CAR-T cell treatment of CNS Autoimmunity

CAR-T细胞治疗中枢神经系统自身免疫

基本信息

批准号：
10641913
负责人：
CHYI S HSIEH
金额：
$ 68.34万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-13 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641913
关键词：
Address Affinity Algorithms Animal Model Antibodies Antigen Presentation Antigen Receptors Antigens Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes Binding CAR T cell therapy CASP3 gene CASP8 gene CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CNS Demyelinating Autoimmune Diseases CNS autoimmune disease CNS autoimmunity CRISPR/Cas technology Cell Death Induction Cells Central Nervous System Diseases Chronic Clinical Data Disease Dominant-Negative Mutation Engineering Epitopes Excision Experimental Autoimmune Encephalomyelitis Frequencies Gene Deletion Gene Targeting Genes Goals Granzyme HLA-DR Antigens Healthcare Human Immune response Immune system Immunosuppression Immunotherapy In Vitro Inflammation JUN gene Knock-out Libraries Lymphocyte Methodology Modeling Modification Multiple Sclerosis Mus Myelin Proteins Nervous System Trauma Pathogenesis Pathway interactions Patients Peptide Receptor Peptides Prevention Proteins Reaction Resolution Severities Signal Transduction Specificity T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes T-cell receptor repertoire Technology Testing Transgenic Organisms Translating Tumor Necrosis Factor-Beta Validation adaptive immunity autoreactive T cell autoreactivity cancer therapy care burden cell killing chemical reaction chimeric antigen receptor chimeric antigen receptor T cells disability efficacy evaluation exhaustion experimental study feasibility testing genetic linkage human disease improved in vivo in vivo evaluation mouse model multiple sclerosis treatment neuroinflammation oligodendrocyte-myelin glycoprotein optimal treatments overexpression perforin pre-clinical receptor response translation to humans vector

项目摘要

PROJECT SUMMARY An immense need for selective and antigen-specific immunotherapy without global immunosuppression exists for autoimmune diseases such as multiple sclerosis (MS) and a closely related condition known as myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD). This has prompted exploration of chimeric antigen receptor (CAR) T cell utilization to specifically eliminate autoreactive cells. We have created a unique version of CAR T cells in which peptide MHCII (pMHCII) was fused with signaling domains in order to recognize specific T cell receptors (TCRs). In preliminary studies we demonstrate that these pMHCII-CAR T cells specifically recognize a cognate TCR in vitro and can selectively kill antigen-specific CD4 T cells in vivo. Efficient depletion of high affinity MOG-specific CD4 T cells was associated with prevention of MOG-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Modifications in pMHCII-CAR construction led to greater efficiency in eliminating lower-affinity MOG-reactive T cells which was associated with resolution of ongoing EAE. These data suggest an “activation energy” model of autoimmunity analogous to that of a chemical reaction, in which higher affinity self-reactive T cells are needed to provide the activation energy to initiate autoimmunity, but lower affinity T cells are capable of sustaining the autoimmune “reaction.” To address the hypothesis that CAR T cell technology can be used to eliminate auto-antigen-specific T cells and abrogate central nervous system (CNS) autoimmunity in mice and humans without global immunosuppression, we have formulated three specific aims. In Aim 1 we will improve the efficiency of low affinity T cell deletion in vivo. In Aim 2, we will test whether we can successfully target autoreactive CD4 T cells specific to all T cell epitopes of a protein in mice, as we predict that such an approach would be useful for treatment of human disease where the T cell autoantigen is identified by an autoantibody. Finally, in Aim 3, we will directly test whether MOGAD patients show an increased frequency of MOG-specific T cells using pMHCII-CARs for antigen discovery. In sum, our proposed studies will explore the “activation energy” model of autoimmunity and establish an optimal CAR T cell approach to eliminate low affinity autoreactive TCR specificities for the treatment of ongoing autoimmune disease. Finally, we will begin to translate these murine observations to human pMHCII-CAR T cells and assess their potential utility in a relevant human autoimmune CNS disease.

项目摘要不存在全局免疫抑制的选择性和抗原特异性免疫疗法的巨大需求用于自身免疫性疾病，例如多发性硬化症（MS）和称为髓磷脂的密切相关疾病少突胶质细胞糖蛋白（MOG）抗体疾病（MOGAD）。这促使探索嵌合抗原受体（CAR）T细胞利用以特异性消除自动反应性细胞。我们创建了一个独特的肽MHCII（PMHCII）的CAR T细胞版本与信号域融合以识别特异性T细胞受体（TCR）。在初步研究中，我们证明了这些PMHCII-CAR T细胞在体外明确识别了同源性TCR，并且可以在体内选择性地杀死抗原特异性的CD4 T细胞。高效的高亲和力MOG特异性CD4 T细胞的耗竭与预防MOG诱导的实验有关自身免疫性脑脊髓炎（EAE），MS动物模型。 PMHCII-CAR构造的修改导致消除低亲和力MOG反应性T细胞的效率更高，这与分辨率有关正在进行的EAE。这些数据表明自身免疫的“激活能量”模型类似于化学反应，其中需要更高的亲和力自反应性T细胞来提供激活能量以启动自身免疫性，但较低的亲和力T细胞能够维持自身免疫性“反应”。解决假设CAR T细胞技术可用于消除自动抗原特异性T细胞并消除中央在没有全球免疫抑制的小鼠和人类中，神经系统（CNS）自身免疫性，我们有锻造三个特定目标。在AIM 1中，我们将提高体内低亲和力T细胞缺失的效率。目标 2，我们将测试我们是否可以成功靶向特定于A的所有T细胞表位的自动反应性CD4 T细胞小鼠中的蛋白质，因为我们预测这种方法对于治疗人类疾病将很有用 T细胞自动抗原通过自身抗体鉴定。最后，在AIM 3中，我们将直接测试Mogad患者是否使用PMHCII-CARS进行抗原发现显示MOG特异性T细胞的频率增加。总而言之拟议的研究将探讨自身免疫性的“激活能量”模型，并建立最佳的CAR T细胞消除低亲和力自动反应性TCR规范以治疗持续自身免疫性疾病的方法。最后，我们将开始将这些鼠的观测转化为人类PMHCII-CAR T细胞，并评估它们相关人类自身免疫性中枢神经系统疾病的潜在效用。