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

• 批准号: 8945644
• 负责人: STEPHEN L HAUSER
• 金额: $ 36.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/8945644
• 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; 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; neglect; nervous system disorder; next generation; novel therapeutics; peripheral blood; programs; public health relevance; research study; rituximab; tositumomab

 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 Unpublished preliminary experiments suggest that CD3+CD20dim T cells in PB may be increased during MS relapses; CD20-expressing T cells are also present in CSF but an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（由申请方提供）：抗CD 20单克隆抗体是目前处于III期临床开发阶段的多发性硬化症（MS）的一种高效疗法。CD 20通常被视为典型的B细胞标志物。然而，人T淋巴细胞（T细胞）的亚群也表达CD 20。目前，对表达CD 20的T细胞的功能或病理相关性知之甚少，但已提出该T细胞亚群可能参与自身免疫性疾病。在类风湿性关节炎（RA）和MS中，CD 20 + T细胞可以呈现促炎性Th 17表型，并且在MS患者的外周血（PB）中可以发现增加数量的CD 3 + CD 20 dim T细胞。与CD 20 + B细胞一样，抗CD 20抗体利妥昔单抗可有效地从MS和RA患者的PB中清除CD 3 + CD 20 dim T细胞，这可能部分地负责抗CD 20治疗策略的有效性。未发表的初步实验表明，PB中的CD 3 + CD 20 dim T细胞可能在MS复发期间增加;表达CD 20的T细胞也存在于CSF中，但与疾病活动性的相关性尚未研究。此外，下一代深层T细胞受体β-链可变区（TCR-VEGF 1）免疫组化测序表明，外周血和CSF中相同的CD 20 dim T细胞克隆型可能参与MS疾病活动。据我们所知，尚未鉴定出与人CD 3 + CD 20 dim T细胞等同的鼠T细胞。然而，发现用对MS 4aB 1（在T细胞上表达的鼠CD 20同源物）具有特异性的抗体治疗小鼠可改善实验性自身免疫性脑脊髓炎（EAE）的疾病严重程度，理论上模拟在不存在B细胞耗竭的情况下利妥昔单抗介导的CD 3 + CD 20 dim T细胞耗竭在人中的治疗效果。本研究项目的目的是描述CD 3 + CD 20 dim T细胞在MS免疫病理学中的潜在病理参与。我们将对PB中的CD 20 + T细胞进行广泛的表型、转录和功能表征（目的1），以检查CD 20 + T细胞和/或其他T细胞亚群是否可以提供抗原特异性的、免疫活性的，以及外周和CNS隔室之间的持续联系（目的2），并确定其在疾病不同阶段的MS CSF中的患病率（目的2），并与其他神经系统疾病进行比较（目的3）。