Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

We show in humans that fumarate treatment induces IL-4–producing Th2 cells in vivo and generates type II dendritic cells that produce IL-10 instead of IL-12 and IL-23

Kamran Ghoreschi; Jürgen Brück; Christina Kellerer; Caishu Deng; Haiyan Peng; Oliver Rothfuss; Rehana Z. Hussain; Anne R. Gocke; Annedore Respa; Ivana Glocova; Nadejda Valtcheva; Eva Alexander; Susanne Feil; Robert Feil; Klaus Schulze-Osthoff; Rudolf A. Rupec; Amy E. Lovett-Racke; Ralf Dringen; Michael K. Racke; Martin Röcken

2011

Scholarcy highlights

  • To determine whether in vivo priming during fumarate treatment induced functional type II dendritic cells that abolished the capacity of autoreactive T cells to cause EAE, we performed two different sets of experiments: we first asked whether DMF requires the induction of IL-4 to suppress EAE and whether this suppression results from the IL-4–producing
  • (2) In vitro and direct ex vivo analysis of DCs and T cells demonstrate that the inhibition of Th1/ Th17 cells and the induction of Th2 cells result from the induction of type II DCs and not from direct modulation of T cell differentiation
  • Based on the observation that different GST genotypes are closely associated with distinct serum IgE levels and the risk of reactive oxygen species-triggered type I allergy on the one hand and the observation that ROS stress impairs IL-12 production on the other, we hypothesized that DMF might exert the antiinflammatory effects by inducing type II DCs through GSH depletion
  • DCs from DMFtreated mice had increased HO-1 messenger RNA expression and significantly reduced IL-12 and IL-23 mRNA expression and cytokine production when stimulated with LPS
  • As GSH-depleting small molecules as well as glatir­ amer acetate have previously been connected with STAT1 signaling, one mode of inducing type II DCs with DMF may be the ROS-mediated prevention of STAT1 phosphorylation in APCs
  • This suggests that successful treatment of autoimmune diseases such as multiple sclerosis and psoriasis requires neutralization of IL-12 and IL-23 by mAb and the alteration of the pathogenic T cells via dendritic cells. The data fit best with a model in which treatment of MS requires, in addition to the inhibition of IL-12 and IL-23, immune deviation and the active induction of protective Th2 cells either by IL-4 or by type II DCs.This is supported by the unique efficacy of IL-4 in the treatment of various inflammatory model diseases in mice, the treatment of psoriasis in humans, and the unique efficacy of DMF and glatiramer acetate, two small molecules which are both effective in MS, to impair IL-12 and IL-23 and, in addition, deviate T helper cell responses toward a Th2 phenotype

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