Investigating a Novel Cellular Therapy to Prevent and Treat Acute Antibody Mediated Kidney Transplant Rejection

研究预防和治疗急性抗体介导的肾移植排斥反应的新型细胞疗法

基本信息

批准号：
10203783
负责人：
GINNY L BUMGARDNER
金额：
$ 53.44万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203783
关键词：
Acute Adoptive Cell Transfers Adoptive Transfer Allograft Tolerance Allografting Antibodies Antibody Formation Antibody Therapy Antigens Attenuated Autoimmunity Automobile Driving B-Lymphocytes BLR1 gene Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cantor Cell Communication Cell Therapy Cell Transplantation Cells Cellular immunotherapy Chronic Clinical Clinical Data Clinical Research Cytometry Data Development Dose Down-Regulation FOXP3 gene Foundations Functional disorder Genetic Graft Rejection Hepatocyte Hepatocyte transplantation Histopathology Human Humoral Immunities Hypersensitivity IgE Immune Immunology Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Incidence Interferon Type II Interleukin-10 Interleukin-2 Islets of Langerhans Transplantation Isoantibodies Kidney Kidney Failure Kidney Transplantation Lymphoid Mediating Microsurgery Modeling Mus Organ Transplantation Pathology Patients Phenotype Production Publishing Qa-1 Antigen Regulatory T-Lymphocyte Reporting Research Research Personnel Risk Role Severities Skin Transplantation Solid Structure of germinal center of lymph node T-Cell Depletion T-Lymphocyte Subsets Testing Tissues Transplant Recipients Transplantation Tumor Immunity Virus Diseases antibody-mediated rejection autoreactivity cancer vaccination cytotoxic donor-specific antibody efficacy testing imaging approach immunoregulation improved in vivo innovation isoimmunity kidney allograft liver allograft mouse model novel pathogen perforin peripheral blood post-transplant pre-clinical preclinical study preservation prevent programmed cell death protein 1 prospective response targeted agent trafficking transplant model treatment choice vaccination strategy

项目摘要

Project Summary Transplant specific antibodies (alloantibodies) are known to mediate acute antibody-mediated rejection (AMR) after kidney transplant and also negatively impact long-term kidney allograft survival. Our group discovered a novel regulatory CD8+ T cell subset which suppresses alloantibody production posttransplant. We refer to these antibody suppressor CD8+ T cells as CD8+ TAb-supp cells and have developed a strategy to enhance their in vivo development, distinguish their phenotype from other alloprimed CD8+ T cells and assess their in vitro and in vivo function. In Aim 1 we will perform pre-clinical studies to investigate the efficacy of CD8+ TAb-supp cells to prevent the development of de novo post-transplant alloantibody and AMR after kidney transplant using a murine model of kidney transplant which reproduces the histopathology of AMR observed in human kidney transplant recipients. In Aim 2 we will perform pre-clinical studies to investigate the efficacy of adoptive cellular therapy with CD8+ TAb-supp cells to treat AMR and prolong kidney transplant function and survival. Our research team assembles investigators with expertise in clinical transplantation, transplant immunology, microsurgery and kidney histopathology.

项目概要已知移植特异性抗体（同种抗体）可介导急性抗体介导的排斥反应 (AMR) 肾移植后，也会对同种异体肾的长期存活产生负面影响。我们小组发现了一个新型调节性 CD8+ T 细胞亚群可抑制移植后同种抗体的产生。我们参考这些抗体抑制 CD8+ T 细胞作为 CD8+ TAb-supp 细胞，并开发了一种策略来增强其体内发育，区分其表型与其他同种异体 CD8+ T 细胞并评估其体外和体内功能。在目标 1 中，我们将进行临床前研究以研究 CD8+ TAb-supp 的功效使用细胞预防肾移植后新发移植后同种抗体和 AMR 的发展小鼠肾移植模型，再现了在人类肾脏中观察到的 AMR 组织病理学移植受者。在目标 2 中，我们将进行临床前研究，以调查过继细胞的功效使用 CD8+ Tab-supp 细胞治疗 AMR 并延长肾移植功能和生存期。我们的研究团队汇集了临床移植、移植免疫学、显微外科专业知识的研究人员和肾脏组织病理学。