TY - JOUR
T1 - Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs
AU - Cassivi, Stephen D.
AU - Liu, Mingyao
AU - Boehler, Annette
AU - Pierre, Andrew
AU - Tanswell, A. Keith
AU - O'Brodovich, Hugh
AU - Mullen, J. Brendan M.
AU - Slutsky, Arthur S.
AU - Keshavjee, Shaf H.
N1 - Funding Information:
This work was supported by a grant from the National Sanitarium Association of Canada. Dr. Liu is a scholar of the Medical Research Council of Canada. Dr. Boehler is a recipient of grants from the Swiss National Scientific Foundation and the Swiss Respiratory Society.
PY - 2000
Y1 - 2000
N2 - Background: Gene therapy provides the potential to modify donor organs to better withstand transplantation, but this has yet to be realized. In vivo gene transfer using adenoviral vectors has had limited success because of host immune response that induces inflammation and limits the amount and duration of transgene expression. We hypothesize that transplantation immunosuppression can attenuate the post-transfection host-immune response to allow for improved gene transfer following adenoviral-mediated transfection. Methods: We intratracheally transfected with adenovirus containing the β-galactosidase gene and randomized the rats to either the immunosuppression group, receiving daily cyclosporine, azathioprine, and methylprednisolone, or the control group, receiving no immunosuppression. We evaluated transgene expression and post-transfection inflammation at time points ranging from 1 day to 5 weeks. Results: Following transfection, control rats showed relatively low levels of transgene expression, which rapidly decreased to non-detectable levels. In contrast, immunosuppressed rats demonstrated significantly higher levels of transgene expression overall (p < 0.00005), peaking at almost 3 times that of the control group (p < 0.02), and showing prolonged and elevated transgene expression at 5 weeks (p < 0.02). On histologic sections of the lungs, immunosuppressed rats exhibited overall lesser grades of post-transfection inflammation. Conclusions: Transplant immunosuppression provides the means to attenuate the severe immune response to adenoviral-mediated gene transfection and thereby increase and prolong transgene expression. Copyright (C) 2000 International Society for Heart and Lung Transplantation.
AB - Background: Gene therapy provides the potential to modify donor organs to better withstand transplantation, but this has yet to be realized. In vivo gene transfer using adenoviral vectors has had limited success because of host immune response that induces inflammation and limits the amount and duration of transgene expression. We hypothesize that transplantation immunosuppression can attenuate the post-transfection host-immune response to allow for improved gene transfer following adenoviral-mediated transfection. Methods: We intratracheally transfected with adenovirus containing the β-galactosidase gene and randomized the rats to either the immunosuppression group, receiving daily cyclosporine, azathioprine, and methylprednisolone, or the control group, receiving no immunosuppression. We evaluated transgene expression and post-transfection inflammation at time points ranging from 1 day to 5 weeks. Results: Following transfection, control rats showed relatively low levels of transgene expression, which rapidly decreased to non-detectable levels. In contrast, immunosuppressed rats demonstrated significantly higher levels of transgene expression overall (p < 0.00005), peaking at almost 3 times that of the control group (p < 0.02), and showing prolonged and elevated transgene expression at 5 weeks (p < 0.02). On histologic sections of the lungs, immunosuppressed rats exhibited overall lesser grades of post-transfection inflammation. Conclusions: Transplant immunosuppression provides the means to attenuate the severe immune response to adenoviral-mediated gene transfection and thereby increase and prolong transgene expression. Copyright (C) 2000 International Society for Heart and Lung Transplantation.
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U2 - 10.1016/S1053-2498(00)00166-2
DO - 10.1016/S1053-2498(00)00166-2
M3 - Article
C2 - 11044694
AN - SCOPUS:0033816159
SN - 1053-2498
VL - 19
SP - 984
EP - 994
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
IS - 10
ER -