Extended Life-Support Duration in a Xenogeneic Lung Transplantation Model Using Pigs With Multiple Genetic Modifications

To date, pig-to-baboon xeno lung transplantation (xLTX) has been characterized by rather short (hrs) graft survival relative to other organs, and life-supporting xeno lung function has rarely been accomplished. Here we report results from 19 recent xLTXs, in a rigorous life-supporting pig-to-baboon model and show that new multi-transgeneic donor pigs, coupled with targetted drug treatments, appear to address several known xeno lung injury mechanisms. Single xLTXs using GalTKO.hCD46.hTBM (2), GalTKO.hCD46.hTBM.hCD47.hCD39 (2), GalTKO.hCD46.+/-hCD55.hEPCR (9), GalTKO.hCD46.hCD55.hEPCR.hTBM.hCD39 (2), GalTKO.hCD46.hCD55.hEPCR.hTBM.hTFPI (2) and GalTKO.hCD46.hCD55.hEPCR.hCD47.hTFPI (3) grafts were performed in baboons. Recipients all received Solumedrol, C1-Esterase Inhibitor, Heparin, anti-GPIb Fab, thromboxane synthase inhibitor 1-BIA and histamine receptor blocker. Pigs were pre-treated with DDAVP. Most recent lung recipients (5) were treated with ATG, Tacrolimus and MMF. Life-supporting (LS) function was assessed by intermittently occluding the right native pulmonary artery. Average LS time was 10hrs. 2 recipients displayed ATG-reaction (lung edema prior xenograft reperfusion) and were excluded from analyses. Best results were achieved with GalTKO.hCD46.hCD55.hEPCR.hCD47.hTFPI lungs when immunosuppression was given (30hrs LS, n=2). In both cases, animals died due to ventricular fibrillation with functioning xenografts. Macro- and microscopically, lung tissue from these experiments appeared grossly normal. Pathologic findings, previously seen in recipient animals, such as progressive ascites, escalating volume and inotrope requirements and native (baboon) lung edema, were not seen in recent experiments. In association with GPIb blockade and donor DDAVP pre-treatment, platelet consumption was <10% during the first hour of perfusion. These preliminary in vivo results support our hypothesis that effective control of complement and coagulation (mainly by pig genetics) and judicious use of drugs to block other important pathways (non-physiologic vWF/GPIb interaction, thromboxane and histamine release) will be necessary and sufficient to accomplish prolonged life-supporting lung xenograft function, and may translate into other xenogeneic model as well.