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

• Published in: European journal of cardio-thoracic surgery 2005-06, Vol.27 (6), p.1030-1035
• Main Authors: Pierog, Jaroslaw, Gazdhar, Amiq, Stammberger, Uz, Gugger, Matthias, Hyde, Steven, Mathiesen, Iacob, Grodzki, Tomasz, Schmid, Ralph A.
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biological and medical sciences; Cardiology. Vascular system; Cyclosporine - administration & dosage; Cyclosporine - therapeutic use; Drug Administration Schedule; Drug Synergism; Electroporation - methods; Gene Expression; Gene transfer; Gene Transfer Techniques; Graft Rejection - prevention & control; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - therapeutic use; In vivo electroporation; Injections, Intramuscular; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-10 - metabolism; Lung Transplantation - immunology; Male; Medical sciences; Organ transplantation; Pneumology; Rats; Rats, Inbred BN; Rats, Inbred F344; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; Transplantation, Homologous
• ISSN: 1010-7940; 1873-734X
• DOI: 10.1016/j.ejcts.2005.03.008

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 (4×20ms 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.