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J Thorac Cardiovasc Surg 2004;127:1558-1563
© 2004 The American Association for Thoracic Surgery

General thoracic surgery

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

^a Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine, Barnes- Jewish Hospital, St Louis, Mo, USA,
^b First Department of Surgery, Nagasaki University School of Medicine, Nagasaki, Japan

Read at the Eighty-third Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 4-7, 2003.

Received for publication May 1, 2003; revisions received August 14, 2003; revisions received September 15, 2003; accepted for publication October 3, 2003.

^* Address for reprints: G. Alexander Patterson, MD, FRCS(C), Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, 3108 Queeny Tower, St Louis, MO 63110-1013, USA
pattersona{at}msnotes.wustl.edu

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- and -ß 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 x 10¹⁰ plaque-forming units of control adenovirus encoding ß-galactosidase, or 1 x 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 x 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 x 10¹⁰ plaque-forming units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered 24 hours before transplantation compared with saline, ß-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.