Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs

Background: Gene therapy provides the potential to modify donor organs to b etter withstand transplantation, but this has yet to be realized. In vivo g ene transfer using adenoviral vectors has had limited success because of ho st immune response that induces inflammation and limits the amount and dura tion of transgene expression, We hypothesize that transplantation immunosup pression 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 P-ga lactosidase gene and randomized the rats to either the immunosuppression gr oup, 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 t hat of the control group (p < 0.02), and showing prolonged and elevated tra nsgene expression at 5 weeks (p < 0.02). On histologic sections of the lung s, immunosuppressed rats exhibited overall lesser grades of post-transfecti on inflammation. Conclusions: Transplant immunosuppression provides the means to attenuate t he severe immune response to adenoviral-mediated gene transfection and ther eby increase and prolong transgene expression.