Long-Term Effects of Alemtuzumab on CD4+ Lymphocytes in Multiple Sclerosis Patients: A 72-Month Follow-Up

• DOI: 10.3389/fimmu.2022.818325
• Publication Date: 2022-02-28T07:53:12Z
• Authors: Simona Rolla; Stefania Federica...; Valentina Bardina; Alessandro Maglione; Daniela Taverna; Francesco Novelli; Eleonora Cocco; Anton Vladic; Mario Habek; Ivan Adamec; Pietro Osvaldo Lu...; Dana Horakova; Marinella Clerico
• Keywords: CD4-Positive T-Lymphocytes; Multiple Sclerosis; alemtuzumab; immune reconstitution; MBP (myelin basic protein); multiple sclerosis; Treg cells; Immunology; immune reconstitution; RC581-607; multiple sclerosis; Alemtuzumab / therapeutic use; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; MBP (myelin basic protein); Alemtuzumab / pharmacology; RNA, Messenger / therapeutic use; MBP (myelin basic protein); Treg cells; Alemtuzumab; Immune reconstitution; Multiple sclerosis; CD4-Positive T-Lymphocytes; Follow-Up Studies; Humans; RNA, Messenger; alemtuzumab; Multiple Sclerosis / drug therapy; Humans; RNA, Messenger; Immunologic diseases. Allergy; Alemtuzumab; Treg cells; Follow-Up Studies

IntroductionAlemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated.MethodsWe followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1).ResultsIn patients receiving only two-course alemtuzumab, the percentage of CD4+ lymphocytes decreased and returned to basal levels only at month 48. Immune reconstitution of the CD4+ subsets was characterized by a significant increase (p < 0.001) in Treg cell percentage at month 24, when compared to baseline, and was accompanied by restoration of the Treg suppressor function that increased within a range from 2- to 6.5-fold compared to baseline and that persisted through to the end of the follow-up. Furthermore, a significant decrease in self-reactive myelin basic protein-specific Th17 (p < 0.0001) and Th1 (p < 0.05) cells reaching HS values was observed starting from month 12. There was a change in mRNA of cytokines, chemokines, and transcriptional factors related to Th17, Th1, and Treg cell subset changes, consequently suggesting a shift toward immunoregulation and a reduction of T cell recruitment to the central nervous system.ConclusionsThese data provide further insight into the mechanism that could contribute to the long-term 6-year persistence of the clinical effect of alemtuzumab on RMS disease activity.