NK Cell Interactions in Transplantation

最近的证据表明，在实体器官移植中，先天免疫系统在移植排斥和诱导耐受中的重要性。然而，参与这些过程的先天免疫系统的特定细胞类型和分子尚未确定。我们已经开始在实体器官移植的背景下定义自然杀伤（NK）细胞激活。我们已经表明，NK细胞构成了大部分的肝脏浸润细胞 移植后早期这些NK细胞具有表达颗粒酶B和FasL的功能活性，并产生大量的IFN-γ。研究已经证明NK细胞和树突状细胞（DC）之间的广泛串扰导致NK细胞和DC的活化或DC的杀伤。去除携带抗原的DC可以阻止T细胞的启动并导致耐受。虽然对NK细胞与DC相互作用的确切性质知之甚少，但有证据表明NK细胞受体NKp 30是重要的。我们最近克隆并鉴定了NKp 30的大鼠同源物。我们假设先天免疫系统，特别是NK细胞的激活，影响移植后的移植结果。这一假设将使用大鼠原位肝移植模型来检验NK细胞在移植物排斥和长期移植物存活期间的作用。在具体目标1中，我们将确定NK细胞在移植排斥和移植后耐受中的作用。将检查免疫抑制药物对NK细胞浸润和活性的调节的作用。我们将检查NK细胞活化受体的表达。NK细胞中活化受体连接的功能效应将重点关注细胞因子产生和细胞毒性活性。在特定目标2中，将在共培养系统中使用移植物相关NK细胞检查NK细胞和DC相互作用的功能结局。将进行实验以评价NK细胞和DC的相互激活以及NK细胞介导的DC杀伤。此外，受体参与，分子机制，以及免疫抑制药物对NK细胞和DC相互作用的影响将被检查。具体目标3的目标是分析肝移植实验模型中NK细胞和DC相互作用的功能后果。我们的研究将具体界定NK的作用 细胞和潜在的相互作用与DC在同种异体移植排斥和接受。调节NK细胞和DC的相互作用可以促进特异性同种异体移植耐受。

Recent evidence suggests 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 expressing both granzyme B and FasL and producing substantial amounts of IFN-gamma. Studies have demonstrated extensive cross talk between NK cells and dendritic cells (DC) resulting in both the activation of NK cells and DC or the killing of DC. Elimination of antigen-bearing DC could prevent T cell priming and lead to tolerance. Although little is known about the precise nature of the NK cell interaction with DC, there is evidence to suggest that the NK cell receptor NKp30 is important. We have recently cloned and characterized the rat homologue of NKp30. 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 Specific Aim 1 we will determine the role of NK cells in both graft rejection and tolerance post-transplant. The effects of immunosuppressive drugs on modulation of NK cell infiltration and activity will be examined. We will examine the expression of NK cell activation receptors. The functional effects of activation receptor ligation in NK cells will be defined with a focus on cytokine production and cytotoxic activity. In Specific Aim 2 the functional outcomes of NK cell and DC interactions will be examined in a co-culture system and with graft-associated NK cells. Experiments will be performed to evaluate reciprocal activation of NK cells and DC and NK cell mediated-DC killing. In addition, the receptors involved, the molecular mechanisms, and the effect of immunosuppressive drugs on NK cell and DC interactions will be examined. The goal of Specific Aim 3 is to analyze the functional consequences of NK cell and DC interactions in an experimental model of liver transplantation. Our studies will specifically define the role of NK cells and potential interactions with DC in both allograft rejection and acceptance. Modulation of NK cell and DC interactions may promote specific allograft tolerance.