Shaf Keshavjee, M.D. (Associate Member)
Professor, Surgery, University of Toronto
Head, Division Thoracic Surgery, Toronto General Hospital, University Health Network
Chair, Division of Thoracic Surgery, University of Toronto

http://www.ctsnet.org/home/skeshavjee

Research Interest    

Two major obstacles to the success of lung transplantation are ischemia reperfusion injury and bronchiolitis obliterans. Dr. Keshavjee's laboratory explores the mechanisms that underlie both of these injuries and is working to develop therapeutic strategies capable of preventing or reversing them. In an early approach, the group developed a technique of lung preservation (use of LPD solution) that has led to significant improvements in lung function after transplantation. In fact, this method has now been translated into clinical use in the lung transplant program at the University of Iowa, as well as in other programs around the world. With respect to ischemia reperfusion injury in particular, the group has explored several contributing factors - including the role of complement- and cytokine-related lung injury related to reperfusion - in cell culture models, as well as in rat and pig single-lung transplant models. Dr. Kashavjee?s group is now attempting to apply gene therapies based on this information, in essence attempting to genetically modify the donor lung so that it is better able to deal with the stress imposed upon it by the transplantation process. Specifically, the group has shown that immunosuppression during transplantation leads to augmented as well as prolonged transgene expression, and that it makes possible effective re-transfection of the recipient without a significant immune response. Furthermore, the group?s studies in a rat tracheal transplant model of fibrous airway obliteration related to transplantation have shown that adenoviral IL-10 gene transfection can prevent the development of bronchiolitis obliterans. This is the first demonstration of a gene therapy strategy that can be used to treat this devastating condition, which affects over 50% of lung transplant patients. The research group is currently studying the effects of IL-10 transfection of the donor on ischemia reperfusion injury, toward developing a therapeutic approach that will simultaneously control ischemia reperfusion injury and obliterative bronchiolitis in a lung transplant patient. Finally, the group is investigating the mechanisms of cell death related to ischemia reperfusion injury, and in particular the genes that control these processes.

Selected Publications:

Fischer, S., De Perrot, M., Liu, M., MacLean, A.A., Cardella, J.A., Imai, Y., Suga, M., and Keshavjee, S. 2003. Interleukin 10 gene transfection of donor lungs ameliorates posttransplant cell death by a switch from cellular necrosis to apoptosis. J Thorac Cardiovasc Surg 126:1174-1180.

de Perrot, M., Fischer, S., Liu, M., Imai, Y., Martins, S., Sakiyama, S., Tabata, T., Bai, X.H., Waddell, T.K., Davidson, B.L., and Keshavjee, S. 2003. Impact of human interleukin-10 on vector-induced inflammation and early graft function in rat lung transplantation. Am J Respir Cell Mol Biol 28:616-625.

Martins, S., de Perrot, M., Imai, Y., Yamane, M., Quadri, S.M., Segall, L., Dutly, A., Sakiyama, S., Chaparro, A., Davidson, B.L., Waddell, T.K., Liu, M., and Keshavjee, S. 2004. Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model. Gene Ther 11:1786-1796.

Kaneda H, Waddell TK, de Perrot M, Bai XH, Gutierrez C, Arenovich T,Chaparro C, Liu M, Keshavjee S. 2006. Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts survival after lung transplantation in humans. Am J Transplant. 6:544-51.

Sato, M., and Keshavjee, S. 2006. Gene therapy in lung transplantation. Curr Gene Ther 6:439-458.

Publications from PubMed