Friday September 24, 2021 - 23:35 to 00:50
Initial experience of orthotopic transplantation of genetically-engineered pig hearts in baboons
Mohamed Bikhet1, David KC Cooper1, Silvio Litovsky1, Jeremy B Foote1, Abhijit Jagdale1, Gregory Walcott1, Hayato Iwase1, Takayuki Yamamoto1, Christophe Hansen-Estruch 1, Mohamed M Ezzelarab 2, David Ayares3, Carlo F Waldemar 1, Leslie A Rhodes1, Jack Crawford1, Santiago Borasino1, Robert Dabal1, Hidetaka Hara1, David Cleveland1.
1University of Alabama at Birmingham, Birmingham, AL, United States; 2University of Pittsburgh, Pittsburgh, PA, United States; 3Revivicor, Blacksburg, VA, United States
Introduction: Although survival of genetically-engineered pig hearts placed heterotopically (in the abdomen) in nonhuman primates has been measured in many months or even years, graft survival after pig orthotopic heart transplantation (OHTx) in baboons has been mixed. The cause for the high incidence of early failure remains uncertain, but does not appear to be associated with antibody-mediated rejection.
Methods: We carried out pig GTKO/CD55 (n=2) or GTKO/CD46/TBM (n=2) OHTx in 4 baboons. Immunosuppressive therapy was based on an anti-CD40mAb. Post-transplant monitoring included hemodynamic and pulmonary function, the immune and inflammatory responses, and histopathology of heart grafts and native baboon lungs at necropsy.
Results: Two baboons died or were euthanized within hours, and two survived for 3 and 8 months, respectively. There was evidence of a significant ‘cytokine storm’ in the immediate post-OHTx period. All 4 baboons demonstrated features of respiratory dysfunction, particularly in the hours following weaning from the ventilator. Histopathological observations suggested that pulmonary inflammation and eosinophils contributed to early lung and cardiac dysfunction. The two longer-term survivors died of a cardiac dysrhythmia (at 3 months) associated with cellular infiltrates around the conducting tissue, and of mixed acute and chronic rejection (at 8 months) that also involved the vasculature with luminal thrombosis.
Conclusions: Attention should be directed towards protecting the baboon lungs from the immediate post-OHTx inflammatory response. The potential role of a pathogenesis similar to transfusion-related acute lung injury (TRALI) and the involvement of eosinophils require further investigation. If this response can be suppressed, consistent longer-term pig heart graft survival may be possible, enabling successful bridging to allotransplantation.
Children’s (Hospital) of Alabama . NIAID U19 grant AI090959. United Therapeutics.