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 me...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2010-06, Vol.184 (11), p.6457-6464
Main Authors: Zheng, Xiufen, Suzuki, Motohiko, Ichim, Thomas E, Zhang, Xusheng, Sun, Hongtao, Zhu, Fei, Shunnar, Aminah, Garcia, Bertha, Inman, Robert D, Min, Weiping
Format: Article
Language:English
Subjects:
Animals
Arthritis, Experimental - immunology
Arthritis, Experimental - therapy
Arthritis, Rheumatoid - immunology
Arthritis, Rheumatoid - therapy
B7-1 Antigen - genetics
B7-2 Antigen - genetics
CD40 Antigens - genetics
Cell Differentiation - immunology
Cell Separation
Dendritic Cells - immunology
Dendritic Cells - transplantation
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Immunotherapy - methods
Lymphocyte Activation - immunology
Male
Mice
Mice, Inbred DBA
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference - immunology
T-Lymphocyte Subsets - immunology
T-Lymphocytes - immunology
Transfection
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0901717