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Eur J Cardiothorac Surg 2003;24:794-806
© 2003 Elsevier Science NL

Review

Gene transfer of cytoprotective and immunomodulatory molecules for prevention of cardiac allograft rejection

^a Department of Cardiology, BH-10, CHUV, University of Lausanne Medical School, Rue du Bugnon 46, 1011 Lausanne, Switzerland
^b Department of Experimental Surgery, University of Lausanne Medical School, Lausanne, Switzerland
^c Department of Cardiovascular Surgery, University of Lausanne Medical School, Lausanne, Switzerland

Received 8 January 2003; received in revised form 8 April 2003; accepted 15 June 2003.

^* Corresponding author. Tel.: +41-21-314-0076; fax: +41-21-314-0013
e-mail: giuseppe.vassalli{at}chuv.hospvd.ch

Current treatments of heart transplantation are limited by incomplete effectiveness, significant toxicity, and failure to prevent chronic rejection. Genetic manipulation of the donor heart at the time of removal offers the unique opportunity to produce a therapeutic molecule within the graft itself, while minimizing systemic effects. Cytoprotective approaches including gene transfer of heme oxygenase (HO)-1, endothelial nitric oxide synthase, and antisense oligodeoxynucleotides specific for nuclear factor (NF)-B or intercellular adhesion molecule (ICAM)-1 reduced ischaemia–reperfusion injury and delayed cardiac allograft rejection in small animals. Exogenous overexpression of immunomodulatory cytokines such as interleukin (IL)-4, IL-10 and transforming growth factor-ß, as well as gene transfer of inhibitors of pro-inflammatory cytokines also delayed graft rejection. Gene transfer-based blockade of T-cell costimulatory activation with CTLA4-Ig or CD40-Ig resulted in long-lasting graft survival and donor-specific unresponsiveness, as manifested by acceptance of a second graft from the original donor strain but rejection of third-party grafts. Similar results were obtained with donor major histocompatibility complex class I gene transfer into bone marrow cells. Gene therapy approaches to chronic rejection included gene transfer of HO-1, soluble Fas, tissue plasminogen activator and antisense oligodeoxynucleotides specific for the anti-apoptotic mediator Bcl-x or the E2F transcription factor. Despite major experimental advances, however, gene therapy for heart transplantation has not entered the clinical arena yet. Fundamental questions regarding the most suitable vector, the best gene, and safety issues remain unanswered. Well-controlled studies that compare gene therapy with established treatments in non-human primates are needed before clinical trials can be started.

Key Words: Transplantation • Heart • Gene therapy • Gene transfer

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