Research Article| Volume 319, ISSUE 1-2, P18-23, August 15, 2012

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Immunoregulatory T cells in multiple sclerosis and the effect of interferon beta and glatiramer acetate treatment on T cell subpopulations



      Multiple sclerosis (MS) is a chronic disease characterized by demyelination and chronic inflammation of the central nervous system (CNS). Many of the immune cells including T and B cells seem to be involved in disease pathogenesis by inducing or controlling the immune responses in the nervous system of MS patients. The objective of this study was to evaluate the differences in subpopulations of T cells between MS patients and healthy controls and the effects of interferon beta (INF-beta) and glatiramer acetate (GA) treatment on T cell subpopulations.

      Material and methods

      We have investigated the frequency of subpopulations of T cells using flow cytometry in 84 relapsing-remitting MS patients; forty-five patients started treatment with INF-beta and eighteen patients with GA, twenty-one patients were not treated. We collected blood samples at the beginning and after 6 and 12 months.


      We observed a significant decrease in CD4+CD25+ Treg cells (p=0.03) and a significant increase in T helper cells (p=0.002) and central memory T cells (p=0.03) in MS patients compared to healthy controls. After INF-beta therapy, we demonstrated a significant increase in naive T cells (p=0.008), a decline in central memory T cells (p=0.01). After GA therapy, we observed a significant increase in naive T cells (p=0.04), a decrease in central memory T cells (p=0.03) and an increase in T-suppressor cells (p=0.008).


      In conclusion, we demonstrated the imbalance of T-cell subpopulations in MS patients and the potential benefit of DMD (disease modifying drugs) treatment on its restoration.


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        • Nikić I.
        • Merkler D.
        • Sorbara C.
        • Brinkoetter M.
        • Kreutzfeldt M.
        • Bareyre F.M.
        • et al.
        A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis.
        Nat Med. 2011; 17: 495-499
        • Hofstetter H.H.
        • Gold R.
        • Hartung H.-P.
        Th17 cells in MS and experimental autoimmune encephalomyelitis.
        Int MS J. 2009; 16: 12-18
        • Lucchinetti C.
        • Brück W.
        • Parisi J.
        • Scheithauer B.
        • Rodriguez M.
        • Lassmann H.
        Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.
        Ann Neurol. 2000; 47: 707-717
        • Neumann H.
        • Medana I.M.
        • Bauer J.
        • Lassmann H.
        Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases.
        Trends Neurosci. 2002; 25: 313-319
        • Raine C.S.
        Multiple sclerosis: immune system molecule expression in the central nervous system.
        J Neuropathol Exp Neurol. 1994; 53: 328-337
        • Sallusto F.
        • Lenig D.
        • Förster R.
        • Lipp M.
        • Lanzavecchia A.
        Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.
        Nature. 1999; 401: 708-712
        • Afzali B.
        • Lombardi G.
        • Lechler R.I.
        • Lord G.M.
        The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease.
        Clin Exp Immunol. 2007; 148: 32-46
        • Fietta P.
        • Delsante G.
        The effector T helper cell triade.
        Riv Biol. 2009; 102: 61-74
        • Haas J.
        • Hug A.
        • Viehöver A.
        • Fritzsching B.
        • Falk C.S.
        • Filser A.
        • et al.
        Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis.
        Eur J Immunol. 2005; 35: 3343-3352
        • Horwitz D.A.
        • Regulatory T.
        Cells in systemic lupus erythematosus: past, present and future.
        Arthritis Res Ther. 2008; 10: 227
        • Jadidi-Niaragh F.
        • Mirshafiey A.
        Th17 cell, the new player of neuroinflammatory process in multiple sclerosis.
        Scand J Immunol. 2011; 74: 1-13
        • Lock C.
        • Hermans G.
        • Pedotti R.
        • Brendolan A.
        • Schadt E.
        • Garren H.
        • et al.
        Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.
        Nat Med. 2002; 8: 500-508
        • Lee D.H.
        • Linker R.A.
        • Gold R.
        Spotlight on fumarates.
        Int MS J. 2008; 15: 12-18
        • Hartung H.P.
        • Bar-Or A.
        • Zoukos Y.
        What do we know about the mechanism of action of disease-modifying treatments in MS?.
        J Neurol. 2004; 251: 12-29
        • Ramgolam V.S.
        • Markovic-Plese S.
        Interferon-beta inhibits Th17 cell differentiation in patients with multiple sclerosis.
        Endocr Metab Immune Disord Drug Targets. 2010; 10: 161-167
        • Dhib-Jalbut S.
        Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis.
        Neurology. 2002; 58: 3-9
        • de Andrés C.
        • Aristimuño C.
        • de Las Heras V.
        • Martínez-Ginés M.L.
        • Bartolomé M.
        • Arroyo R.
        • et al.
        Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis.
        J Neuroimmunol. 2007; 182: 204-211
        • Axtell R.C.
        • de Jong B.A.
        • Boniface K.
        • van der Voort L.F.
        • Bhat R.
        • De Sarno P.
        • et al.
        Helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis.
        Nat Med. 2010; 16: 406-412
        • Toker A.
        • Slaney C.Y.
        • Bäckström B.T.
        • Harper J.L.
        Glatiramer acetate treatment directly targets CD11b(+)Ly6G(−) monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis.
        Scand J Immunol. 2011; 74: 235-243
        • Chitnis T.
        The role of CD4 T cells in the pathogenesis of multiple sclerosis.
        Int Rev Neurobiol. 2007; 79: 43-72
        • O'Brien K.
        • Gran B.
        • Rostami A.
        T-cell based immunotherapy in experimental autoimmune encephalomyelitis and multiple sclerosis.
        Immunotherapy. 2010; 2: 99-115
        • Okuda Y.
        • Okuda M.
        • Apatoff B.R.
        • Posnett D.N.
        The activation of memory CD4(+) T cells and CD8(+) T cells in patients with multiple sclerosis.
        J Neurol Sci. 2005; 235: 11-17
        • Crucian B.
        • Dunne P.
        • Friedman H.
        • Ragsdale R.
        • Pross S.
        • Widen R.
        Alterations in levels of CD28-/CD8+ suppressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in the peripheral blood of multiple sclerosis patients.
        Clin Diagn Lab Immunol. 1995; 2: 249-252
        • Hafler D.A.
        • Slavik J.M.
        • Anderson D.E.
        • O'Connor K.C.
        • De Jager P.
        • Baecher-Allan C.
        Multiple sclerosis.
        Immunol Rev. 2005; 204: 208-231
        • Anderton S.M.
        Treg and T-effector cells in autoimmune CNS inflammation: a delicate balance, easily disturbed.
        Eur J Immunol. 2010; 40: 3321-3324
        • Feger U.
        • Luther C.
        • Poeschel S.
        • Melms A.
        • Tolosa E.
        • Wiendl H.
        Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients.
        Clin Exp Immunol. 2007; 147: 412-418
        • Viglietta V.
        • Baecher-Allan C.
        • Weiner H.L.
        • Hafler D.A.
        Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis.
        J Exp Med. 2004; 199: 971-979
        • Venken K.
        • Hellings N.
        • Thewissen M.
        • Somers V.
        • Hensen K.
        • Rummens J.L.
        • et al.
        Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level.
        Immunology. 2008; 123: 79-89
        • Puissant-Lubrano B.
        • Viala F.
        • Winterton P.
        • Abbal M.
        • Clanet M.
        • Blancher A.
        Thymic output and peripheral T lymphocyte subsets in relapsing-remitting multiple sclerosis patients treated or not by IFN-beta.
        J Neuroimmunol. 2008; 193: 188-194
        • Pentón-Rol G.
        • Cervantes-Llanos M.
        • Cabrera-Gómez J.A.
        • Alonso-Ramírez R.
        • Valenzuela-Silva C.
        • Rodríguez-Lara R.
        • et al.
        Treatment with type I interferons induces a regulatory T cell subset in peripheral blood mononuclear cells from multiple sclerosis patients.
        Int Immunopharmacol. 2008; 8: 881-886
        • Namdar A.
        • Nikbin B.
        • Ghabaee M.
        • Bayati A.
        • Izad M.
        Effect of IFN-beta therapy on the frequency and function of CD4(+)CD25(+) regulatory T cells and Foxp3 gene expression in relapsing-remitting multiple sclerosis (RRMS): a preliminary study.
        J Neuroimmunol. 2010; 218: 120-124
        • Lalive P.H.
        • Neuhaus O.
        • Benkhoucha M.
        • Burger D.
        • Hohlfeld R.
        • Zamvil S.S.
        • et al.
        Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action.
        CNS Drugs. 2011; 25: 401-414
        • Putheti P.
        • Soderstrom M.
        • Link H.
        • Huang Y.-M.
        Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis.
        J Neuroimmunol. 2003; 144: 125-131
        • Bequm-Haque S.
        • Christy M.
        • Ochoa-Reparaz J.
        • Nowak E.C.
        • Mielcarz D.
        • Haque A.
        • et al.
        Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate.
        J Neuroimmunol. 2011; 232: 136-144
        • Vallittu A.M.
        • Saraste M.
        • Airas L.
        CCR7 expression on peripheral blood lymphocytes is up-regulated following treatment of multiple sclerosis with interferon-beta.
        Neurol Res. 2007; 29: 763-766
        • Kivisäkk P.
        • Mahad D.J.
        • Callahan M.K.
        • Sikora K.
        • Trebst C.
        • Tucky B.
        • et al.
        Expression of CCR7 in multiple sclerosis: implications for CNS immunity.
        Ann Neurol. 2004; 55: 627-638