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）：天然杀手（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裂解目标细胞，并且在宿主防御对病原体和转化细胞的宿主防御中起重要作用。 NK细胞功能由通过编码的抑制性和激活受体传播的负和正信号的平衡控制。尽管“缺失自我”的概念表明NK细胞可以针对异物同种异体移植，但现行的教条是NK细胞并不是在最终导致移植物排斥反应的机制中积极参与者。然而，最近的研究挑战了这一结论，而是暗示了NK细胞在急性和慢性同种异体移植排斥反应中。矛盾的是，NK细胞也已被证明可促进同种异体移植物的耐受性。为了调和这些不同的观察结果，我们假设通过激活受体的表达和功能，NK细胞调节免疫系统的其他细胞，尤其是树突状细胞（DC）。实际上，我们已经证明了DC-介导的NK细胞激活取决于通过NKP46激活受体信号传导。该探索性/发育建议的目的是确定NK相互作用如何调节移植后适应性免疫反应。我们提出了两个集成的特定目的：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，以测试我们的假设，即NKP46在调节NK介导的NK介导的免疫功能后移植后移植后具有重要意义。我们的创新研究将在设计策略以防止移植物排斥和促进同种异体移植的耐受性方面具有重要意义。