Treatment of Autoimmune Arthritis Using RNA Interference-Modulated Dendritic Cells

Abstract

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-γ, TNF-α, 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.

Ionic complex systems based on hyaluronic acid and PEGylated TNF-related apoptosis-inducing ligand for treatment of rheumatoid arthritis

“…CIA is an autoimmune model of RA that is the most widely used for analyzing molecular and cellular mediators and assessing potential therapeutic agents [29,30]. In this study, CIA was induced by injecting DBA/1J mice with CII emulsified in CFA, followed by booster immunization 21 days later with CII emulsified in IFA.…”

Gene Therapy Challenges in Arthritis

“…From these data, Zheng et al have studied the efficiency of DC transfected with siRNA targeting CD40, CD80 and CD86 in CIA. The i.a injection of transfected DC in mice resulted in less bone destruction and a reduced number of immune cells (neutrophils and mononuclear cells) infiltrating the joint (Zheng et al, 2010). As described, DC are good cell candidates for ex vivo GT.…”

IFN-γ siRNA Effectively Knocked Down IFN-γ Gene Expression and Reduced Cytokine Secretion in Peripheral Blood Mononuclear Cells of Patients with Autoimmune Hepatitis

“…These powerful tools have revolutionized basic biomedical science and applied for disease treatment in a sequence-specific manner (12). Up to now, 21 different siRNA drugs have been evaluated in clinical trial setting and used for genetic disorders, such as, Alzheimer's, Parkinson's, and cancer (15,16).…”