Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-7 |
| Number of pages | 7 |
| Journal | Journal of Thoracic and Cardiovascular Surgery |
| Volume | 117 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1999 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Surgery
Cite this
Transgene expression after adenovirus-mediated retransfection of rat lungs is increased and prolonged by transplant immunosuppression. / Cassivi, S. D.; Liu, M.; Boehler, A.; Tanswell, A. K.; Slutsky, A. S.; Keshavjee, S.; Wechsler, A. S.; Rosengart, T.; Carpentier, A. F.; Robbins, R. C.
In: Journal of Thoracic and Cardiovascular Surgery, Vol. 117, No. 1, 1999, p. 1-7.Research output: Contribution to journal › Article
}
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=0032893898&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032893898&partnerID=8YFLogxK
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 -