T cell-tissue interaction models

T细胞-组织相互作用模型

基本信息

批准号：
9205538
负责人：
Brian D Brown
金额：
$ 22.88万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9205538
关键词：
Ablation Address Affinity Alpha Cell Animal Model Antigen-Presenting Cells Antigens Area Autoimmune Diseases Autoimmune Process Autoimmune Responses Awareness Behavioral Research Biocompatible Materials Biomedical Research Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer cell line Cardiac Cell Communication Cell model Cell physiology Cells Chickens Clinical Research Communities Complex Data Development Diphtheria Toxin Engineering Epitopes Eragrostis Generations Goals Guidelines HCN4 gene Heart Histocompatibility Antigens Class I Immune response Immunity Immunologist Immunology Inflammatory Insulin-Dependent Diabetes Mellitus Intestines Lead MHC Class I Genes MHC Class II Genes Mediating Medicine Methodology Methods Modeling Monitor Mus Organ Outcome Outcome Study Ovalbumin Pancreas Peptide/MHC Complex Peptides Population Proteins Reagent Regulatory T-Lymphocyte Reporter Research Resolution Scanning Solid Spleen Stem cells Study Section Surface T cell response T-Cell Receptor T-Lymphocyte Techniques Testing Tissues Transgenic Mice Transgenic Model Virus animal model development base cancer cell cell killing cell type diphtheria toxin receptor in vivo interest killings live cell imaging novel novel vaccines pathogen public health relevance research study response technology development tool virology virtual

项目摘要

DESCRIPTION (provided by applicant): This R21 proposal is in direct response to PA-13-145, entitled "Development of Animal Models and Related Biological Materials for Research". The goal of this proposal is to develop two new animal models to fill major unmet needs in a broad array of fields, including immunology, virology, and stem cell medicine. The surface of all nucleated cells are covered in MHC class I molecules that present peptides derived from proteins made in the cell. T cells scan the surface of a cell, and engage only cells in which their T cell receptor has affinity for a specific MHC-peptide complex. Once the T cell engages, the outcome is highly dependent on the cell presenting the antigen and the local context. Different cell types can result in different T cell responses; for example some cells may direct CD4+ T cell to differentiate into an effector, whereas presentation by other cells may direct them to become regulatory. How a T cell interacts with a particular cell type is one of the most important questions in immunology. The answer can tell us why some cell types are more prone to autoimmune responses, and why other cell types, such as cancer cells, may be less prone to T cell killing. While we know how T cells react with some cell types, there are many cell types whose interaction with T cells has never been studied. For example, we do not know how T cells interact with many types of stem cells. We hypothesize that if green florescent protein (GFP) can be utilized as a model antigen, than T cell interactions with numerous cell types, which were not previously studied including many types of stem cells, can be investigated. The objective of Aim 1 is to generate mice in which the T cells recognize an epitope of GFP presented in MHC class I or II. The outcome of Aim 1 would establish an antigen-specific T cell model that targets a commonly used, easily monitored, florescent reporter. Since GFP-specific CD8+ T cells can kill GFP-expressing cells, we hypothesize that GFP-specific CD8+ T cells can be used to selectively deplete almost any cell population in a mouse, if the cell type of interest s expressing GFP. We have already obtained preliminary data showing that we can use GFP-specific T cells to kill GFP expressing cells in the spleen, pancreas, gut, and heart. The objective of Aim 2 is to compare T cell mediated cell ablation to diphtheria toxin (DT)-mediated depletion, and to determine how effectively we can use the GFP-specific T cells to kill cells in the brain. The outcome of these studies will establish a new method of cell depletion that can be used with the 100s of cell type-specific GFP expressing mice that already exist, and it is potentially less inflammatory than DT-mediated depletion. The abundance of GFP-based reagents and animal models makes the GFP-specific T cell mice relevant for numerous labs doing a wide variety of research including, but not limited to: (i) understanding the antigen presenting capacity of specific cell types, (ii) modeling autoimmune destruction, (iii) characterization of pathogen-T cell interactions, and for (iv) identifying the function of specific cells in vivo.

描述（由适用提供）：该R21提案直接响应PA-13-145，标题为“动物模型的开发及相关的研究生物材料”。该提案的目的是开发两个新的动物模型，以满足各种领域的主要未满足需求，包括免疫学，病毒学和干细胞医学。所有核细胞的表面均覆盖在MHC的I类分子中，这些MHC分子表现出源自细胞中蛋白质的肽。 T细胞扫描细胞的表面，仅吸引其在其上的细胞 T细胞接收器对特定的MHC肽复合物具有亲和力。一旦T细胞参与，结果就高度取决于呈现抗原和局部环境的细胞。不同的细胞类型会导致不同的T细胞反应。例如，某些细胞可能会引导CD4+ T细胞分化为效应子，而其他细胞的呈现可能会导致它们成为调节性。 T细胞如何与特定细胞类型相互作用是免疫学中最重要的问题之一。答案可以告诉我们为什么某些细胞类型更容易发生自身免疫反应，以及为什么其他细胞类型（例如癌细胞）可能不太容易发生T细胞杀死。虽然我们知道T细胞与某些细胞类型的反应如何，但有许多细胞类型的相互作用与T细胞的相互作用从未研究过。例如，我们不知道T细胞如何与多种类型的干细胞相互作用。我们假设，如果可以将绿色荧光蛋白（GFP）用作模型抗原，而不是与多种细胞类型的相互作用（以前没有研究过包括多种类型的干细胞）。目标1的目的是生成小鼠，其中T细胞识别了MHC I或II类中GFP发作的发作。 AIM 1的结果将建立一个抗原特异性T细胞模型，该模型针对常用，易于监测的荧光记者。由于GFP特异性的CD8+ T细胞可以杀死表达GFP的细胞，因此我们假设GFP特异性的CD8+ T细胞可用于选择性地复制小鼠中的几乎所有细胞群，如果感兴趣的细胞类型S表达GFP。我们已经获得了初步数据，表明我们可以使用GFP特异性的T细胞杀死脾，胰腺，肠和心脏中表达细胞的GFP。目标2的目的是将T细胞介导的细胞消融与白喉毒素（DT）介导的部署进行比较，并确定我们如何有效地使用GFP特异性T细胞来杀死大脑中的细胞。这些研究的结果将建立一种新的细胞部署方法，该方法可以与已经存在的100种细胞类型特异性GFP表达小鼠一起使用，并且它可能比DT介导的部署较小。基于GFP的试剂和动物模型的丰富度使GFP特异性T细胞小鼠与众多实验室相关，进行了多种研究，包括但不限于：（i）了解特定细胞类型的抗原表现能力，（ii）建模自动免疫性销毁，（iii）（iii）（iii）对病原体 - T细胞相互作用的表征（IV），以及（iv）特定（IV）的特定功能（IV）功能（IV）功能（IV）功能（IV）功能（功能）细胞体内。