Novel vaccination for allergy through gene silencing of CD40 using small interfering RNA.
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.
Department of Surgery, University of Western Ontario, London, ON, Canada.
Motohiko
M
Suzuki
Xiufen
X
Zheng
Xusheng
X
Zhang
Mu
M
Li
Costin
C
Vladau
Thomas E
TE
Ichim
Hongtao
H
Sun
Lisa R
LR
Min
Bertha
B
Garcia
Wei-Ping
WP
Min
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005240:Feasibility Studies; D020868:Gene Silencing / Q000276:immunology*; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology*
D019013:CD40 Antigens; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D034741:RNA, Small Interfering; D014614:Vaccines, Synthetic; D007073:Immunoglobulin E; D010047:Ovalbumin