OVERCOMING COAGULATION DYSREGULATION IN PIG SOLID ORGAN TRANSPLANTATION IN NONHUMAN PRIMATES: RECENT PROGRESS

There has recently been considerable progress in the results of pig organ transplantation in nonhuman primates (NHPs), largely associated with the availability of (i) pigs genetically-engineered to overcome coagulation dysregulation, and (ii) novel immunosuppressive agents. The barriers of thrombotic microangiopathy and/or consumptive coagulation were believed to be associated with (i) activation of the graft vascular endothelial cells (VECs) by a low level of anti-pig antibody binding and/or complement deposition and/or innate immune cell activity, and (ii) molecular incompatibilities between the NHP and pig coagulation-anticoagulation systems. The introduction of a human coagulation-regulatory transgene, eg, thrombomodulin, endothelial protein C receptor, into the pig VECs has contributed to preventing a procoagulant state from developing, resulting in a considerable increase in graft survival. In the heterotopic (non-life-supporting) heart transplant model, graft survival has increased from a maximum of 179 days in 2005 to 945 days. After life-supporting kidney transplantation, survival has been extended from 90 days in 2004 to 499 days. In view of the more complex coagulation dysfunction seen after pig liver and, particularly, lung transplantation, progress has been less dramatic, but the maximum survival of a pig liver has been increased from 7 days in 2010 to 29 days, and of a pig lung from 4 days in 2007 to 9 days. There is a realistic prospect that the transplantation of a kidney or heart, in combination with a conventional immunosuppressive regimen, will enable long-term recipient survival. Address for correspondence: Hayato Iwase MD, PhD, Xenotransplantation Program, University of Alabama at Birmingham (UAB), ZRB 701, 1720 2nd Avenue South, Birmingham, AL 35294-0007, USA. Tel: 205-975-3938; Fax: 205-934-8344. E-mail: hiwase@uabmc.edu Authorship Data were collected by LW, LB, YW, HI, and DKCC. The manuscript was prepared by LW, LB, YW, HI, and DKCC, and revised and approved by all authors. Disclosure The authors declare no conflicts of interest. Funding Work on xenotransplantation at the University of Alabama at Birmingham is supported in part by NIH NIAID U19 grant AI090959. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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