Dimethyl fumarate as a first- vs second-line therapy in MS

Objective To elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a “1st-line” vs “2nd-line” therapy. Methods B cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up. Results 1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10+ B-cell subsets and TGFβ+ B cells were increased. Proinflammatory LTα+ and TNFα+ B cells were reduced, while IL4+ B cells elevated, whereas IFNγ+ B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86+ B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased. Conclusions DMF is associated with increased transitional and IL10+ and TGFβ+ regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.

[1]  Ariel Miller,et al.  Effector and regulatory B cells in Multiple Sclerosis. , 2017, Clinical immunology.

[2]  Kyle A. Martin,et al.  Dimethyl fumarate alters B‐cell memory and cytokine production in MS patients , 2017, Annals of clinical and translational neurology.

[3]  A. Bar-Or,et al.  Dimethyl fumarate–induced lymphopenia in MS due to differential T-cell subset apoptosis , 2017, Neurology: Neuroimmunology & Neuroinflammation.

[4]  A. Bar-Or,et al.  Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis , 2017, The Journal of Immunology.

[5]  R. Milo.  Therapeutic strategies targeting B-cells in multiple sclerosis. , 2016, Autoimmunity reviews.

[6]  E. Waubant,et al.  Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. , 2016, JAMA neurology.

[7]  Ariel Miller,et al.  Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis. , 2016, Journal of autoimmunity.

[8]  Alexander Parajeles Vindas,et al.  Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS , 2016, Neurology. Clinical practice.

[9]  Y. Mao-Draayer,et al.  Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets , 2016, Neurology: Neuroimmunology & Neuroinflammation.

[10]  A. Bar-Or,et al.  Proinflammatory GM-CSF–producing B cells in multiple sclerosis and B cell depletion therapy , 2015, Science Translational Medicine.

[11]  L. Weiner,et al.  Effects of dimethyl fumarate on lymphocyte subsets. , 2015, Multiple sclerosis and related disorders.

[12]  E. Rosser,et al.  Regulatory B cells: origin, phenotype, and function. , 2015, Immunity.

[13]  S. Zamvil,et al.  Reduction of CD8+ T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate , 2015, Neurology: Neuroimmunology & Neuroinflammation.

[14]  F. Faure,et al.  New regulatory CD19+CD25+ B-cell subset in clinically isolated syndrome and multiple sclerosis relapse. Changes after glucocorticoids , 2014, Journal of Neuroimmunology.

[15]  D. Isenberg,et al.  CD19+CD24hiCD38hi B Cells Maintain Regulatory T Cells While Limiting TH1 and TH17 Differentiation , 2013, Science Translational Medicine.

[16]  Ariel Miller,et al.  Laquinimod modulates B cells and their regulatory effects on T cells in Multiple Sclerosis , 2012, Journal of Neuroimmunology.

[17]  David H. Miller,et al.  Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. , 2012, The New England journal of medicine.

[18]  D. Arnold,et al.  Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. , 2012, The New England journal of medicine.

[19]  E. Sabo,et al.  Human CD19(+)CD25(high) B regulatory cells suppress proliferation of CD4(+) T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. , 2012, Autoimmunity reviews.

[20]  Yuhong Yang,et al.  Dimethyl Fumarate Inhibits Dendritic Cell Maturation via Nuclear Factor κB (NF-κB) and Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress-activated Kinase 1 (MSK1) Signaling* , 2012, The Journal of Biological Chemistry.

[21]  S. Cepok,et al.  Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS , 2011, Neurology.

[22]  W. Brück,et al.  Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. , 2011, Brain : a journal of neurology.

[23]  Jeffrey A. Cohen,et al.  Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria , 2011, Annals of neurology.

[24]  E. S. St. Clair,et al.  Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. , 2011, Blood.

[25]  P. Calabresi,et al.  Abnormal B‐cell cytokine responses a trigger of T‐cell–mediated disease in MS? , 2010, Annals of neurology.

[26]  D. Isenberg,et al.  CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. , 2010, Immunity.

[27]  P. Youinou,et al.  Regulatory B Cells in Autoimmune Diseases , 2009, Annals of the New York Academy of Sciences.

[28]  F. Macian,et al.  IL-2 signaling prevents T cell anergy by inhibiting the expression of anergy-inducing genes. , 2009, Molecular immunology.

[29]  D. Arnold,et al.  Rituximab in relapsing‐remitting multiple sclerosis: A 72‐week, open‐label, phase I trial , 2008, Annals of neurology.

[30]  N. Sheikh,et al.  CD54 is a surrogate marker of antigen presenting cell activation , 2008, Cancer Immunology, Immunotherapy.

[31]  D. Arnold,et al.  B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. , 2008, The New England journal of medicine.

[32]  T. Dörner,et al.  The Human Immunomodulatory CD25+ B Cell Population belongs to the Memory B Cell Pool , 2007, Scandinavian journal of immunology.

[33]  U. Mrowietz,et al.  Dimethylfumarate inhibits nuclear binding of nuclear factor κB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein β in activated human T cells , 2007, The British journal of dermatology.

[34]  Roland Martin,et al.  Immunology of multiple sclerosis. , 2005, Annual review of immunology.

[35]  Felix Treumer,et al.  Dimethylfumarate is a potent inducer of apoptosis in human T cells. , 2003, The Journal of investigative dermatology.

[36]  H. Koenen,et al.  Blockade of CD86 and CD40 induces alloantigen-specific immunoregulatory T cells that remain anergic even after reversal of hyporesponsiveness. , 2000, Blood.

[37]  F. Ronchese,et al.  The role of B7 costimulation in T‐cell immunity , 1999, Immunology and cell biology.

[38]  James M. Wilson,et al.  CD40 Ligand-Dependent T Cell Activation: Requirement of B7-CD28 Signaling Through CD40 , 1996, Science.