Alemtuzumab Long Term Immunological Study: The Immunosuppressive Effect Does Not Last More Than 48 Months (S2.008)

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OBJECTIVE: Phenotypic and functional analysis of CD4+ T cell subsets and of immunologically relevant molecules mRNA serum levels after alemtuzumab in relapsing remitting multiple sclerosis(RRMS) patients: A four-year follow-up. BACKGROUND: Alemtuzumab induces a long-standing lymphopenia, particularly of T CD4+ subset, and it is highly effective in RRMS DESIGN/METHODS: Multicenter follow-up of 29 alemtuzumab-treated RRMS patients from 6 European sites in the CARE-MS I and CARE-MS II trials. Patients received two course of alemtuzumab at month 0 and 12. Clinical and immunological evaluation were performed at months 0, 6, 12, 18, 24, 36 and 48. The percentages of Treg, Th1 and Th17 cells in the peripheral blood mononuclear cells(PBMC) were evaluated by FACS analysis. mRNA levels of cytokines, chemokines, chemokine receptors and transcriptional factors with pro-inflammatory (IL-1β, IL-2, IL-6, IL-12, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-26, IFN-γ, Tbet, RORC, TNF-α, CCR3, CCR4, CCR5, CCR6, CXCR3, CXCL10, CCL20, VLA4) or anti-inflammatory function (IL-10, IL-27, TGF-β and FoxP3) were quantified by TaqMan® low density array(TLDA) real-time polymerase chain reaction in whole blood. Treg suppressor activity on Myelin basic protein(MBP)-specific Th17 and Th1 cells was assessed by IL-17 and IFN-γ ELISPOT on total PBMC and PBMC depleted of CD25highT cells. RESULTS: No patient received further alemtuzumab courses after the first two years. CD4+ lymphocyte percentage decreased and slowly returned to basal levels only at Month 48. Within this population, no significant variation was observed in Th1 and Th17 cells, with the exception of an increase of Th17 cells in patients with a documented relapse. Treg cells percentage and suppressive function significantly increased at Month 24 and returned to baseline levels within Month 48. CONCLUSIONS: The long-term follow-up of immune system reconstitution showed that alemtuzumab effects lasted not more that 48 months. Clinical and MRI follow-up could suggest the need for repeated alemtuzumab courses.

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