NK Cells in GVHD and GVT

描述(申请人提供)：造血细胞移植(HCT)是治疗多种恶性血液病患者的有效方法。HCT的好处在很大程度上来自于对恶性细胞的免疫识别，导致它们被移除，被称为移植物抗肿瘤(GVT)效应，清楚地表明了基于免疫的控制恶性肿瘤的影响。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。在这项提案中，我们将重点关注自然杀伤(NK)细胞，这种细胞具有已知的抗肿瘤能力，但不会导致GVHD。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。将从一种新型的荧光素酶(Luc)转基因小鼠中分离出感兴趣的NK和T细胞群，并发出光。可以高精度和高灵敏度地实时跟踪LUC细胞的移动和存活。BLI将被用来确定GVHD诱导的主要部位，并基于我们丰富的T细胞成像经验来探索NK细胞在GVHD诱导中的影响。这些研究将指导对浸润性组织和细胞群体的更深入的分析。我们已经证明，GVHD是通过淋巴细胞在空间和时间上迁移到关键的解剖部位而发展起来的，在这些部位，同种异体反应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细胞贩运和存活的影响，并探索NK细胞贩运，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NKG2D配体的表达，NKG2D通过NKG2D被NK细胞识别，从而诱导细胞凋亡。我们将进一步评估能够增殖和运输到肿瘤部位的特定的NK细胞群体，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免疫重建。本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，更深入地了解NK细胞生物学，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、免疫效应器和调节性淋巴细胞之间的相互作用以及可能转化为临床的策略的基本生物学见解。 这项建议的目的是通过对自然杀伤细胞的研究，加深我们对造血细胞移植免疫生物学的理解，自然杀伤细胞具有独特的能力，在不引起移植物对宿主疾病的情况下提高抗肿瘤效果。我们希望通过新的基于生物发光的成像策略，在这些事件的模型中探索自然杀伤细胞生物学中的时间和空间事件，以了解在没有移植物对宿主疾病的情况下，移植物对肿瘤的改善作用的机制。

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.