Inducing Tolerance with 5-Module chimeric Antigen Receptor (5MCAR) T Cells

使用 5 模块嵌合抗原受体 (5MCAR) T 细胞诱导耐受

基本信息

批准号：
10247395
负责人：
Michael S Kuhns
金额：
$ 77.78万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247395
关键词：
Agonist Antigens Autoantigens Autoimmune Diseases Autoimmune Process Basic Science Binding Biological Assay Biological Models Biomimetics CAR T cell therapy CD28 gene CD3 Antigens CD4 Antigens CD4 Positive T Lymphocytes CD58 gene CD8-Positive T-Lymphocytes CD80 gene CD86 gene CD8B1 gene CTLA4 gene Cell physiology Cells Cytotoxic T-Lymphocytes Data Development Disease Engineering Future Generations Generations Goals Head Histocompatibility Antigens Human Immunity Immunosuppression Immunotherapy In Vitro Inbred NOD Mice Left Lymphocyte-Specific p56LCK Tyrosine Protein Kinase Mediating Memory Mouse Protein Operative Surgical Procedures Pathogenicity Pathology Peptides Pharmaceutical Preparations Phenotype Population Regulatory T-Lymphocyte Research Risk Signal Transduction Specificity System T cell response T cell therapy T-Cell Activation T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Tissues Transmembrane Domain Work autoreactive T cell base chimeric antigen receptor chimeric antigen receptor T cells cytotoxic design efficacy testing humanized mouse immune checkpoint blockade in vivo insight mouse model novel peripheral tolerance prevent receptor recruit research study response scaffold src-Family Kinases

项目摘要

PROJECT SUMMARY T cells respond to peptide antigens presented by MHC molecules (pMHC). They are driven by 5-module macrocomplexes, composed of one receptor module [the T cell receptor (TCR)], three signaling modules (CD3δε, CD3γε, CD3ζζ), and a CD4 or CD8 coreceptor module, that allow T cells to respond to a single agonist pMHC and direct differentiation to cytotoxic (CTL), helper (Th), regulatory (Treg), or memory (Tm) cell phenotypes that are essential for productive immunity. Importantly, T cells also pose the risk of pathogenic responses if they are specific to self or transplant antigens and are not controlled by peripheral tolerance mechanisms. The macrocomplexes that drive T cell activity are therefore interesting both from an engineering standpoint, as they serve as an ideal framework upon which to design novel chimeric receptors for redirected T cell therapy, and from a targeting standpoint for therapies aimed at mitigating T cell-mediated pathologies when tolerance breaks down. This proposal will test the efficacy of using a novel 5-module chimeric antigen receptor system (5MCAR), which has been engineered to operate according to the mechanistic principles that govern the TCR-CD3-pMHC-CD4/CD8 macrocomplexes, to redirect CTLs to target pathogenic T cells. Our goals are to: use 5MCAR-CTLs to eliminate pMHC-specific T cell populations, including pathogenic T cells, via a surgical strike in order to induce tolerance in mouse models; and, engineer and test humanized 5MCARs in a humanized mouse model system. When completed, the work will provide a blueprint for using 5MCAR-CTL therapy to induce tolerance to defined pMHC and mitigate T cell-mediated pathologies.

项目概要 T 细胞对 MHC 分子 (pMHC) 呈递的肽抗原作出反应，它们由 5 模块驱动。大复合物，由一个受体模块 [T 细胞受体 (TCR)] 和三个信号模块组成（CD3δε、CD3γε、CD3zez）和 CD4 或 CD8 辅助受体模块，使 T 细胞能够对单个激动剂 pMHC 并直接分化为细胞毒性 (CTL)、辅助 (Th)、调节 (Treg) 或记忆 (Tm) 细胞重要的是，T 细胞也带来致病风险。如果它们是针对自身或移植抗原的特异性且不是外周耐受性的反应因此，驱动 T 细胞活性的宏观复合物从工程角度来看都很有趣。站立，因为它们作为一个理想的框架来设计用于重定向 T 的新型嵌合受体细胞疗法，以及旨在减轻 T 细胞介导的病理的疗法的靶向立场当耐受性崩溃时，该提案将测试使用新型 5 模块嵌合抗原的功效。受体系统（5MCAR），其设计根据以下机械原理进行操作：控制 TCR-CD3-pMHC-CD4/CD8 宏复合物，将 CTL 重定向至靶向致病性 T 细胞。目标是：使用 5MCAR-CTL 消除 pMHC 特异性 T 细胞群，包括致病性 T 细胞，通过进行外科手术以诱导小鼠模型产生耐受性；并在小鼠模型中设计并测试人源化 5MCAR。人源化小鼠模型系统完成后，将为使用 5MCAR-CTL 提供蓝图。诱导对特定 pMHC 的耐受性并减轻 T 细胞介导的病理的治疗。