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Right arrow Lung - transplantation

Ann Thorac Surg 2002;73:1092-1097
© 2002 The Society of Thoracic Surgeons

Original article: general thoracic

Transplant immunosuppression enhances efficiency of adenoviral-mediated gene retransfection: inhibition of interferon-{gamma} and immunoglobin G

Michiharu Suga, MDa, Rebecca Gladdy, MDa, Zhou Xing, MD, PhDa, Shaf H. Keshavjee, MDa, Mingyao Liu, MD*a

a Thoracic Surgery Research Laboratory, University Health Network, Toronto General Hospital Research Institute, Department of Surgery, University of Toronto, Toronto, Ontario, Canada

Accepted for publication November 19, 2001.

* Address reprint requests to Dr Liu, Department of Surgery, Thoracic Surgery Research Laboratory, Toronto General Hospital, Room CCRW 1-816, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada
e-mail: mingyao.liu{at}utoronto.ca

Background. Transplant immunosuppression regimen facilitates successful adenovirus-mediated gene transfection and retransfection in the rat lung. Herein, we investigated the effect of this strategy on circulating cytokines and antiadenoviral immunoglobin G antibody.

Methods. Male Lewis rats were transfected with 1 x 109 pfu/mL of E1-deleted Ad5CMVLacZ vector transtracheally. Rats were randomly assigned to receive daily intraperitoneal triple immunosuppression regimen consisting of cyclosporine (15 mg/kg per day), azathioprine (6 mg/kg per day), and methylprednisolone (2.5 mg/kg per day), or normal saline solution. Retransfection was performed 35 days later to all nonimmunosuppressed animals, whereas immunosuppressed rats were further randomized to receive retransfection or phosphate-buffered saline. Animals were sacrificed on days 1, 2, 7, 35, 42, and 49 after the initial transfection. ß-Galactosidase activity was measured on lung homogenates. Interferon-{gamma}, tumor necrosis factor-{alpha}, and antiadenoviral immunoglobin G were measured from the serum.

Results. Enhanced and prolonged transgene expression was observed in immunosuppressed animals, especially after retransfection. Concentrations of serum tumor necrosis factor-{alpha} in both groups were less than 12 pg/mL throughout the study. A significant increase in serum interferon-{gamma} levels was observed in nonimmunosuppressed animals after retransfection; this was not seen in the immunosuppressed animals. Serum antiadenoviral immunoglobin G titers in both groups were sharply elevated on day 1, and declined to basal levels by day 7, reflecting a preexisting level of humoral immunity to adenovirus. The titer in nonimmunosuppressed rats was significantly increased after retransfection, but remained at very low level in immunosuppressed animals.

Conclusions. Inhibition of interferon-{gamma} and antiadenoviral immunoglobin G production by triple immunosuppressants may be part of the mechanisms that lead to enhanced and prolonged transgene expression after retransfection.




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