Gene expression in cardiac and lung xenografts

Abstract

Objectives: We have previously shown that lung xenografts could undergo “accommodation” in the same fashion as cardiac xenografts treated with cobra venom factor (CVF) and cyclosporin A (CsA). In this study, we asked if the gene expression profile of accommodated cardiac and lung xenografts was universal or specific to each organ. Methods: We used hamster-to-rat cardiac and lung xenotransplantation (XT) models. Cardiac XTs were treated with CVF CsA and compared to untreated controls. Lung XTs were treated with either CVF CsA or FK506 cyclophosphamide (Cp) and compared to untreated controls. We analyzed graft survival, protein expression of protective genes, histological and immunohistological findings and used microarray technology to identify other genes potentially involved in accommodation. Results: Rejection occurred rapidly in untreated rats. CVF CsA or FK506 Cp treatment significantly influenced graft survival. 8 of 12 heart transplants treated with CVF CsA survived at least 21 days. 7 of 16 in the CVF CsA group and 5 of 12 in the FK506 Cp group survived 21 days after lung transplantation. As expected, we observed significant protein expression of bcl-2, bcl-XL and HO-1 in cardiac and lung xenografts treated with CVF CsA, compared with untreated donor hearts. The overall pattern of gene expression in lung xenografts was distinct from that seen in accommodated cardiac xenografts. However, 38 genes were expressed in both organs after CVF CsA treatment, including insulin-like growth factor binding protein-6 and interferon regulatory factor6. Also, twelve genes, including interleukin-11and interferon regulatory factor-6, were expressed in accommodated cardiac xenografts and both groups of lung xenografts. Microarray results were validated with western blotting. Conclusion: After induction of accommodation, distinct genetic changes are seen in lungs compared to hearts, with only a few genes regulated in parallel.