NK Cells in GVHD and GVT

描述（由申请人提供）：造血细胞移植（HCT）是一种治疗多种血液恶性肿瘤患者的有效疗法。HCT的益处在很大程度上来源于恶性细胞的免疫识别，导致它们的去除，称为移植物抗肿瘤（GVT）效应，清楚地证明了基于免疫的恶性肿瘤控制的影响。HCT的成功受到移植物抗宿主病（GVHD）风险的限制，GVHD会导致组织特异性免疫破坏。在本提案中，我们将重点关注具有已知抗肿瘤能力但不会引起GVHD的自然杀伤（NK）细胞。我们将利用一种新的生物发光成像（BLI）策略来探测GVHD和GVT反应。感兴趣的NK和T细胞群将从新型荧光素酶（luc）转基因小鼠中分离并发光。luc+细胞的运输和存活可以以高精度和灵敏度在真实的时间内跟踪。BLI将用于确定GVHD诱导的主要位点，并根据我们之前广泛的T细胞成像经验探索NK细胞对GVHD诱导的影响。这些研究将指导对浸润组织和细胞群进行更深入的分析。我们已经表明，GVHD通过淋巴细胞向关键解剖部位的空间和时间迁移而发展，由此同种异体反应性细胞增殖并上调进入GVHD靶器官所需的其他细胞表面分子。我们将评估NK细胞对T细胞运输和存活的影响，并探索NK细胞运输，以研究为什么这种细胞群不会导致GVHD的潜在机制。我们的假设是NK细胞能够调节同种异体反应性T细胞的增殖和存活，并能诱导淋巴组织部位活化的同种异体反应性T细胞的凋亡。我们进一步假设同种异体反应性T细胞上调NK细胞通过NKG2D识别的NKG2D配体表达，导致细胞凋亡诱导。我们将进一步评估能够增殖和运输到肿瘤部位的NK细胞的特定群体，并探索在存在和不存在NK细胞的情况下移植后的表型和功能性免疫重建。该项目的目标是在临床上重要但复杂的GVHD和GVT反应的背景下，对NK细胞生物学进行更深入的生物学研究，并探索NK细胞在这些反应中的作用。我们相信这些研究将揭示重要免疫反应的病理生理学的基本生物学见解，免疫效应细胞和调节淋巴细胞之间的相互作用以及可能转化为临床的策略。 与公众健康的关系这项建议的目的，是透过研究自然杀伤细胞，加深我们对造血细胞移植的免疫生物学的认识。自然杀伤细胞具有独特的能力，可改善抗肿瘤效果，而不会引起移植物抗宿主病。我们希望了解改善移植物抗肿瘤效应的机制，而没有移植物抗宿主病，使用新的基于生物发光的成像策略来探索自然杀伤细胞生物学中的时间和空间事件。

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) is an effective therapy for patients with a broad range of hematologic malignancies. The benefits of HCT are in large part derived from the immunological recognition of malignant cells resulting in their removal termed the graft vs. tumor (GVT) effect clearly demonstrating the impact of immune based control of malignancy. The success of HCT is limited by the risk of graft vs. host disease (GVHD) which results in tissue specific immune destruction. In this proposal we will focus on natural killer (NK) cells which have known anti-tumor capabilities yet do not cause GVHD. We will utilize a novel bioluminescent imaging (BLI) strategy to probe GVHD and GVT reactions. NK and T cell populations of interest will be isolated from a novel luciferase (luc) transgenic mouse and emit light. Trafficking and survival of luc+ cells can be followed in real time with high precision and sensitivity. BLI will be utilized to identify the major sites of GVHD induction and explore the impact of NK cells on GVHD induction building upon our extensive previous experience of T cell imaging. These studies will direct more probing analysis of the infiltrating tissues and cell populations. We have shown that GVHD develops through the spatial and temporal migration of lymphocytes to key anatomical sites whereby alloreactive cells proliferate and upregulate other cell surface molecules required for entry into GVHD target organs. We will evaluate the impact of NK cells on T cell trafficking and survival as well as explore NK cell trafficking to examine underlying mechanisms of why this cell population does not result in GVHD. Our hypothesis is that NK cells are capable of modulating the proliferation and survival of alloreactive T cells and can induce apoptosis of activated alloreactive T cells at lymphoid tissue sites. We further hypothesize that alloreactive T cells up-regulate NKG2D ligand expression which is recognized by NK cells via NKG2D resulting in apoptosis induction. We will further evaluate the specific populations of NK cells capable of proliferating and trafficking to tumor sites and explore phenotypic and functional immune reconstitution following transplantation in the presence and absence of NK cells. The goals of this Project are to gain greater biological insight into NK cell biology in the context of the clinically important yet complex GVHD and GVT reactions and to explore the role of NK cells in these reactions. We believe these studies will reveal basic biological insights into the pathophysiology of important immune reactions, the interplay between immune effector and regulatory lymphocytes and strategies which may be translated to the clinic. PUBLIC HEALTH RELEVANCE The goal of this proposal is to further our understanding of the immunobiology of hematopoietic cell transplantation through the study of natural killer cells which have the unique capabilities of improving anti-tumor effects without causing graft vs host disease. We hope to understand the mechanisms of improved graft vs. tumor effects without graft vs host disease using novel bioluminescent based imaging strategies to explore the temporal and spatial events in natural killer cell biology in models of these events.