rnai-mediated cd40-cd154 interruption promotes tolerance in autoimmune arthritisrnai-mediated cd40-cd154中断促进自身免疫性关节炎的宽容.pdfVIP

Zheng et al. Arthritis Research Therapy 2010, 12:R13 /content/12/1/R13 R E S E A R C H A R T I C L E Open Access Research article RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis †1 †1 1 1,3 2 1 1 Xiufen Zheng , Motohiko Suzuki , Xusheng Zhang , Thomas E Ichim , Fei Zhu , Hong Ling , Aminah Shunnar , 1 1 2 1,4,5 Michael H Wang , Bertha Garcia , Robert D Inman* and Wei-Ping Min* Abstract Introduction: We have previously demonstrated that ex vivo inhibition of costimulatory molecules on antigen-pulsed dendritic cells (DCs) can be useful for induction of antigen-specific immune deviation and suppression of autoimmune arthritis in the collagen induced arthritis (CIA) model. The current study evaluated a practical method of immune modulation through temporary systemic inhibition of the costimulatory molecule CD40. Methods: Mice with collagen II (CII)-induced arthritis (CIA) were administered siRNA targeting the CD40 molecule. Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses. Results: Systemic administration of CD40-targeting siRNA can inhibit antigen-specific T cell response to collagen II, as well as prevent pathogenesis of disease in both a pre- and post-immunization manner in the CIA model. Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells. Conclusions: These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive imm