Treatment of autoimmune arthritis using RNA interference-modulated dendritic cells.
Dendritic cells (DCs) have a dual ability to either stimulate or suppress immunity, which is primarily associated with the expression of costimulatory molecules. Ag-loaded DCs have shown encouraging clinical results for treating cancer and infectious diseases; however, the use of these cells as a means of suppressing immune responses is only recently being explored. Here, we describe the induction of RNA interference through administering short interfering RNA (siRNA) as a means of specifically generating tolerogenic DCs. Knockdown of CD40, CD80, and CD86, prior to loading DCs with the arthritogenic Ag collagen II, led to a population of cells that could effectively suppress onset of collagen-induced arthritis. Maximum benefits were observed when all three genes were concurrently silenced. Disease suppression was associated with inhibition of collagen II-specific Ab production and suppression of T cell recall responses. Downregulation of IL-2, IFN-gamma, TNF-alpha, and IL-17 and increased FoxP3(+) cells with regulatory activity were observed in collagen-induced arthritis mice treated with siRNA-transfected DCs. Collectively, these data support the use of ex vivo gene manipulation in DCs using siRNA to generate tailor-made tolerogenic vaccines for treating autoimmunity.
Zheng
Xiufen
X
Department of Surgery, University of Western Ontario, Ontario, Canada.
Suzuki
Motohiko
M
Ichim
Thomas E
TE
Zhang
Xusheng
X
Sun
Hongtao
H
Zhu
Fei
F
Shunnar
Aminah
A
Garcia
Bertha
B
Inman
Robert D
RD
Min
Weiping
W
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy; D018122:B7-1 Antigen / Q000235:genetics; D051940:B7-2 Antigen / Q000235:genetics; D019013:CD40 Antigens / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D034622:RNA Interference / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens