title: Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months.
abstract: OBJECTIVE
  To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS).
  
  
  METHODS
  Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)-specific Treg suppressor activity.
  
  
  RESULTS
  We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)-10, IL-27, and transforming growth factor-β persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells.
  
  
  CONCLUSIONS
  The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function.
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: De Mercanti
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rolla
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Angele
authors.initials: A
authors.lastname: Cucci
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bardina
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cocco
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Anton
authors.initials: A
authors.lastname: Vladic
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Silva
authors.initials: S
authors.lastname: Soldo-Butkovic
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Habek
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Ivan
authors.initials: I
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authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
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authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Annovazzi
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
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authors.initials: L
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authors.affiliation: Division of Neurology (S.D.M., S.R., A.C., L.D., M.C.) and the Department of Clinical and Biological Sciences (S.D.M., A.C., L.D., M.C.), University of Torino, San Luigi Gonzaga University Hospital, Orbassano; Center for Experimental Research and Medical Studies (CERMS) (S.R., V.B., F.N.), Azienda Ospedaliera Città della Salute e della Scienza di Torino; Department of Molecular Biotechnology and Health Sciences (V.B., F.N.), Università degli Studi di Torino; Multiple Sclerosis Center (E.C.), Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy; Department of Neurology (A.V., S.S.-B.), Clinical Hospital Sveti Duh Zagreb; Medical Faculty University (A.V., S.S.-B.), J.J. Strossmayer Osijek; Department of Neurology (M.H., I.A.), Referral Center for Demyelinating Diseases of the Central Nervous System, University Hospital Center Zagreb, Croatia; Department of Neurology and Center of Clinical Neuroscience (D.H.), Charles University in Prague, First Faculty of Medicine and General University Hospital, Czech Republic; and Multiple Sclerosis Study Center (P.A.), AO S. Antonio Abate, Gallarate (VA), Italy.
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