A novel allergen-specific therapy for allergy using CD40-silenced dendritic cells.
BACKGROUND
Induction of RNA interference with small interfering RNA (siRNA) has demonstrated therapeutic potential through the knockdown of target genes. We have previously reported that systemic administration of CD40 siRNA is capable of attenuating allergic symptoms but in an allergen-nonspecific fashion. However, siRNA-based allergen-specific therapy for allergy has not been developed.


OBJECTIVE
We attempted to develop a new allergen-specific therapy for allergy using CD40-silenced and allergen-pulsed dendritic cells (DCs).


METHODS
Bone marrow-derived DCs were silenced with CD40 siRNA and pulsed with ovalbumin (OVA). Mice had allergy after intraperitoneal sensitization with OVA and keyhole limpet hemocyanin, followed by intranasal challenge with the same allergens. The mice were treated with CD40-silenced and OVA-pulsed DCs (CD40-silenced OVA DCs) either before allergic sensitization or after establishing allergic rhinitis.


RESULTS
Mice receiving CD40-silenced OVA DCs either before or after the establishment of allergic rhinitis showed remarkable reductions in allergic symptoms caused by OVA challenge, as well as anti-OVA IgE levels in sera. Additionally, CD40-silenced OVA DCs suppressed eosinophil infiltration at the nasal septum, OVA-specific T-cell responses, T-cell production of IL-4 and IL-5 after stimulation with OVA, and CD4(+)CD25(-) effector T-cell responses. Furthermore, CD40-silenced OVA DCs facilitated the generation of CD4(+)CD25(+) forkhead box protein 3-positive OVA-specific regulatory T cells, which inhibit allergic responses in vivo. However, CD40-silenced OVA DCs suppressed only OVA-specific allergy but did not inhibit keyhole limpet hemocyanin-induced allergy, suggesting that CD40-silenced OVA DCs induce allergen-specific tolerance.


CONCLUSIONS
This study is the first to demonstrate a novel allergen-specific therapy for allergy through DC-mediated immune modulation after gene silencing of CD40.
Departments of Surgery, Pathology, Microbiology, and Immunology, University of Western Ontario, Ontario, Canada. suzu-mo@med.nagoya-cu.ac.jp
Motohiko
M
Suzuki
Xiufen
X
Zheng
Xusheng
X
Zhang
Zhu-Xu
ZX
Zhang
Thomas E
TE
Ichim
Hongtao
H
Sun
Yoshihisa
Y
Nakamura
Akira
A
Inagaki
Marianne
M
Beduhn
Aminah
A
Shunnar
Bertha
B
Garcia
Wei-Ping
WP
Min
D000818:Animals; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006967:Hypersensitivity / Q000628:therapy*; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D034622:RNA Interference / Q000276:immunology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D019013:CD40 Antigens; D034741:RNA, Small Interfering; D010047:Ovalbumin