Gene transfer of tumor necrosis factor inhibitor improves the function of lung allografts.

Abstract

Tumor necrosis factor is an important mediator of lung transplant acute rejection. Soluble type I tumor necrosis factor receptor binds to tumor necrosis factor-alpha and -beta 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. Three groups of Fischer rats (n = 6 per group) underwent recipient intramuscular transfection 24 hours before transplantation with saline, 1 x 10(10) plaque-forming units of control adenovirus encoding beta-galactosidase, or 1 x 10(10) plaque-forming units of adenovirus encoding human sTNF-RI-Ig (Ad.sTNF-RI-Ig). One group (n = 6) received recipient intramuscular transfection with 1 x 10(10) 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. Recipient intramuscular transfection with 1 x 10(10) plaque-forming units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered 24 hours before transplantation compared with saline, beta-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. 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.