Therapeutic Effect of Anti-CD52 Monoclonal Antibody in Multiple Sclerosis and Its Animal Models Is Mediated via T Regulatory Cells.
Therapeutic Effect of Anti-CD52 Monoclonal Antibody in Multiple Sclerosis and Its Animal Models Is Mediated via T Regulatory Cells.
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DOI：
10.4049/jimmunol.2100176
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发表时间：
2022-07-01
影响因子：
4.4
通讯作者：
Markovic-Plese, Silva
中科院分区：
文献类型：
--
作者：
Kiapour, Nazanin;Wu, Bing;Wang, Yan;Seyedsadr, Maryamsadat;Kapoor, Sahil;Zhang, Xin;Elzoheiry, Manal;Kasimoglu, Ezgi;Wan, Yisong;Markovic-Plese, Silva
本研究旨在探讨αCD52mAb治疗复发缓解型多发性硬化症的作用机制。采用实验性自身免疫性脑脊髓炎(EAE)的动物模型，研究T调节细胞(Treg)在αCD52Maab诱导的疾病抑制中的作用。对RRMS患者和健康对照组(HCS)外周血单个核细胞(PBMC)进行体外培养，观察IL-7对CD4+CD25+CD127+Tregs扩增和抑制表型的影响。应用EAE MS动物模型的研究表明，联合应用IL-7可增强小鼠αCD52mAb对临床疾病的抑制作用，而αIL-7mAb可部分逆转其对临床疾病的抑制作用。体外人体实验表明，IL-7可诱导CD4+CD25+CD127+Tregs的扩增，并增加其Foxp3、GITIR、CD46、CTLA-4、GZMB和穿孔素的表达。Foxp3+α+γ+Treg细胞在周围免疫器官和中枢神经系统浸润物中的表达受到抑制，而Foxp3+CD52单抗诱导的Treg细胞增殖。治疗后立即检测到疗效，并在长期随访中保持疗效。在诱导的Foxp3耗竭后，Foxp3+CD_4+Treg介导的IL-17A+CD_4~+细胞和干扰素-γ~+CD_4~+细胞抑制作用被逆转。我们的结果表明，FDA批准的αCD52mAb的治疗效果依赖于Treg细胞的存在。
The objective of this study is to determine the mechanism of action of αCD52 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 αCD52 maAb-induced suppression of the disease. In-vitro studies on PBMCs from RRMS patients and matched healthy controls (HCs) determined the effect of IL-7 on the expansion of CD4+CD25+CD127+ Tregs and induction of their suppressive phenotype. The present sudy using EAE animal models of MS has shown that mouse (mu) αCD52 mAb suppression of clinical disease was augmented by co-administration of IL-7, and partially reversed by αIL-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, GZMB and perforin expression. αCD52 mAb treatment of mice with RREAE induced expansion of Foxp3+CD4+ Treg cells and the suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in peripheral immune organs and in CNS infiltrates. The effect was detected immediately after the treatment and maintained over a long-term follow-up. Foxp3+CD4+ Treg-mediated suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in the spinal cord infiltrates were reversed after inducible Foxp3 depletion in DEREG mice. Our results demonstrated that the therapeutic effect of FDA-approved αCD52 mAb is dependent on the presence of Treg cells.
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影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
3.3
作者：
Turner, Michael J.;Pang, Petti T.;Siders, William M.
通讯作者：
Siders, William M.
影响因子：
9.9
作者：
Coles, A. J.;Fox, E.;Compston, D. A. S.
通讯作者：
Compston, D. A. S.
影响因子：
4.4
作者：
Gondek, DC;Lu, LF;Noelle, RJ
通讯作者：
Noelle, RJ