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

 描述(申请人提供)：抗CD20的单抗是一种治疗多发性硬化症(MS)的高效疗法，目前正处于III期临床开发中。CD20通常被视为典型的B细胞标志物。然而，人类T淋巴细胞(T细胞)的一个亚群也表达CD20。目前，对表达CD20的T细胞的功能或病理相关性了解不多，但这一T细胞亚群可能参与了自身免疫性疾病。类风湿关节炎(RA)和多发性硬化症(MS)患者外周血中CD20dim T细胞数量增加，CD20T细胞呈Th17表型。与CD20 B细胞一样，抗CD20抗体利妥昔单抗可以有效地清除MS和RA患者外周血中的CD3 CD20dim T细胞，这可能是抗CD20治疗策略的有效性的部分原因。未发表的初步实验表明，在MS复发期间，外周血中CD3、CD20dim T细胞可能增加；表达CD20的T细胞也存在于脑脊液中，但与疾病活动性的关系仍有待研究。此外，下一代深层T细胞受体-链可变区(TCR-Vü)免疫谱系测序表明，外周血和脑脊液中相同的CD20dim T细胞克隆型可能与MS疾病活动有关。据我们所知，目前还没有鉴定出与人CD3 CD20dim T细胞等同的小鼠。然而，用一种针对MS4aB1(一种表达在T细胞上的小鼠CD20同源物)的抗体治疗小鼠被发现可以改善实验性自身免疫性脑脊髓炎(EAE)的疾病严重程度，理论上模仿了利妥昔单抗介导的CD3 CD20dim T细胞耗竭的治疗效果，而不是B细胞耗尽。本研究的目的是阐明CD3 CD20dim T细胞在MS免疫病理中的潜在病理参与。方法：我们将对外周血中CD20T细胞进行广泛的表型、转录和功能鉴定(目标1)，检查CD20 T细胞和/或其他T细胞亚群是否能够在外周和中枢神经系统之间提供抗原特异性的、免疫活性的和持续的联系(目标2)，并确定它们在MS CSF中的患病率(目标2)以及与其他神经系统疾病(目标3)的比较。

 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 Unpublished preliminary experiments suggest that CD3+CD20dim T cells in PB may be increased during MS relapses; CD20-expressing T cells are also present in CSF but an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).