Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model.
Interleukin-10 (IL-10) gene transfection of donor lungs prior to transplantation is an attractive strategy to reduce ischemia-reperfusion induced lung injury. However, experimental data with gene therapy in large animal models of lung transplantation are generally lacking. We have developed a simple clinically applicable technique for adenoviral-mediated gene delivery of human IL-10 to the lung of large animals that provides homogenous gene expression after 12-24 h of transfection. Using this technique of gene delivery, we have studied the dynamics of adenoviral gene delivery to the lung in the setting of lung transplantation. Although there is a persistent inflammatory response to the adenoviral vector, we achieved significant expression of human IL-10 in lung tissue before lung retrieval to obviate the deleterious impact of the adenoviral vector on the donor lung. The administration of adenoviral-mediated human IL-10 to the donor lung reduced ischemia-reperfusion injury and improved graft function after lung transplantation in this pig lung transplantation model. Transfection of adenoviral-mediated human IL-10 to the donor lung prevented the release of inflammatory cytokines such as IL-6 in lung tissue and plasma. We have demonstrated that IL-10 gene therapy has significant potential to prevent or treat the inflammatory response associated with ischemia-reperfusion injury in lung transplantation. In the future, IL-10 gene therapy could also be used for immunomodulation or tolerance induction.
Thoracic Surgery Research Laboratory, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.
S
S
Martins
M
M
de Perrot
Y
Y
Imai
M
M
Yamane
S M
SM
Quadri
L
L
Segall
A
A
Dutly
S
S
Sakiyama
A
A
Chaparro
B L
BL
Davidson
T K
TK
Waddell
M
M
Liu
S
S
Keshavjee
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D007442:Intubation, Intratracheal; D008168:Lung / Q000276:immunology / Q000502:physiology; D016040:Lung Transplantation / Q000502:physiology; D008297:Male; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine; D014162:Transfection; D019076:Transgenes
D016207:Cytokines; D016753:Interleukin-10