PDF(Pubmed)
Abstract：
The objective of this study is to determine the mechanism of action of anti-CD52 mAb treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Experimental autoimmune encephalomyelitis (EAE), an animal model of the disease, was used to address the role of T regulatory cells (Tregs) in the anti-CD52 mAb-induced suppression of the disease. In vitro studies on PBMCs from RRMS patients and matched healthy controls determined the effect of IL-7 on the expansion of CD4+CD25+CD127- Tregs and induction of their suppressive phenotype. This study using EAE animal models of MS has shown that mouse anti-CD52 mAb suppression of clinical disease was augmented by coadministration of IL-7 and partially reversed by anti-IL-7 mAb. In vitro human studies showed that IL-7 induced expansion of CD4+CD25+CD127- Tregs and increased their FOXP3, GITIR, CD46, CTLA-4, granzyme B, and perforin expression. Anti-CD52 mAb treatment of mice with relapsing-remitting EAE induced expansion of Foxp3+CD4+ Tregs and the suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in peripheral immune organs and CNS infiltrates. The effect was detected immediately after the treatment and maintained over long-term follow-up. Foxp3+CD4+ Treg-mediated suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in the spinal cord infiltrates was reversed after inducible Foxp3 depletion. Our results demonstrated that the therapeutic effect of U.S. Food and Drug Administration-approved anti-CD52 mAb is dependent on the presence of Tregs.
摘要：
这项研究的目的是确定抗CD52mAb治疗复发缓解型多发性硬化症（RRMS）患者的作用机制。实验性自身免疫性脑脊髓炎（EAE），疾病的动物模型，用于解决T调节细胞（Tregs）在抗CD52mAb诱导的疾病抑制中的作用。对来自RRMS患者和匹配的健康对照的PBMC的体外研究确定了IL-7对CD4+CD25+CD127-Treg的扩增和其抑制表型的诱导的影响。使用MS的EAE动物模型的这项研究表明，通过共同施用IL-7增强了小鼠抗CD52mAb对临床疾病的抑制，并被抗IL-7mAb部分逆转。体外人体研究表明，IL-7诱导CD4+CD25+CD127-Tregs的扩增，并增加其FOXP3，GITIR，CD46，CTLA-4，颗粒酶B，和穿孔素表达。抗CD52mAb治疗复发缓解型EAE小鼠诱导Foxp3+CD4+Tregs扩增和抑制外周免疫器官和CNS浸润中的IL-17A+CD4+和IFN-γ+CD4+细胞。治疗后立即检测到效果，并在长期随访中保持。Foxp3+CD4+Treg介导的脊髓浸润中IL-17A+CD4+和IFN-γ+CD4+细胞的抑制在诱导型Foxp3耗竭后被逆转。我们的结果表明，美国食品和药物管理局批准的抗CD52mAb的治疗效果取决于Treg的存在。
