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Eur J Cardiothorac Surg 2005;27:1030-1035
© 2005 Elsevier Science NL

Synergistic effect of low dose Cyclosporine A and human interleukin 10 overexpression on acute rejection in rat lung allotransplantation

^a Division of General Thoracic Surgery, University Hospital, CH-3010 Bern, Switzerland
^b Department of Pathology, University of Bern, Switzerland
^c John Radcliff Hospital, University of Oxford, UK
^d Inovivo Oslo Research Park, Oslo, Norway
^e Regional Hospital for Lung Diseases, Szczecin-Zdunowo, Poland

Received 22 September 2004; received in revised form 7 February 2005; accepted 9 March 2005.

^* Corresponding author. Tel.: +41 31 632 2330; fax: +41 31 632 2327. (E-mail: ralph.schmid{at}insel.ch).

Objective: Electroporation mediated transfer of plasmid DNA into peripheral muscle results in high transfection efficiency. The aim of this study was to investigate the effect of gene transfer of human IL-10 (hIL-10) into the tibialis anterior muscle (MTA) in combination with low dose Cyclosporine A (CsA) on acute rejection of lung allografts in the rat. Methods: Lung allotransplantation was performed from male BN donor to male Fisher F344 rats. Gene transfer was achieved by intramuscular injection into the MTA of the recipient followed by electroporation (4x20ms impulses at 200V/cm) 24h prior to the transplantation. Group A (n=5) received CsA (2.5mg/kg bw ip) for 5 days post-transplant and group B (n=5) 2.5µg of PCIK hIL-10 (plasmid expression vector containing human CMV immediate early gene promoter and enhancer) and a low dose CsA (2.5mg/kg bw i.p.). Graft function was assessed by blood gas at day 5 after exclusion of the native lung. Animals were sacrificed and blood was drawn to measure serum hIL-10 levels (ELISA) and tissue was sampled for histological grading of rejection. Results: Local expression of hIL-10 was confirmed at the mRNA level by in situ hybridization. All group A control animals showed severe signs of rejection. At day 5 all grafts in group B showed good gas exchange mean PaO2 233±123mmHg, vs 44±8mmHg in group A. Histological examination revealed moderate to severe rejection in all animals in group A (IIIB, ISHLT) in contrast to low moderate rejection in group B (II–IIIA). hIL-10 serum levels on day 5 were 14±7pg/ml in group B vs. 0 in group A. Conclusions: Electroporation mediated hIL-10 overexpression in a peripheral muscle of the recipient in combination with low dose CsA reduces acute rejection in this model of rat lung allotransplantation.

Key Words: Organ transplantation • In vivo electroporation • Gene transfer