Inhibition of allergic responses by CD40 gene silencing.
BACKGROUND
Gene silencing using small interfering RNA (siRNA) is a potent method of specifically knocking down molecular targets. Small interfering RNA is therapeutically promising, however, treatment of allergic diseases with siRNA has not been explored in vivo. The aim of this study was to evaluate therapeutic effects of CD40 siRNA on inhibition of allergic responses.


METHODS
Mice sensitized with ovalbumin (OVA) and alum were treated with CD40 siRNA, scrambled siRNA, or phosphate buffer saline (PBS) alone, and then challenged intranasally with OVA.


RESULTS
A significant reduction in nasal allergic symptoms was observed in the CD40 siRNA treated OVA-allergic mice compared to the controls of scrambled siRNA and PBS alone, which is correlated with the decrease of local eosinophil accumulation. CD40 siRNA treatment knocked down CD40 expression on dendritic cells (DCs) in vivo and impaired their antigen presenting function. Treatment with CD40 siRNA resulted in inhibition of OVA-specific T cell response and decrease of interleukin-4 (IL-4), IL-5, and interferon-gamma production from T cells stimulated with OVA. Administration of CD40 siRNA also suppressed CD40 expression on B cells, resulting in down-regulation of OVA-specific immunoglobulin E (IgE), IgG1, and IgG2a levels. Additionally, increased regulatory T cells were observed in the CD40 siRNA treated mice.


CONCLUSIONS
The present study demonstrates a novel therapeutic use for siRNA in allergy. CD40 siRNA attenuated allergy through inhibition of DC and B cell functions and generation of regulatory T (Treg) cells.
Suzuki
M
M
Department of Surgery, University of Western Ontario, London, ON, Canada.
Zheng
X
X
Zhang
X
X
Ichim
T E
TE
Sun
H
H
Kubo
N
N
Beduhn
M
M
Shunnar
A
A
Garcia
B
B
Min
W-P
WP
D000485:Allergens / Q000276:immunology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics* / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D020868:Gene Silencing; D006967:Hypersensitivity / Q000235:genetics*; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000485:Allergens; D019013:CD40 Antigens; D007074:Immunoglobulin G; D034741:RNA, Small Interfering; D007073:Immunoglobulin E; D010047:Ovalbumin