Perspectives on the Optimal Genetically-Engineered pig in 2018 for Initial Clinical Trials of Kidney or Heart Xenotransplantation

For a clinical trial today, what might realistically be the optimal pig among those currently available? Deletion of expression of the 3 pig carbohydrate antigens against which humans have natural (preformed) antibodies (triple-knockout [TKO] pigs) should form the basis of any clinical trial. However, because both complement and coagulation can be activated in the absence of antibody, the expression of human complement- and coagulation-regulatory proteins is likely to be important in protecting the graft further. Any genetic manipulation that might reduce inflammation of the graft, eg, expression of hemeoxygenase-1 (HO-1) or A20, may also be beneficial to the long-term survival of the graft. The transgene for human CD47 is likely to have a suppressive effect on monocyte/macrophage and T cell activity. Furthermore, deletion of xenoantigen expression, and expression of a human complement-regulatory protein, are both associated with a reduced T cell response. Although there are several other genetic manipulations that may reduce the T cell response further, it seems likely that exogenous immunosuppressive therapy, particularly if it includes costimulation blockade, will be sufficient. We would therefore suggest that, with our present knowledge and capabilities, the optimal pig might be a TKO pig that expressed 1 or more human complement-regulatory proteins, 1 or more human coagulation-regulatory proteins, a human antiinflammatory transgene, and CD47. Absent or minimal antibody binding is important, but we suggest that the additional insertion of protective human transgenes will be beneficial, and may be essential. Address for correspondence: David K.C. Cooper MD, PhD, FRCS, ZRB 701, 1720 2nd Avenue South, University of Alabama at Birmingham, Birmingham, AL 35294, USA, Tel: (USA) 205-996-7772. E-mail: dkcooper@uabmc.edu Authorship The initial draft of the manuscript was prepared by DKCC with subsequent contributions and approval by all authors. Disclosure The authors declare no conflicts of interest. Funding Work on xenotransplantation at UAB is supported in part by NIH grant #U19 AI090959/08. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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