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. DCs that were modified by the immunosuppressive drug tacrolimus were considered to be endowed with tolerogenic functions.


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-β increased after 12h of tacrolimus stimulation, with the strongest responses being observed after 24h. The mRNA was further upregulated after tDCs were treated with LPS and IFN-γ. tDCs secreted more IL-10 and less TNF-α 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 TNF-α and IFN-γ 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.
Blood Engineering Laboratory, Shanghai Blood Center, Shanghai 200051, China. Electronic address: yana.ren021@hotmail.com.
Yana
Y
Ren
Blood Engineering Laboratory, Shanghai Blood Center, Shanghai 200051, China.
Yiming
Y
Yang
Blood Engineering Laboratory, Shanghai Blood Center, Shanghai 200051, China.
Jie
J
Yang
Blood Engineering Laboratory, Shanghai Blood Center, Shanghai 200051, China.
Rufeng
R
Xie
Blood Engineering Laboratory, Shanghai Blood Center, Shanghai 200051, China.
Huahua
H
Fan
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016559:Tacrolimus / Q000494:pharmacology
D016207:Cytokines; D016559:Tacrolimus
Cell therapy; Collagen-induced arthritis; Tacrolimus; Tolerogenic dendritic cells; Tolerogenic function