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 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, for example, expression of hemeoxygenase-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 triple-knockout pig that expressed 1 or more human complement-regulatory proteins, 1 or more human coagulation-regulatory proteins, a human anti-inflammatory 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.
The authors summarize the optimal genetically-engineered pig models for preclinical studies of heart and kidney transplantation. It is suggested that not only the deletion of xenoantigenes is important, but also the additional insertion of protective human transgenes is beneficial, and may be essential.
1 Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.
2 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
Received 14 May 2018. Revision received 15 August 2018.
Accepted 18 August 2018.
Work on xenotransplantation at UAB is supported in part by NIH grant U19 AI090959/08.
The authors declare no conflicts of interest.
The initial draft of the article was prepared by D.K.C.C. with subsequent contributions and approval by all authors.
Correspondence: David K.C. Cooper, MD, PhD, FRCS, LHRB 752, 1720 2nd Avenue South, University of Alabama at Birmingham, Birmingham, AL 35294. (firstname.lastname@example.org).