title: Dimethyl Fumarate Therapy Significantly Improves the Responsiveness of T Cells in Multiple Sclerosis Patients for Immunoregulation by Regulatory T Cells.
abstract: Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), a process termed Treg resistance. Here we investigated whether the disease-modifying therapy of relapsing-remitting MS (RRMS) with dimethyl fumarate (DMF) influences the sensitivity of T cells in the peripheral blood of patients towards Treg-mediated suppression. We demonstrated that DMF restores responsiveness of Teff to the suppressive function of Treg in vitro, presumably by down-regulation of interleukin-6R (IL-6R) expression on T cells. Transfer of human immune cells into immunodeficient mice resulted in a lethal graft-versus-host reaction triggered by human CD4⁺ Teff. This systemic inflammation can be prevented by activated Treg after transfer of immune cells from DMF-treated MS patients, but not after injection of Treg-resistant Teff from therapy-naïve MS patients. Furthermore, after DMF therapy, proliferation and expansion of T cells and the immigration into the spleen of the animals is reduced and modulated by activated Treg. In summary, our data reveals that DMF therapy significantly improves the responsiveness of Teff in MS patients to immunoregulation.
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany. jschloed@uni-mainz.de.
authors.forename: Janine
authors.initials: J
authors.lastname: Schlöder
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany. caberges@uni-mainz.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Berges
authors.affiliation: Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany. luessi@uni-mainz.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany. helmut.jonuleit@unimedizin-mainz.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
mesh_terms: D000328:Adult; D000818:Animals; D000069462:Dimethyl Fumarate / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D019947:Receptors, Interleukin-6; D000069462:Dimethyl Fumarate
keywords: T effector cells; Treg resistance; dimethyl fumarate; humanized mice; immune regulation; multiple sclerosis; therapy