Tolerogenic dendritic cells modified by tacrolimus suppress CD4+ T-cell proliferation and inhibit collagen-induced arthritis in mice

Background: Tolerogenic dendritic cells (tDCs) can be generated in vitro by a variety of methods, including genetic or pharmacological modification. tDCs that were modified by the immunosuppressive drug tacrolimus were considered to be endowed with tolerogenic functions. Study design and methods: DCs derived from human monocytes were induced in vitro by GM-CSF/IL-4 with tacrolimus. The phenotype and production of cytokines in these DCs were analyzed. The functionality of tDCs modified by tacrolimus was subsequently determined via a CFSE proliferation assay. The severity of arthritis was monitored in CIA mice after treatment with tDCs modified by tacrolimus. Results: tDCs that were modified by tacrolimus exhibited an immature phenotype. The expression of mRNA encoding IL-10 and TGF-beta increased after 12 h of tacrolimus stimulation, with the strongest responses being observed after 24 h. The mRNA was further upregulated after tDCs were treated with LPS and IFN-gamma. tDCs secreted more IL-10 and less TNE-alpha and had a reduced ability to activate allo-CD4(+)CD25(-)T cells. These cells suppressed mDC-induced-proliferation of CD4(+)CD25(-)T cells and produced less TNE-alpha and IFN-gamma but increased the level of IL-10 than imDCs. Treatment of arthritic mice with tDCs modified by tacrolimus significantly inhibited the severity and progression of the disease. tDC treatment also altered the proportion of the Th1 and Th17 populations in the spleen. Conclusions: tDCs modified by tacrolimus suppressed CD4(+)T cell proliferation and inhibited collagen-induced arthritis. These results suggest the potential use of tDCs as a therapeutic approach for autoimmune arthritis. (C) 2014 Elsevier B.V. All rights reserved.