health relevance; receptor; research study; response; tumor

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.

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，无需事先致敏即可裂解靶细胞，在宿主防御病原体和转化细胞中发挥重要作用。 NK 细胞功能由通过种系编码的抑制性和激活性受体传递的负信号和正信号的平衡控制。尽管“自我缺失”的概念表明 NK 细胞可以靶向外源同种异体移植物，但普遍的教条是 NK 细胞并不是最终导致移植物排斥的机制的积极参与者。然而，最近的研究对这一结论提出了质疑，并认为 NK 细胞与急性和慢性同种异体移植排斥有关。相当矛盾的是，NK 细胞也被证明可以促进对同种异体移植物的耐受。为了协调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来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。该探索性/开发提案的目标是确定 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具体目标：1）确定移植后 NK 细胞的表型和功能特征，2）确定 NKp46 如何促进移植后 NK 细胞的功能，以检验我们的假设，即 NKp46 在调节 NK 介导的过程中很重要移植后的免疫功能。我们的创新研究将对设计预防移植排斥和促进同种异体移植耐受的策略具有重要意义。