Abstract
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.
Highlights
Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, of CD4+ T lymphocytes
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
There was a change in mRNA of cytokines, chemokines, and transcriptional factors related to Th17, Th1, and Treg cell subset changes, suggesting a shift toward immunoregulation and a reduction of T cell recruitment to the central nervous system
Summary
Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, of CD4+ T lymphocytes. Alemtuzumab, a monoclonal antibody that targets the CD52 antigen, is the first immune reconstitution therapy in Europe and the USA to be approved for patients with relapsing multiple sclerosis (PwRMS). Alemtuzumab administration determines a rapid and marked reduction in peripheral T and B lymphocytes, which express CD52 molecules at high levels on their membrane, due to antibody-dependent cell-mediated cytotoxicity, complement-dependent cytolysis, and induction of apoptosis [1] with a subsequent beneficial reconstitution of the immune system [2]. We had previously organized a multicenter 24-month study [7] to analyze the changes in Th subsets, Treg proportion and function, and mRNA levels of cytokines and other immunologically related molecules in 29 patients from phase III trials CARE-MS I [3] and CARE-MS II [4]. We report the complete long-term follow-up of 72 months focusing on the study of the CD4+ immune cell reconstitution in those 24 patients who had received the two classical alemtuzumab administrations at months 0 and 12, and studying the CD4+ immune cell reconstitution so as to compare it to the healthy subjects (HS)
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