NK Cell Biology

NK 细胞生物学

基本信息

批准号：
8209107
负责人：
LEWIS Lee LANIER
金额：
$ 28.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-14 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8209107
关键词：
Address Adult Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Bacteria Biological Models Bone Marrow Cancer Patient Celiac Disease Cell surface Cellular biology Communicable Diseases Dendritic Cells Detection Development Disease Excision Family GPI Membrane Anchors Goals Heart Transplantation Host Defense Human Immune Immune response Immunity Infection Insulin-Dependent Diabetes Mellitus Islet Cell Leukocytes Ligands Major Histocompatibility Complex Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mus Natural Killer Cells Organ Pancreas Pathway interactions Proteins Research Personnel Rheumatoid Arthritis Role Serum Solid T-Lymphocyte Tissues Transgenic Mice Virus abstracting cell type insight interest meetings mouse model neoplastic cell pancreatic neoplasm pathogen pre-clinical receptor research clinical testing selective expression therapeutic target tumor

项目摘要

Abstract The activating NKG2D receptor expressed on T cells and NK cells recognizes a polygenic and polymorphic family of ligands with structural homology to major histocompatibility complex class I proteins. These ligands are not expressed or are expressed in only low amounts by healthy tissues of adults, but they are frequently over- expressed by tumors, are up-regulated after infection with viruses and bacteria, and have been detected in certain autoimmune diseased tissues. Although the NKG2D ligands are typically expressed on the cell surface as transmembrane-anchored or glycosylphosphatidylinositol (GPI)-anchored protein, some of these ligands, including MICA, MICB, and ULBP-2, can either be secreted or shed from tumor cells. These soluble NKG2D ligands are frequently detected in the sera of human cancer patients, leading to the hypothesis that they may allow tumors to escape NKG2D-mediated immune responses by serving as decoy ligands for NKG2D. The overall goal of this project is to determine the consequences of NKG2D ligand expression in autoimmune diseases and in innate and adaptive immune responses against cancer and infectious diseases. To meet this goal, we will develop new mouse models that will help us and other investigators to understand the functions of NKG2D ligands and how these functions can be regulated to relieve disease. In aim 1, we will establish mice in which a cell surface NKG2D ligand, Rae-1, can be selectively expressed in any cell type or tissue of interest. Initially, we will use these mice to express Rae-1 exclusively on islet cells in the pancreas to determine the impact on the development of autoimmunity and, separately, on the development of primary pancreatic tumors. In aim 2, these mice will be used to express Rae-1 on dendritic cells (DC) to explore how this impacts the cross- talk between DC, NK cells, and T cells. In aim 3, we will express a soluble NKG2D ligand systemically in transgenic mice or in a tumor cell-specific manner to formally address whether soluble NKG2Dligands can allow immune evasion by tumors and if soluble NKG2D ligands impair immune defense against pathogens. Collectively, these studies will provide new insights into the role of NKG2D and its ligands in autoimmunity and in host defense, and they will provide new model systems for the pre-clinical evaluation of therapeutics targeting the NKG2D pathway for treatment of autoimmunity and cancer.

抽象的 T 细胞和 NK 细胞上表达的激活 NKG2D 受体可识别与主要配体具有结构同源性的多基因和多态性配体家族组织相容性复合体 I 类蛋白。这些配体不表达或不表达成人的健康组织仅表达少量，但它们经常过量表达由肿瘤表达，在感染病毒和细菌后上调，并且已在某些自身免疫性疾病组织中检测到。虽然NKG2D 配体通常在细胞表面表达为跨膜锚定或糖基磷脂酰肌醇 (GPI) 锚定蛋白，其中一些配体，包括 MICA、MICB 和 ULBP-2 可以从肿瘤细胞分泌或脱落。这些可溶性 NKG2D 配体经常在人类癌症患者的血清中检测到，导致了这样的假设：它们可能会让肿瘤逃脱 NKG2D 介导的通过充当 NKG2D 的诱饵配体来调节免疫反应。本次活动的总体目标该项目旨在确定 NKG2D 配体表达对自身免疫性疾病的影响疾病以及针对癌症和传染病的先天和适应性免疫反应疾病。为了实现这一目标，我们将开发新的鼠标模型，这将帮助我们和其他研究人员了解 NKG2D 配体的功能以及这些配体如何可以调节机能，缓解疾病。在目标 1 中，我们将建立小鼠，其中细胞表面 NKG2D 配体 Rae-1 可以在任何细胞类型或感兴趣的组织。最初，我们将使用这些小鼠在胰岛上专门表达 Rae-1 胰腺细胞以确定对自身免疫发展的影响，分别关于原发性胰腺肿瘤的发展。在目标 2 中，这些小鼠将用于在树突状细胞 (DC) 上表达 Rae-1，以探索这如何影响交叉 DC、NK 细胞和 T 细胞之间的对话。在目标 3 中，我们将表达可溶的 NKG2D 配体在转基因小鼠中系统地或以肿瘤细胞特异性方式正式解决可溶性 NKG2D 配体是否可以允许肿瘤逃避免疫，以及是否可以可溶性 NKG2D 配体会损害针对病原体的免疫防御。总的来说，这些研究将为 NKG2D 及其配体在自身免疫中的作用提供新的见解在宿主防御方面，他们将为临床前研究提供新的模型系统评估针对 NKG2D 通路治疗自身免疫性疾病的疗法和癌症。