TY - JOUR
T1 - Transgene expression after adenovirus-mediated retransfection of rat lungs is increased and prolonged by transplant immunosuppression
AU - Cassivi, S. D.
AU - Liu, M.
AU - Boehler, A.
AU - Tanswell, A. K.
AU - Slutsky, A. S.
AU - Keshavjee, S.
AU - Wechsler, A. S.
AU - Rosengart, T.
AU - Carpentier, A. F.
AU - Robbins, R. C.
N1 - Funding Information:
The investigational protocol was reviewed and approved by the Toronto Hospital Research Institute Animal Care and Biohazard committees. All animals received humane care in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research, the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Science and published by the National Institutes of Health (NIH publication No. 85-23, revised 1985), and the “Guide to the Care and Use of Experimental Animals” formulated by the Canadian Council on Animal Care.
PY - 1999
Y1 - 1999
N2 - Objectives: Adenovirus-mediated gene therapy has been proposed as a potential treatment modality in lung transplantation. However, to date its utility has been limited by an inflammatory host immune response that not only limits the amount and duration of transgene expression but also obviates successful retransfection. Having previously shown that by administering triple-immunosuppression, as is routine in lung transplantation, we could increase and prolong transgene expression after initial transfection, we hypothesized that transgene expression after retransfection could also be increased and prolonged. Methods: Lewis rats underwent intratracheal adenovirus-mediated transfection with the β-galactosidase gene and were randomized to either the immunosuppression group, receiving daily cyclosporine (INN: ciclosporin), azathioprine, and methylprednisolone, or the control group (no immunosuppression). Five weeks later, rats were similarly retransfected and transgene expression and post-transfection inflammation were evaluated 1, 7, and 14 days after retransfection. Results: After retransfection, immunosuppressed rats had significantly higher levels of transgene expression (P < .001), whereas control rats had virtually no detectable levels. On histologic sections of the lungs, immunosuppressed rats had overall lesser grades of post-transfection inflammation. Conclusions: Transplant immunosuppression attenuates the severe immune response to gene transfer and permits increased, prolonged, and repeated transfection. Retransfection is now achievable in the immunosuppressed lung transplant setting to allow for chronic, repeated administrator of gene therapy.
AB - Objectives: Adenovirus-mediated gene therapy has been proposed as a potential treatment modality in lung transplantation. However, to date its utility has been limited by an inflammatory host immune response that not only limits the amount and duration of transgene expression but also obviates successful retransfection. Having previously shown that by administering triple-immunosuppression, as is routine in lung transplantation, we could increase and prolong transgene expression after initial transfection, we hypothesized that transgene expression after retransfection could also be increased and prolonged. Methods: Lewis rats underwent intratracheal adenovirus-mediated transfection with the β-galactosidase gene and were randomized to either the immunosuppression group, receiving daily cyclosporine (INN: ciclosporin), azathioprine, and methylprednisolone, or the control group (no immunosuppression). Five weeks later, rats were similarly retransfected and transgene expression and post-transfection inflammation were evaluated 1, 7, and 14 days after retransfection. Results: After retransfection, immunosuppressed rats had significantly higher levels of transgene expression (P < .001), whereas control rats had virtually no detectable levels. On histologic sections of the lungs, immunosuppressed rats had overall lesser grades of post-transfection inflammation. Conclusions: Transplant immunosuppression attenuates the severe immune response to gene transfer and permits increased, prolonged, and repeated transfection. Retransfection is now achievable in the immunosuppressed lung transplant setting to allow for chronic, repeated administrator of gene therapy.
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U2 - 10.1016/S0022-5223(99)70462-9
DO - 10.1016/S0022-5223(99)70462-9
M3 - Article
C2 - 9869751
AN - SCOPUS:0032893898
VL - 117
SP - 1
EP - 7
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
SN - 0022-5223
IS - 1
ER -