Purpose: Recent progress in genetic engineering has facilitated generation of pigs expressing various multi-transgene and knock-out combinations. Which transgenes and what targeted drug treatments are required to prevent injury of lung xenografts remains unknown. Here we report progress in a rigorous life-supporting pig-to-baboon lung xenograft model. Methods: 46 left single lung transplants were performed into baboons using porcine GalTKO.hCD46 donor organs with up to 4 additional genetic modifications (6GE), including hCD55, hTBM, hEPCR, hTFPI, hCD47, hCD39, hHO-1, and A20. Recipients consistently received steroids, sC1Inh, thromboxane synthase inhibitor, histamine receptor blockers, and anti-GPIb Fab to block known pathogenic pathways. Donor pigs were treated with DDAVP prior to lung procurement, to deplete pig endothelial VWF. In recent recipients, immunosuppression (ATG, MMF, and FK506 or aCD40), anti-IL6R moAb and/or Alpha-1 Antitrypsin were given. Xenograft function was assessed intermittently by transplant blood flow measurements and radiographs. Results: Recipients of 6GE lungs of the hCD55.hEPCR.hCD47.hTFPI and other phenotypes consistently exhibited life-supporting (LS) lung function for 24-30h, with relatively normal macro- and microscopic lung appearance until 48-72 hrs. The longest follow up times of xenogenically lung-transplanted baboons were 8d (hCD55.hEPCR.hTBM.hCD39) and 9d (hEPCR.hTBM.hCD47.HO-1). Predominant experimental failure mode was loss of lung vascular barrier function with alveolar flooding and consolidation, consistent with “delayed xenograft rejection”. Conclusion: Significant prolongation of life-supportive lung function and recipient survival has been consistently achieved by combining multi-transgenic donor organs with mechanism-directed drug treatments. If DXR lung rejection mechanism (including residual anti-non-Gal antibody, recipient NK cells, and donor macrophage activation) resemble those driving DXR of other organs, targeted genetic modifications (CMAH KO, hHLA-E) and drug additions (donor liposomal clodronate treatment) may significantly advance lung xenotransplantation towards clinical application.

CITATION INFORMATION: Burdorf L, Laird C, O'Neill N, Zhang T, Parsell D, Tatarov I, Cimeno A, Sendil S, Thomas K, Phelps C, Ayares D, Azimzadeh A, Pierson III R. Xenogeneic Lung Transplantation: Identifying Transgenes and Supportive Drug Treatments to Achieve Long-Term Survival. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress