NK Cell Biology

NK 细胞生物学

基本信息

批准号：
8433487
负责人：
LEWIS Lee LANIER
金额：
$ 27.14万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433487
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.

抽象的在T细胞和NK细胞上表达的激活NKG2D受体识别具有结构同源的配体的多基因和多态性家族与主要同源组织相容性复合物I类蛋白质。这些配体未表达或仅由成年人的健康组织以低量表示，但它们经常过度通过肿瘤表达，在感染病毒和细菌后被上调，在某些自身免疫性疾病组织中已检测到。虽然是NKG2D 配体通常以跨膜锚定或糖基磷脂酰肌醇（GPI）锚定蛋白，其中一些配体，包括云母，MICB和ULBP-2可以分泌或从肿瘤细胞中分泌或脱落。这些在人类癌症患者的血清中经常检测到可溶性NKG2D配体，导致假设它们可能允许肿瘤逃脱NKG2D介导通过作为NKG2D的诱饵配体来免疫反应。总体目标项目是确定自身免疫中NKG2D配体表达的后果疾病以及对癌症和感染性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，以帮助我们和其他研究人员了解NKG2D配体的功能以及如何可以调节功能以减轻疾病。在AIM 1中，我们将建立小鼠细胞表面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专门在胰岛上表达RAE-1 胰腺中的细胞确定对自身免疫发展的影响和另外，关于原发性胰腺肿瘤的发展。在AIM 2中，这些老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AIM 3中，我们将表达一个可溶的NKG2D 配体在转基因小鼠或以肿瘤细胞特异性方式进行正式解决可溶性nkg2dligands是否可以通过肿瘤逃避免疫可溶性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性中的作用提供新的见解在主持人的防御中，他们将为临床前提供新的模型系统针对NKG2D途径的治疗自身免疫性的治疗疗法的评估和癌症。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NK cell development, homeostasis and function: parallels with CD8⁺ T cells.

DOI：
10.1038/nri3044
发表时间：
2011-08-26
期刊：
Nature reviews. Immunology
影响因子：
0
作者：
通讯作者：

Natural killer cell education and tolerance.

DOI：
10.1016/j.cell.2010.08.031
发表时间：
2010-09-17
期刊：
Cell
影响因子：
64.5
作者：
Orr MT;Lanier LL
通讯作者：
Lanier LL

Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis.

DOI：
10.1002/stem.1760
发表时间：
2014-10
期刊：
STEM CELLS
影响因子：
5.2
作者：
Weinger, Jason G.;Plaisted, Warren C.;Maciejewski, Sonia M.;Lanier, Lewis L.;Walsh, Craig M.;Lane, Thomas E.
通讯作者：
Lane, Thomas E.

Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity?