NK Cells in GVHD and GVT

GVHD 和 GVT 中的 NK 细胞

• 批准号: 8265305
• 负责人: Robert S Negrin
• 金额: $ 28.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-11 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265305
• 关键词: Animal Model; Animals; Apoptosis; Biological; Biology; Bioluminescence; Cell surface; Cells; Cellular biology; Clinic; Complex; Cytolysis; Disease; Dissection; Effector Cell; Event; Excision; Fluorescence; Functional disorder; Gastrointestinal tract structure; Goals; Graft vs Tumor Effect; Hematologic Neoplasms; Histocompatibility; Homologous Transplantation; Human; Image; Immune; Immunobiology; Induction of Apoptosis; Infiltration; Life; Ligands; Light; Liver; Location; Longevity; Luciferases; Lymphocyte; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mediating; Modeling; Natural Killer Cells; Nodal; Organ; Patients; Population; Proliferating; Proteins; Reaction; Recovery of Function; Residual Tumors; Risk; Role; Site; Skin; Source; Structure; T-Cell Activation; T-Lymphocyte; Time; Tissue Grafts; Tissues; Transgenic Mice; Translating; Transplantation; Tumor Tissue; base; cancer cell; cellular imaging; clinically relevant; disorder control; disorder risk; effective therapy; experience; graft versus host disease induction; graft vs host disease; hematopoietic cell transplantation; image processing; improved; insight; interest; migration; neoplastic cell; novel; public health relevance; reconstitution; response; success; trafficking; tumor

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.

描述（由申请人提供）：造血细胞移植（HCT）是治疗多种血液恶性肿瘤患者的有效疗法。 HCT 的好处在很大程度上源自对恶性细胞的免疫识别，从而将其去除，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。我们将利用一种新型生物发光成像 (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) 转基因小鼠中分离出来并发光。可以高精度和灵敏地实时跟踪 luc+ 细胞的运输和存活。基于我们之前丰富的 T 细胞成像经验，BLI 将用于确定 GVHD 诱导的主要位点，并探索 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多探测分析。我们已经表明，GVHD 通过淋巴细胞在空间和时间上迁移到关键解剖部位而发生，从而同种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，以检查该细胞群不会导致 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，并且可以诱导淋巴组织部位活化的同种异体反应性 T 细胞凋亡。我们进一步假设同种异体反应性 T 细胞上调 NKG2D 配体表达，NKG2D 配体表达被 NK 细胞通过 NKG2D 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 NK 细胞群，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 反应的背景下获得对 NK 细胞生物学的更深入的生物学见解，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病理生理学的基本生物学见解、免疫效应子和调节性淋巴细胞之间的相互作用以及可转化为临床的策略。 公共健康相关性 该提案的目标是通过研究自然杀伤细胞来进一步了解造血细胞移植的免疫生物学，自然杀伤细胞具有提高抗肿瘤效果而不引起移植物抗宿主疾病的独特能力。我们希望使用基于生物发光的新型成像策略来了解在没有移植物抗宿主疾病的情况下改善移植物抗肿瘤效应的机制，以探索这些事件模型中自然杀伤细胞生物学中的时间和空间事件。