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.
Highlights
Multiple sclerosis (MS) is a neurodegenerative, T cell-mediated inflammatory autoimmune disease caused by autoaggressive immune reactions against myelinated axons in the central nervous system (CNS), leading to their destruction and producing significant physical disability
We recently showed that T effector cells (Teff) from IFN-β-treated patients exhibit a restored responsiveness for immune suppression by Treg associated with a diminished IL-6R expression compared to therapy-naïve MS patients [8]
In the case of MS, T cells from therapy-naïve patients are widely insensitive to Treg-mediated suppression when compared to Teff from healthy controls (HC) [3,8]
Summary
Multiple sclerosis (MS) is a neurodegenerative, T cell-mediated inflammatory autoimmune disease caused by autoaggressive immune reactions against myelinated axons in the central nervous system (CNS), leading to their destruction and producing significant physical disability. Recent studies have identified a dysfunction of patient-derived regulatory T cells (Treg) and a dysregulation of effector T cells (Teff) as important key mechanisms in the course of disease [1,2,3]. Among all immune-modifying options, interferon-β (IFN-β) is the first-line treatment for patients with a relapsing-remitting MS (RRMS) [5,6]. In addition to its modulatory and immunosuppressive function by increasing interleukin-10 (IL-10) serum levels in RRMS patients [7], the influence of IFN-β on Treg resistance has been extensively studied by our group in the last few years. We recently showed that Teff from IFN-β-treated patients exhibit a restored responsiveness for immune suppression by Treg associated with a diminished IL-6R expression compared to therapy-naïve MS patients [8]. We identified a novel therapeutic immunoregulatory mechanism of DMF therapy
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