Treatment of autoimmune arthritis using RNA interference-modulated dendritic cells

• 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0901717

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.