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J Thorac Cardiovasc Surg 2001;122:29-38
© 2001 The American Association for Thoracic Surgery

General Thoracic Surgery (GTS)

Lipid-mediated ex vivo gene transfer of viral interleukin 10 in rat lung allotransplantation

From the Division of Cardiothoracic Surgery,^a Department of Pathology,^b Department of Radiology,^c Washington University School of Medicine, St Louis, Mo, and the Genzyme Corporation,^d Framingham, Mass.

This work was supported by National Institutes of Health grant R01 HL 41281 (G.A.P.) and HL 56643 (T.M.) and the Genzyme Corporation. The nitric oxide analyzer was purchased through a grant from the Whitaker Foundation (T.J.M.). H.I. was supported by the Okayama University Medical School.

Presented at the 2000 Clinical Congress of the American College of Surgeons, October 22-27, 2000, in Chicago, Ill.

Received for publication Oct 9, 2000. Revisions requested Nov 28, 2000; revisions received Jan 18, 2001. Accepted for publication Jan 23, 2001. Address for reprints: G. Alexander Patterson, MD, 3108 Queeny Tower, One Barnes-Jewish Hospital Plaza, St. Louis, MO 63110 (E-mail: kellym{at}msnotes.wustl.edu).

Abstract

Background: Recent studies suggest that viral interleukin 10 suppresses alloimmune response in transplantation and that cationic lipids are one of the most promising nonviral vehicles for gene therapy. The aim of this study was to examine the effect of ex vivo lipid-mediated viral IL10 gene transfer into rat lung allografts on subsequent rejection.
Methods: Male F344 rats (RT1lvl) underwent left lung transplantation with allografts from Brown Norway rats (RT1n). Allografts were transvascularly transfected 15 minutes after harvest with 5 mL of 1:20-diluted (group 1, n = 7) or 1:40-diluted (group 2, n = 6) GL67-pCMVievIL-10 complex. Group 3 (n = 7), serving as the control group, received 1:40-diluted GL67-pCF1-chloramphenicol acetyltransferase complex. All allografts were preserved for 3 hours at 10°C before transplantation. In all groups recipients were killed on postoperative day 5. Transgene expression of viral interleukin 10 was assessed by means of both reverse transcriptase–polymerase chain reaction and immunohistochemistry. Histologic rejection score, allograft gas exchange, exhaled nitric oxide level, and allograft cytokine mRNA expression were also assessed.
Results: Dose-dependent transgene expression of viral interleukin 10 was detected by means of both reverse transcriptase–polymerase chain reaction and immunohistochemistry. Allograft gas exchange (PaO₂) in groups 1 (114.06 ± 61.1 mm Hg) and 2 (108.58 ± 35.7 mm Hg) was significantly better than that in group 3 (66.4 ± 8.22 mm Hg; P = .020 and P = .023, respectively). The vascular rejection score in group 1 was significantly lower than that in group 3 (P = .032, Kruskal-Wallis test). Exhaled nitric oxide levels in group 2 (5.150 ± 6.38 ppb) were significantly lower than those in group 3 (13.517 ± 10.4 ppb; P = .039). Allograft interleukin 2 mRNA expression levels in group 1 (1.123 ± 0.23 relative units) were significantly lower than those in group 3 (1.753 ± 0.71 relative units; P = .038 vs group 3).
Conclusions: Lipid-mediated ex vivo viral IL10 gene transfer into rat lung allografts improved graft gas exchange, reduced histologic rejection scores, downregulated graft interleukin 2 mRNA expression, and reduced exhaled nitric oxide levels by postoperative day 5. These results suggest a therapeutic potential of graft viral IL10 gene transfer as an effective immunosuppressive strategy against lung allograft rejection.

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