NK Cells in GVHD and GVT

GVHD 和 GVT 中的 NK 细胞

• 批准号: 7523519
• 负责人: Robert S Negrin
• 金额: $ 29.44万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7523519
• 关键词: Animal Model; Animals; Apoptosis; Biological; Biology; Bioluminescence; Cell Transplantation; Cell surface; Cells; Cellular biology; Clinic; Complex; Cytolysis; Depth; Dissection; Effector Cell; Event; Excision; Fluorescence; Functional disorder; Gastrointestinal tract structure; Goals; Graft vs Tumor Effect; Hematologic Neoplasms; Hematopoietic; 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; Public Health; Range; Reaction; Recovery of Function; Residual state; 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; experience; graft vs host disease; image processing; improved; insight; interest; killer T cell; migration; neoplastic cell; novel; 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）是一种有效的血液系统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，导致其去除称为移植物与肿瘤（GVT）效应，这清楚地表明了基于免疫的恶性肿瘤的影响。 HCT的成功受到移植与宿主疾病（GVHD）的风险的限制，这导致特定于组织的免疫破坏。在此提案中，我们将重点关注具有已知抗肿瘤功能但不会引起GVHD的自然杀手（NK）细胞。我们将利用一种新型的生物发光成像（BLI）策略来探测GVHD和GVT反应。 NK和T细胞群体将从新型的荧光素酶（LUC）转基因小鼠中分离出来，并发出光。 Luc+细胞的运输和存活可以实时遵循高精度和敏感性。 BLI将用于识别GVHD诱导的主要部位，并探索NK细胞对GVHD诱导构建对我们以前广泛的T细胞成像经验的影响。这些研究将指导对浸润组织和细胞种群的更多探测分析。我们已经表明，GVHD通过淋巴细胞的空间和时间迁移到关键的解剖部位而发展，从而使异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细胞运输和生存的影响，并探索NK细胞运输，以检查为什么该细胞群不会导致GVHD的基本机制。我们的假设是NK细胞能够调节同种反应性T细胞的增殖和存活，并可以诱导淋巴组织部位激活的同种反应性T细胞的凋亡。我们进一步假设同种反应性T细胞上调NKG2D配体表达，NK细胞通过NKG2D识别，从而导致凋亡诱导。我们将进一步评估能够在存在和不存在NK细胞的情况下移植和不存在后，能够扩增和运输到肿瘤部位的NK细胞的特定种群，并探索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细胞生物学的更大洞察力，并探索NK细胞在这些反应中的作用。我们认为，这些研究将揭示对重要免疫反应的病理生理学的基本生物学见解，免疫效应子与调节性淋巴细胞之间的相互作用以及可以转化为诊所的策略。 公共卫生相关性该提案的目的是通过研究自然杀伤细胞的研究，以进一步了解造血细胞移植的免疫生物学，这些细胞具有改善抗肿瘤作用而不引起移植物与宿主疾病的独特能力。我们希望使用新型的基于生物发光的成像策略来了解改善移植物与肿瘤效应的机制，而没有移植物与宿主疾病的疾病，以探索这些事件模型中天然杀伤细胞生物学中的时间和空间事件。