Treatment of Presumptive Rejection After Orthotopic Pig-to-Baboon Cardiac Xenotransplantation

Abstract

Background: Significant progress has been made in the long-term survival of non-human primates after orthotopic gene-edited pig cardiac xenotransplantation. However, to our knowledge, there are no reports of the successful reversal of an acute rejection episode in such an experiment. We present evidence suggesting that rejection can be reversed with corticosteroids and complement inhibition.

Methods: Orthotopic transplantation of a pig heart (with 69 gene-edits) was carried out in a baboon. The immunosuppressive regimen was based on CD40/CD154 T cell co-stimulation pathway blockade and rapamycin. Cardiac function remained excellent until Day 162, when there were increases in heart rate, ventricular septal wall thickness, left ventricular end-diastolic pressures (LVEDP), and troponin level, which were associated with a low serum level of rapamycin (<4 ng/mL). Anti-rejection treatment was begun with an increase in rapamycin dosage, steroid bolus therapy, two doses of a C1-esterase inhibitor, and an extra dose of the anti-CD154mAb.

Results: There was a rapid correction of all hemodynamic parameters, and the troponin T level (which had risen to 139 ng/L) returned to pre-rejection levels. Ventricular septal thickness and LVEDP returned to pre-rejection levels after treatment. The baboon remains well with normal graft function. Baseline heart rate remains faster than before the rejection episode.

Conclusions: As we transition to the clinical application of gene-edited pig cardiac xenotransplantation, the ability to treat rejection is of vital importance. The optimal treatment for rejection remains uncertain but we suggest that systemic complement inhibition is important.

Keywords: cardiac xenotransplantation; genetically modified xenograft; pediatric; rejection.