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Therapeutic effects of TGT-β induced regulatory T cells on the established autoimmune and inflammatory diseases

Abstract : Recent studies revealed that nTregs has less therapeutic effects on established autoimmune diseases. Current study asks if iTregs induced ex-vivo with TGF- can treat the established autoimmune diseases. In allergic asthma we observed that adoptive transfer of iTreg significantly suppressed airway and peri-vascular inflammation, reduced airway résistance, eosinophil recruitment, mucus hyper-production, airway remodeling and IgE levels. This therapeutic effect was associated with increase of Tregs (CD4⁺Foxp3⁺) in the draining LNs, and with reduction of Th1, Th2, and Th17 responses. In collagen-induced arthritis (CIA) both antigen-specific iTregs and expanded nTregs prevented CIA. However, only iTregs transfer suppressed established CIA. nTregs but not iTregs were converted into Th17 and lost Foxp3 in vitro and in vivo in established CIA. iTregs suppressed Th17 cell differentiation that paralleled with improved clinical scores and symptoms. In the chronic GVHD model mimicking lupus the iTregs infusion significantly decreased lupus symptoms. Blocking of TGF-β/TGF-βR or IL-10 signaling pathways significantly abolished the therapeutic effects. iTregs induced the formation of tolerogenic DCs through TGF-β but not IL-10 signaling on DC. DC isolated from lupus mice receiving iTregs can suppress lupus development through TGF-β but not IL-10 signaling. Thus, iTregs target DC in the inflammatory milieu and newly formed tolerogenic DC suppress disease progression through its direct or indirect effect (inducing new iTregs) in autoimmune disease settings. Moreover, we demonstrated that all-trans retinoic acid (atRA) promotes and sustains the Foxp3⁺ regulatory T cells. atRA increased histone methylation and acetylation within Foxp3 gene locus, while DNA methylation in Foxp3 gene was not significantly altered. These results may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.
Keywords : Treg
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Song Guo Zheng. Therapeutic effects of TGT-β induced regulatory T cells on the established autoimmune and inflammatory diseases. Agricultural sciences. Université d'Orléans, 2011. English. ⟨NNT : 2011ORLE2061⟩. ⟨tel-00698579⟩

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