NK Cell Interactions in Transplantation

最近的证据表明，先天免疫系统在移植排斥和移植后免疫反应中的重要性。 实体器官移植耐受诱导。然而，特定的细胞类型和分子的 参与这些过程的先天免疫系统尚未确定。我们已经开始定义 自然杀伤（NK）细胞在实体器官移植中的激活。我们已经证明NK细胞 包括移植后早期的大部分肝浸润细胞。这些NK细胞在功能上 活性并产生大量IFN-γ。此外，NK细胞的消耗导致细胞内的NK细胞减少。 IFN-γ水平和延长移植物存活。基于这些数据，我们提出了一个模型，其中手术 应激和缺血/再灌注损伤刺激肝移植物诱导几种 趋化因子在移植后早期指导免疫细胞源性NK细胞向同种异体移植物中的募集， 移植由NK细胞产生的IFN-γ进一步诱导活化的淋巴细胞募集到淋巴细胞。 从而增强效应子功能和移植物损伤。我们假设先天免疫系统 系统，特别是NK细胞的活化，影响移植后的移植物结果。这 将使用大鼠原位肝移植模型来检验这一假设，以检查NK细胞在肝移植过程中的作用。 移植物排斥和长期移植物存活。在第一个具体目标中，我们将确定NK细胞在以下方面的作用： 肝移植后的移植物结局。我们将：1）分析移植后NK细胞的作用，2） 确定NK细胞耗竭对移植后趋化因子和IFN-γ产生和细胞毒性的影响， 3)分析在不存在NK细胞的情况下混合嵌合体的建立和4）确定 免疫抑制剂对NK细胞效应子功能的影响。第二个具体目标的目标是确定 特异性NK细胞受体在移植物结局中的功能意义。我们拥有的独特试剂 开发和组装，将被用来专门解决的表达和功能意义， 大鼠NK细胞受体在实体器官移植中的作用具体而言，我们将：1）确定 移植后NK细胞活化受体的表达模式，2）确定是否通过NK细胞 受体诱导细胞因子的产生和细胞毒性，和3）检查阻断的功能结果 移植模型中的NK细胞受体。我们的研究将具体定义NK的功能意义 细胞在同种异体移植排斥和接受中的作用，将导致诱导肝脏耐受的新方法。 同种异体移植

Recent evidence indicates the importance of the innate immune system in both graft rejection and the induction of tolerance in solid organ transplantation. However, the specific cell types and molecules of the innate immune system involved in these processes have not been determined. We have begun to define natural killer (NK) cell activation in the context of solid organ transplantation. We have shown that NK cells comprise the majority of liver infiltrating cells early post-transplantation. These NK cells are functionally active and producing substantial amounts of IFN-y. Furthermore, depletion of NK cells results in decreased levels of IFN-y and prolonged graft survival. Based on these data we suggest a model in which surgical stress and ischemia/reperfusion injury stimulate the liver allograft to induce the early expression of several chemokines that direct the recruitment of recipient-derived NK cells into the allograft early after transplantation. IFN-y produced by NK cells further induces the recruitment of activated lymphocytes to the graft thereby augmenting effector function and graft damage. We hypothesize that the innate immune system, specifically the activation of NK cells, influences graft outcome post transplantation. This hypothesis will be tested using a rat orthotopic liver transplant model to examine the role of NK cells during graft rejection and long term graft survival. In the first Specific Aim we will determine the role of NK cells in graft outcome following liver transplantation. We will: 1) analyze the role of NK cells post-transplant, 2) determine the effect of NK cell depletion on chemokine and IFN-y production and cytotoxicity post-transplant, 3) analyze the establishment of mixed chimerism in the absence of NK cells and 4) determine the effect of Immunosuppressive agents on NK cell effector function. The goal of the second specific aim is to determine the functional significance of specific NK cell receptors in graft outcome. Unique reagents we have developed and assembled, will be used, to specifically address the expression and functional significance of the rat NK cell receptors in the context of solid organ transplantation. Specifically we will: 1) determine the expression pattern of NK cell activation receptors after transplant, 2) determine if signaling through NK cell receptors induces cytokine production and cytotoxicity, and 3) examine the functional outcome of blocking NK cell receptors in a transplant model. Our studies will specifically define the functional significance of NK cells in both allograft rejection and acceptance an will lead to new approaches to induce tolerance to liver allografts.