serval:BIB_607CA3C6C298
Gene transfer of cytoprotective and immunomodulatory molecules for prevention of cardiac allograft rejection
10.1016/S1010-7940(03)00456-1
000186857400018
14583314
Vassalli
G.
author
Fleury
S.
author
Li
J.
author
Goy
J. J.
author
Kappenberger
L.
author
von Segesser
L. K.
author
article
review
2003-11
European Journal of Cardio-Thoracic Surgery
1010-7940
journal
24
5
794-806
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)-kappa 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-beta, 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.
Animals
Cytokines/genetics
Cytoprotection/genetics
Forecasting
Gene Therapy/*methods
*Gene Transfer Techniques
Graft Rejection/*prevention & control
*Heart Transplantation/immunology
Humans
60_published
true
Journal Article
Research Support, Non-U.S. Gov't
Review --- Old month value: Nov
University of Lausanne
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