RNAi-mediated CD40-CD154 Interruption Promotes Tolerance in Autoimmune Arthritis

Authors

Xiufen Zheng, University of Western Ontario
Motohiko Suzuki, University of Western Ontario
Xusheng Zhang, University of Western Ontario
Thomas E. Ichim, University of Western Ontario
Fei Zhu, Toronto Western Hospital
Hong Ling, University of Western Ontario
Aminah Shunnar, University of Western Ontario
Michael H. Wang, University of Western Ontario
Bertha Garcia, University of Western Ontario
Robert D. Inman, Toronto Western Hospital
Wei-Ping Min, University of Western Ontario

Document Type

Article

Publication Date

1-26-2010

Journal

Arthritis Research & Therapy

Volume

12

Issue

R13

URL with Digital Object Identifier

http://dx.doi.org/10.1186/ar2914

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 immunity.