Chimeric antigen receptor (CAR) therapy for autoimmune arthritis

嵌合抗原受体（CAR）疗法治疗自身免疫性关节炎

基本信息

批准号：
9295586
负责人：
Edward F Rosloniec
金额：
$ 13.86万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9295586
关键词：
Adoptive Transfer Adverse effects Alpha Cell Antigens Arthritis Asses Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Biological Assay CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Complementary DNA Complex DR1 gene Development Disease Engineering Event Flow Cytometry Generations Genetic Engineering Goals HLA-DR Antigens HLA-DR1 Antigen HLA-DRB1 Histology Immunization Immunofluorescence Immunologic Lead Link Longevity Lymphoid MHC Class II Genes Measurement Measures Mediating Mus Onset of illness Organ Peptides Phosphorylation Predisposition Production Recombinants Rheumatoid Arthritis Severities Signal Transduction Specificity Staining method Stains T-Cell Proliferation T-Lymphocyte TNFRSF10A gene Testing Therapeutic Time Transfection Visual ZAP-70 Gene autoimmune arthritis base chimeric antigen receptor cytokine experimental study genetically modified cells humanized mouse in vivo innovation killings mouse model novel peripheral blood response targeted treatment

项目摘要

Abstract The focus of this proposal is the development of novel chimeric antigen receptor (CAR) T cells that specifically target and eliminate CD4+ autoimmune T cells, and will therapeutically alter the disease course of autoimmune arthritis. This innovative approach is based on the generation of CD8+ T cells genetically engineered to express HLA-DR CAR molecules loaded with an autoantigenic peptide. Using our well characterized HLA-DR humanized mouse model of rheumatoid arthritis (RA), we will test the hypothesis that CD8+ T cells can be engineered to express HLA-DR class II CAR with CD28/CD3ζ intracellular signaling domains, and that after peptide loading of the CAR DR molecules on these CD8+ T cells, they will function as CTL and specifically target and eliminate CD4+ autoimmune T cells. Two approaches will be pursued to generate antigen specific targeting of the CD4+ T cells. Initial experiments will be focused on using DRB1 cDNA encoding an antigenic peptide that is covalently linked to the DR1 molecule. This approach will be used to demonstrate the feasibility of the CAR CTL generation and their function in vivo in the inhibition of an active autoimmune disease. In the second approach, we will generate CAR CTL with “empty “ DR1 molecules, and soluble peptide will be used to load the DR1 CAR before measuring the CAR CTL function. This approach will allow for targeting CD4+ T cells specific for posttranslationally modified (PTM) peptides which are components of the autoimmunity of the mouse model and potentially important components of RA autoimmunity. Through the specific aims of this proposal, we will investigate the specificity of the CAR T cells, their ability to receive signals through the CAR CD28/CD3 domains, and their efficacy in treating an active autoimmune disease.

抽象的该提案的重点是开发新型嵌合抗原受体（CAR）T 特异性靶向并消除 CD4+ 自身免疫 T 细胞的细胞，并且将在治疗上这种创新方法是基于改变自身免疫性关节炎的病程。产生经过基因工程改造的 CD8+ T 细胞，以表达负载的 HLA-DR CAR 分子使用我们充分表征的 HLA-DR 人源化小鼠模型。类风湿性关节炎 (RA) 的治疗，我们将检验 CD8+ T 细胞可以被改造为表达具有 CD28/CD3ze 细胞内信号结构域的 HLA-DR II 类 CAR，并且在将 CAR DR 分子肽装载到这些 CD8+ T 细胞上，它们将充当 CTL 和将采用两种方法来特异性靶向并消除 CD4+ 自身免疫 T 细胞。产生针对 CD4+ T 细胞的抗原特异性靶向。使用编码与 DR1 分子共价连接的抗原肽的 DRB1 cDNA。该方法将用于证明 CAR CTL 生成的可行性及其在第二种方法中，我们在体内发挥抑制活动性自身免疫性疾病的作用。将生成带有“空”DR1分子的CAR CTL，并使用可溶性肽来负载在测量 CAR CTL 功能之前先测量 DR1 CAR，此方法将允许定位。 CD4+ T 细胞对翻译后修饰 (PTM) 肽具有特异性，该肽是小鼠模型的自身免疫和 RA 的潜在重要组成部分通过该提案的具体目标，我们将研究自身免疫的特殊性。 CAR T 细胞，它们通过 CAR CD28/CD3 结构域接收信号的能力，以及它们的治疗活动性自身免疫性疾病的功效。