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F3. ELECTROPORATION MEDIATED INTERLEUKIN-10 OVEREXPRESSION IN SKELETAL MUSCLE REDUCES ACUTE REJECTION IN RAT CARDIAC ALLOGRAFTS
Reza Tavakoli, Amiq Gazdhar, Jaroslaw Pierog, Anna Bagdannova, Matthias Gugger, Steven C Hyde, Michele Genoni, Ralph A Schmid; ZurichBern, Switzerland; Oxford, United Kingdom

Objective: Electroporation mediated transfer of plasmid DNA has been demonstrated to enhance gene transduction dramatically. The aim of this study was to investigate the effect of overexpression of human IL-10 (hIL-10) on acute rejection of cardiac allografts in the rat.
Method: Heterotopic heart allotransplantation was carried out from male BN donors to male Fischer recipients. Gene transfer was performed by i.m. injection into the tibialis anterior muscle (M.ta) of the recipient followed by electroporation (4x10ms impulses at 200V/cm) 24h prior to transplantation. In group A (n=6) 2.5 μg of pCIK hIL-10 (human CMV early promoter-enhancer) and group B (n=6) distilled water was injected. Graft function was assessed by daily palpation. Animals were sacrificed at day 7 or at cessation of the heart beat. At sacrifice venous blood was drawn for hIL-10 ELISA and graft tissue for myeloperoxidase (MPO) measurement and histological rejection grading was assserved.
Results: At day 7 all heart allografts were still beating in group A, whereas they stopped beating at day 5±1 in group B (p<0.05). Serum hIL-10 levels were 60±31 pg/ml in group A versus 0 in group B. hIL-10 mRNA expression was localized by in situ hybridization in the transduced M.ta. MPO activity in the graft was significantly lower in group A than in group B (18±7 versus 32±14 mU/mg protein, p=0.05). Histological examination revealed severe rejection (IV) in all animals in group B in contrast to low moderate rejection (IIIA/B) in group A.
Conclusion: Electroporation mediated intramuscular overexpression of hIL-10 improves survival of heterotopic heart allografts in the rat. This was accompanied by and significant reduction of neutrophil infiltration and rejection grade. This study demonstrates that electroporation mediated overexpression in skeletal muscle of immunomodulatory genes may reduce acute rejection in rat cardiac allografts.

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