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Novel Vaccination for Allergy through Gene Silencing of CD40 Using Small Interfering RNA¹

Motohiko Suzuki^*, Xiufen Zheng^*, Xusheng Zhang^*, Mu Li^*, Costin Vladau^*, Thomas E. Ichim, Hongtao Sun^*, Lisa R. Min^*, Bertha Garcia^* and Wei-Ping Min^2,*,,

^* Department of Surgery, Department of Pathology, and Department of Microbiology and Immunology, University of Western Ontario, Multi-Organ Transplant Program, University Hospital, and Transplantation and Regenerative Medicine, Lawson Health Research Institute, London, Ontario, Canada; and Medistem Laboratories, San Diego, CA 92122

Small interfering RNA (siRNA) is a potent means of inducing gene-specific silencing. Gene silencing strategies using siRNA have demonstrated therapeutic benefits in animal models of various diseases, and are currently in clinical trials. However, the utility of gene silencing as a treatment for allergic diseases has not yet been reported. In this study, we report a novel therapy for allergy through gene silencing of CD40, a critical costimulatory molecule and a key factor in allergic immune responses. Silencing CD40 resulted in generation of immunoregulatory dendritic cells (DCs). Administration of CD40 siRNA remarkably reduced nasal allergic symptoms and local eosinophil accumulation in the OVA-induced allergic mice. The OVA-specific T cell response was inhibited after the CD40 siRNA treatment. Additionally, anti-OVA specific IgE and production of IL-4 and IL-5 of T cells stimulated by OVA were significantly decreased in CD40 siRNA-treated mice. Furthermore, we demonstrated that the therapeutic effects by CD40 siRNA were associated with impaired Ag-presenting functions of DCs and B cells, and generation of regulatory T cells. The present study highlights a therapeutic potential of siRNA-based treatment for allergic diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study is partially supported by the Canadian Institutes of Health Research and a grant from London Health Sciences Centre to the Multi-Organ Transplant Program.

² Address correspondence and reprints requests to Dr. Wei-Ping Min, Multi-Organ Transplant Program, C9-136, London Health Sciences Centre, University Hospital, 339 Windermere Road, London, Ontario N6A 5A5, Canada. E-mail address: weiping.min{at}uwo.ca

³ Abbreviations used in this paper: siRNA, small interfering RNA; DC, dendritic cell; Treg, regulatory T.