TY - JOUR
T1 - Gene transfer of tumor necrosis factor inhibitor improves the function of lung allografts
AU - Tagawa, Tsutomu
AU - Kozower, Benjamin D.
AU - Kanaan, Samer A.
AU - Daddi, Niccolò
AU - Muraoka, Masashi
AU - Oka, Tadayuki
AU - Ritter, Jon H.
AU - Patterson, G. Alexander
AU - Korst, Robert J.
AU - Allen, Mark S.
AU - Wood, Douglas E.
PY - 2004/6
Y1 - 2004/6
N2 - Background: Tumor necrosis factor is an important mediator of lung transplant acute rejection. Soluble type I tumor necrosis factor receptor binds to tumor necrosis factor-α and -β and inhibits their function. The objectives of this study were to demonstrate efficient in vivo gene transfer of a soluble type I tumor necrosis factor receptor fusion protein (sTNF-RI-Ig) and determine its effects on lung allograft acute rejection. Methods: Three groups of Fischer rats (n = 6 per group) underwent recipient intramuscular transfection 24 hours before transplantation with saline, 1 × 10 10 plaque-forming units of control adenovirus encoding β-galactosidase, or 1 × 1010 plaque-forming units of adenovirus encoding human sTNF-RI-Ig (Ad.sTNF-RI-Ig). One group (n = 6) received recipient intramuscular transfection with 1 × 1010 Ad.sTNF-RI-Ig at the time of transplantation. Brown Norway donor lung grafts were stored for 5 hours before orthotopic lung transplantation. Graft function and rejection scores were assessed 5 days after transplantation. Time-dependent transgene expression in muscle, serum, and lung grafts were evaluated by using enzyme-linked immunosorbent assay of human soluble type I tumor necrosis factor receptor. Results: Recipient intramuscular transfection with 1 × 10 10 plaque-forming units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered 24 hours before transplantation compared with saline, β-galactosidase, and Ad.sTNF-RI-Ig transfection at the time of transplantation (435.8 ± 106.6 mm Hg vs 142.3 ± 146.3 mm Hg, 177.4 ± 153.7 mm Hg, and 237.3 ± 185.2 mm Hg; P = .002, .005, and .046, respectively). Transgene expression was time dependent, and there was a trend toward lower vascular rejection scores (P = .066) in the Ad.sTNF-RI-Ig group transfected 24 hours before transplantation. Conclusions: Recipient intramuscular Ad.sTNF-RI-Ig gene transfer improves allograft function in a well-established model of acute rejection. Maximum benefit was observed when transfection occurred 24 hours before transplantation.
AB - Background: Tumor necrosis factor is an important mediator of lung transplant acute rejection. Soluble type I tumor necrosis factor receptor binds to tumor necrosis factor-α and -β and inhibits their function. The objectives of this study were to demonstrate efficient in vivo gene transfer of a soluble type I tumor necrosis factor receptor fusion protein (sTNF-RI-Ig) and determine its effects on lung allograft acute rejection. Methods: Three groups of Fischer rats (n = 6 per group) underwent recipient intramuscular transfection 24 hours before transplantation with saline, 1 × 10 10 plaque-forming units of control adenovirus encoding β-galactosidase, or 1 × 1010 plaque-forming units of adenovirus encoding human sTNF-RI-Ig (Ad.sTNF-RI-Ig). One group (n = 6) received recipient intramuscular transfection with 1 × 1010 Ad.sTNF-RI-Ig at the time of transplantation. Brown Norway donor lung grafts were stored for 5 hours before orthotopic lung transplantation. Graft function and rejection scores were assessed 5 days after transplantation. Time-dependent transgene expression in muscle, serum, and lung grafts were evaluated by using enzyme-linked immunosorbent assay of human soluble type I tumor necrosis factor receptor. Results: Recipient intramuscular transfection with 1 × 10 10 plaque-forming units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered 24 hours before transplantation compared with saline, β-galactosidase, and Ad.sTNF-RI-Ig transfection at the time of transplantation (435.8 ± 106.6 mm Hg vs 142.3 ± 146.3 mm Hg, 177.4 ± 153.7 mm Hg, and 237.3 ± 185.2 mm Hg; P = .002, .005, and .046, respectively). Transgene expression was time dependent, and there was a trend toward lower vascular rejection scores (P = .066) in the Ad.sTNF-RI-Ig group transfected 24 hours before transplantation. Conclusions: Recipient intramuscular Ad.sTNF-RI-Ig gene transfer improves allograft function in a well-established model of acute rejection. Maximum benefit was observed when transfection occurred 24 hours before transplantation.
UR - http://www.scopus.com/inward/record.url?scp=2642578435&partnerID=8YFLogxK
U2 - 10.1016/j.jtcvs.2003.09.023
DO - 10.1016/j.jtcvs.2003.09.023
M3 - Article
C2 - 15173707
AN - SCOPUS:2642578435
SN - 0022-5223
VL - 127
SP - 1558
EP - 1563
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
IS - 6
ER -