Disease relevance of CD20 expression on T cells in multiple sclerosis patients

多发性硬化症患者 T 细胞 CD20 表达的疾病相关性

基本信息

批准号：
9127811
负责人：
STEPHEN L HAUSER
金额：
$ 38.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127811
关键词：
Address Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving B-Lymphocytes Blood - brain barrier anatomy CD3 Antigens Clinical Development Diagnosis Disease Effectiveness Experimental Autoimmune Encephalomyelitis Flow Cytometry Health Homologous Gene Human Immune Immunoglobulin Variable Region In Vitro Inflammatory Link Lymphocyte Lymphocyte Subset MS4A1 gene Magnetic Resonance Imaging Measures Mediating Methods Molecular Profiling Monoclonal Antibodies Multiple Sclerosis Mus Myelin Neuraxis Pathology Patients Pattern Phase Phenotype Prevalence Relapse Research Resolution Rheumatoid Arthritis Safety Severity of illness Staging T-Cell Depletion T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Therapeutic Effect Therapeutic Monoclonal Antibodies Time cell motility clinical Diagnosis effective therapy multiple sclerosis patient neglect nervous system disorder next generation novel therapeutics peripheral blood programs research study rituximab tositumomab

项目摘要

DESCRIPTION (provided by applicant): Monoclonal antibodies against CD20 are a highly effective therapy for multiple sclerosis (MS) currently in phase III clinical development. CD20 is commonly viewed as an archetypical B cell marker. However, a subset of human T lymphocytes (T cells) also expresses CD20. Presently, not much is known about the functional or pathological relevance of CD20-expressing T cells, but a possible involvement of this T cell subpopulation in autoimmune disorders has been suggested. CD20+ T cells can assume a pro-inflammatory Th17 phenotype in rheumatoid arthritis (RA) and MS, and increased numbers of CD3+CD20dim T cells can be found in peripheral blood (PB) of MS patients. Like CD20+ B cells, CD3+CD20dim T cells are effectively depleted from PB of MS and RA patients by the anti-CD20 antibody rituximab, which may, in part, be responsible for the effectiveness of anti-CD20 therapeutic strategies. Unpublished preliminary experiments suggest that CD3+CD20dim T cells in PB may be increased during MS relapses; CD20-expressing T cells are also present in CSF but an association with disease-activity has yet to be studied. Furthermore, next-generation deep T cell receptor ß-chain variable region (TCR-Vß) immune-repertoire sequencing suggests that identical CD20dim T cell clonotypes in peripheral blood and CSF may be involved in MS disease-activity. To our knowledge, no murine equivalent to human CD3+CD20dim T cells has been identified. However, treatment of mice with an antibody specific for MS4aB1, a murine CD20 homolog expressed on T cells, was found to ameliorate disease severity of experimental autoimmune encephalomyelitis (EAE), theoretically mimicking the therapeutic effect of rituximab-mediated CD3+CD20dim T cell depletion, in the absence of B cell depletion, in humans. The objective of this research program is to delineate the potential pathological involvement of CD3+CD20dim T cells in the immune pathology of MS. Methods: We will perform extensive phenotypic, transcriptional, and functional characterizations of CD20+ T cells in PB (Aim 1), to examine whether CD20+ T cells and/or other T cell subsets can provide an antigen-specific, immunologically active, and sustained connection between the periphery and CNS compartments (Aim 2), and to determine their prevalence in MS CSF during different stages of the disease (Aim 2) and compared to other neurological diseases (Aim 3).

描述（由申请人提供）：针对 CD20 的单克隆抗体是目前处于 III 期临床开发中的多发性硬化症 (MS) 的高效疗法，CD20 通常被视为典型的 B 细胞标记物。目前，对于表达 CD20 的 T 细胞的功能或病理相关性知之甚少，但该 T 细胞亚群可能参与自身免疫性疾病。研究表明，在类风湿性关节炎 (RA) 和 MS 中，CD20+ T 细胞可以呈现促炎性 Th17 表型，并且与 CD20+ B 细胞一样，在 MS 患者的外周血 (PB) 中可以发现 CD3+ CD20dim T 细胞数量增加。抗 CD20 抗体利妥昔单抗可有效消除 MS 和 RA 患者 PB 中的 CD3+CD20dim T 细胞，这可能在一定程度上负责未发表的初步实验表明，在 MS 复发期间，PB 中的 CD3+CD20dim T 细胞可能会增加；CSF 中也存在表达 CD20 的 T 细胞，但其与疾病活动性的关系仍有待研究。新一代深层 T 细胞受体 β 链可变区 (TCR-Vß) 免疫库测序表明，外周血和脑脊液中相同的 CD20dim T 细胞克隆型可能参与据我们所知，尚未发现与人类 CD3+CD20dim T 细胞相当的鼠类药物，但是，使用针对 MS4aB1（T 细胞上表达的鼠类 CD20 同源物）的特异性抗体进行治疗可改善疾病的严重程度。实验性自身免疫性脑脊髓炎 (EAE) 的治疗效果，理论上模拟利妥昔单抗介导的 CD3+CD20dim T 细胞耗竭的治疗效果，在 B 缺失的情况下该研究项目的目的是阐明 CD3+CD20dim T 细胞在 MS 免疫病理学中的潜在病理学参与。方法：我们将在人类中对 CD20+ T 细胞进行广泛的表型、转录和功能表征。 PB（目标 1），检查 CD20+ T 细胞和/或其他 T 细胞亚群是否可以在外周细胞和外周细胞之间提供抗原特异性、免疫活性和持续的连接CNS 区室（目标 2），并确定其在疾病不同阶段（目标 2）在 MS CSF 中的患病率，并与其他神经系统疾病进行比较（目标 3）。