Therapeutic effect of αCD52 mAb in multiple sclerosis and its animal models is mediated via T-regulatory cells

• Published in: The Journal of immunology (1950) Vol. 209; no. 1; pp. 49 - 56
• Main Authors: Kiapour, Nazanin, Wu, Bing, Wang, Yan, Seyedsadr, Maryamsadat, Kapoor, Sahil, Zhang, Xin, Elzoheiry, Manal, Kasimoglu, Ezgi, Wan, Yisong, Markovic-Plese, Silva
• Format: Journal Article
• Language: English
• Published: 24.06.2022
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2100176

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.