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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.

项目总结