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

Tsutomu Tagawa, Benjamin D. Kozower, Samer A. Kanaan, Niccolò Daddi, Masashi Muraoka, Tadayuki Oka, Jon H. Ritter, G. Alexander Patterson, Robert J. Korst, Mark S. Allen, Douglas E. Wood

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1558-1563
Number of pages6
JournalJournal of Thoracic and Cardiovascular Surgery
Volume127
Issue number6
DOIs
StatePublished - Jun 2004

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