权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Generation of Islet Specific T Follicular Regulatory Like Cells for Autologous Cell Therapy of Type 1 Diabetes

用于 1 型糖尿病自体细胞治疗的胰岛特异性滤泡调节性 T 细胞的产生

基本信息

批准号：
10437608
负责人：
Puchong Thirawatananond
金额：
$ 4.09万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-16 至 2026-05-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437608
关键词：
Adoptive Cell Transfers Adoptive Transfer Affinity Age Animal Disease Models Animal Model Antigens Autoantibodies Autoimmune Diseases Autoimmunity Autologous B-Cell Activation B-Lymphocytes BLR1 gene Back Beta Cell Biological Models Bystander Suppression C-Peptide CD3 Antigens CD4 Positive T Lymphocytes CXCL13 gene Cell Therapy Cells Characteristics Chemotaxis Clinical Management Confocal Microscopy Data Dendritic Cells Dependence Detection Development Diabetes Mellitus Diabetes prevention Diagnosis Disease Progression Educational process of instructing Engineering Enzyme-Linked Immunosorbent Assay Exhibits Female Florida Flow Cytometry Gene Transfer Generations Genes Genome Growth Helper-Inducer T-Lymphocyte Histology Homing Immune Immune Targeting Immune response Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunology Immunomodulators In Vitro Inbred BALB C Mice Inbred NOD Mice Incidence Infiltration Infusion procedures Injections Institutes Insulin Insulin-Dependent Diabetes Mellitus Interruption Investigational Therapies Islets of Langerhans Knock-in Location Mature B-Lymphocyte Measures Mediating Mesentery Methods Migration Assay Modality Modeling Mus Onset of illness Organ Ovalbumin Pancreas Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Physicians Play Population Prediabetes syndrome Principal Investigator Production Prognosis Protocols documentation Rattus Regulatory T-Lymphocyte Reporting Research Research Design Research Personnel Risk Role Scientist Serum Site Specificity Stains Structure of beta Cell of islet Structure of germinal center of lymph node T-Cell Receptor T-Cell Receptor Genes TNFSF5 gene Technical Expertise Testing Therapeutic Training Transgenic Mice Transgenic Organisms Translating Universities Writing cancer therapy cellular engineering chemokine receptor clinical translation cytokine design diabetogenic diphtheria toxin receptor early phase clinical trial engineered T cells experience experimental study genome editing glucose monitor immune activation immunoregulation improved in vitro testing in vivo insulin secretion insulitis islet islet cell antibody lymph nodes pre-clinical prevent promoter repaired response skills targeted treatment trafficking

项目摘要

Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disease leading to pancreatic beta cell destruction and lifelong dependence on exogenous insulin injections. Immunomodulatory agents that aim to reverse beta cell autoimmunity have been shown to delay T1D diagnosis but cannot halt the decline of C-peptide levels that reflect insulin production. Autologous cell therapy (ACT) is an investigational therapy that aims to restore the immune set point back to tolerance by infusion of ex vivo expanded regulatory T cells (Tregs). Tregs are responsible for downregulating the immune response and their absence in animal models of diabetes leads to accelerated disease progression. Early clinical trials of ACT, however, show that transfused Tregs persist for years in patients but were ineffective in preventing C-peptide decline. This project proposes to generate islet specific T follicular regulatory (Tfr) cells from Tregs through gene editing to improve their utility as ACT for T1D. Tfr cells are a specialized subset of Tregs that act in the germinal centers of lymph nodes where mature B cells are activated by T follicular helper (Tfh) cells. Early B cell activation is an important step in T1D prognosis as the detection of class-switched islet autoantibodies in the pre-diabetic phase predicts onset of disease. Therefore, creating Tfr-like cells represents a potential avenue of T1D prevention through suppression of Tfh-mediated activation. The following Specific Aims outline the objectives for utilizing genome targeting to produce Tfr-like cells as potential cellular therapies of T1D. In Aim 1, islet reactive Tregs will be produced through non-viral genome editing to knock in islet reactive TCR in the TCR locus. Engineered Tregs will be tested in vitro for islet antigen reactivity and tested in vivo through adoptive transfer into NOD mice to determine its effects on diabetes incidence. In Aim 2, the Tfr cell characteristic chemokine receptor CXCR5 will be knocked in the Rosa26 locus of islet reactive Tregs and tested for responsivity to CXCL13. Engineered CXCR5-positive islet reactive Tregs will be transferred into NOD mice to assess diabetes incidence and Treg trafficking to the pancreas and pancreatic lymph nodes. The proposed training will take place at the University of Florida Diabetes Institute under the guidance of Dr. Todd Brusko and Dr. Michael Haller. The training plan will provide the applicant with research design and technical skills in autoimmunity, cell engineering, and diabetes models as well as professional skills in teaching and scientific writing to facilitate growth as an independent investigator.

项目总结/文摘