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 Unpublished preliminary experiments suggest that CD3+CD20dim T cells in PB may be increased during MS relapses; CD20-expressing T cells are also present in CSF but an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（由适用提供）：针对CD20的单克隆抗体是目前在III期临床开发中的多发性硬化症（MS）的高效疗法。 CD20通常被视为原型B细胞标记。但是，人类T淋巴细胞（T细胞）的一部分也表达CD20。目前，对于表达CD20的T细胞的功能或病理相关性并不了解，但是已经提出了该T细胞亚群参与自身免疫性疾病。 CD20+ T细胞可以假设类风湿关节炎（RA）和MS中的促炎性Th17表型，并且在MS患者的外周血（PB）中发现CD3+ CD20DIM T细胞的数量增加。像CD20+ B细胞一样，CD3+ CD20DIM T细胞有效地从MS和RA患者的PB中耗尽了抗CD20抗体利妥昔单抗，该抗体可能部分负责抗CD20治疗策略的有效性。未发表的初步实验表明，在MS继电器期间，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，但与疾病活性的关联尚未研究。此外，下一代深T细胞受体ß链可变区域（TCR-Vß）免疫 - 替代测序表明，外周血中的CD20DIM T细胞插型相同，CSF可能参与MS疾病活动。据我们所知，尚未确定与人CD3+CD20DIM T细胞相等的鼠。 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 deployment, in the absence of B cell deployment, in humans.该研究计划的目的是描述CD3+CD20DIM T细胞在MS的免疫病理学中的潜在病理学参与。方法：我们将执行PB中CD20+ T细胞的广泛表型，转录和功能特征（AIM 1），以检查CD20+ T细胞和/或其他T细胞子集是否可以提供抗原特异性，免疫学上的活性，并在周围和CNS隔离区（AIM 2）之间进行抗原特异性，具有持续的联系（AIM 2），目的是SSF中的其他目的。神经疾病（AIM 3）。