Date: Tuesday, May 5, 2015
Session Time: 4:00pm-5:30pm
Presentation Time: 5:00pm-5:12pm
Location: Room 119-A
Purpose: Prolonged life-supporting (LS) xenolung function has proven difficult to accomplish. Here we report results from 21 xLTXs in a rigorous, LS pig-to-baboon model, asking whether multi-transgeneic donor pigs, when coupled with targeted drug treatments, effectively prevent xenolung injury. Methods: Left 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 (4) pig lungs were transplanted into baboons. Recipients received methylprednisolone, C1 inhibitor, heparin, and some were treated with anti-GPIb Fab, thromboxane synthase inhibitor, and histamine receptor blockers. DDAVP was given to donor pigs prior lung procurement, to deplete VWF. These interventions were chosen based on evidence that these pathways contribute to pig lung injury during perfusion with human blood. 5 recent recipients were also treated with immunosuppression (ATG, Tacrolimus, MMF); 2 recipients that displayed ATG-reaction (lung edema prior xenograft reperfusion) were excluded from analysis. LS function was confirmed by intermittently occluding the right pulmonary artery. Results: LS was prolonged in several 3-, 4-, and 5-gene pig lungs up to 12 hrs, but with progressive xenograft injury. In contrast, GalTKO.hCD46.hCD55.hEPCR.hCD47.hTFPI lung recipients treated with full drug regimen exhibited modest fluid and inotrope requirements and prolonged LS (>20 hrs in one case without IS, >30hrs LS in 2 cases with IS). In these cases, recipients exhibited unexpected ventricular fibrillation. Pig lungs from longest surviving experiments appeared macro- and microscopically grossly normal. Physiologic perturbations seen in previous recipients (progressive ascites, escalating volume and inotrope requirements, native (baboon) lung edema) were minimal in 2 longest survivors. Conclusion: Results support our hypothesis that effective control of complement activation and coagulation dysregulation (mainly using pig genetic modifications) and use of drugs to block other pathways (VWF/GPIb interaction, thromboxane and histamine release) appear necessary, and may prove sufficient, to further prolong LS xenolung function. These encouraging findings set the stage to unveil residual mechanistic and model-dependent obstacles to clinical xenograft application.
To cite this abstract in AMA style:Burdorf L, Rybak E, Zhang T, Harris D, Dahi S, Kubicki N, Parsell D, Sievert E, Ayares D, Azimzadeh A, III RPierson. Extended Life-Supporting Xenogeneic Lung Function With Multi-Transgeneic Donor Pigs and Targeted Drug Treatments [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/extended-life-supporting-xenogeneic-lung-function-with-multi-transgeneic-donor-pigs-and-targeted-drug-treatments/. Accessed January 27, 2021.
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