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

• 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
• 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

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.

项目摘要 T细胞对由MHC分子（pMHC）呈递的肽抗原应答。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）]，三个信号传导模块 (CD3δε、CD 3 γε、CD 3 γ ε）和CD 4或CD 8辅助受体模块，其允许T细胞对单个 激动剂pMHC和直接分化为细胞毒性（CTL）、辅助（Th）、调节（Treg）或记忆（Tm）细胞 表型是生产性免疫所必需的。重要的是，T细胞也有致病性的风险。 如果它们对自身或移植抗原具有特异性并且不受外周耐受性控制， 机制等因此，驱动T细胞活性的大复合物是有趣的， 这是因为它们作为一个理想的框架，在此基础上设计新的嵌合受体，用于重定向T 细胞疗法，以及从靶向角度来看，旨在减轻T细胞介导的病理学的疗法 当宽容被打破。该提案将测试使用新型5模块嵌合抗原的功效 受体系统（5 MCAR），它已被设计为根据机械原理运行， 控制TCR-CD 3-pMHC-CD 4/CD 8大复合物，将CTL重定向至靶向病原性T细胞。我们 目标是：使用5 MCAR-CTL消除pMHC特异性T细胞群，包括致病性T细胞， 外科手术打击，以诱导小鼠模型的耐受性;以及，工程化和测试人源化5 MCAR， 人源化小鼠模型系统。完成后，这项工作将为使用5 MCAR-CTL提供蓝图 治疗以诱导对限定的pMHC的耐受性并减轻T细胞介导的病理。