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.

Analysis of IL-6, IL-1β and TNF-α production in monocytes isolated from multiple sclerosis patients treated with disease modifying drugs

“…Previous studies of this nature on other immune cell types demonstrated that DMF treatment resulted in a significant decrease in the frequency of B cells expressing IL-6, TNF-α and GM-CSF, and that DMF treatment improves the responsiveness of MS patients’ effector T cells to allogeneic regulatory T cells in vitro [14, 15]. In this study, we show that the amount of IL-6 produced by classically stimulated monocytes was significantly greater from RRMS subjects compared to HC.…”

Humanized Mouse Models of Rheumatoid Arthritis for Studies on Immunopathogenesis and Preclinical Testing of Cell-Based Therapies

“…To explore therapeutic strategies to overcome the resistance of effector T cells toward Treg-mediated suppression in multiple sclerosis (MS) patients, a humanized model based on newborn Rag2 −/− γ −/− mice engrafted with CD25-depleted PBMCs from different MS patients was applied (287). Transfer of gp120-activated Treg cells from healthy subjects into these mice prevented GvHD only when engrafted PBMCs were derived from MS patients that received disease-modifying therapy but not from those being therapy-naïve (287).…”

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

“…DMF-treated MS patients have demonstrated reduced immune cells, particularly CD4 + and CD8 + T lymphocytes (Longbrake et al, 2016). It can also recover effector T cells response to the inhibitory function of Treg (Schlöder, Berges, Luessi, & Jonuleit, 2017). Moreover, there is evidence implying that DMF induces apoptosis in activated T cells (Treumer et al, 2003).…”