From bench to bedside: immune and genetic innovations driving the future of cardiac, renal, and hepatic xenotransplantation
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Lu, T., Yang, B., Wang, R., Qin, C. Xenotransplantation: Current Status in Preclinical Research. Front. Immunol. 2020, 10, 3060, doi:10.3389/fimmu.2019.03060
Abouna, G. M. Organ shortage crisis: problems and possible solutions. Transplantation proceedings 2008, 40, 34–38, doi:10.1016/j.transproceed.2007.11.067
Lewis, A., Koukoura, A., Tsianos, G. I., et al. Organ donation in the US and Europe: The supply vs demand imbalance. Transplant. Rev. (Orlando) 2021, 35, 100585, doi:10.1016/j.trre.2020.100585
Saidi, R. F., Hejazii Kenari, S. K. Challenges of organ shortage for transplantation: solutions and opportunities. Int. J. Organ Transplant. Med. 2014, 5, 87–96
Wadiwala, I. J., Garg P., Yazji J. H., et al. Evolution of Xenotransplantation as an Alternative to Shortage of Donors in Heart Transplantation. Cureus 2022, 14, e26284, doi:10.7759/cureus.26284
Ekser, B., Cooper, D. K. C., Tector, A. J. The need for xenotransplantation as a source of organs and cells for clinical transplantation. Int. J. Surg. 2015, 23, 199–204, doi:10.1016/j.ijsu.2015.06.066
Niu, D., Wei H. J., Lin L., et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science 2017, 357, 1303–1307, doi:10.1126/science.aan4187
Bottino, R., Wijkstrom M., van der Windt D. J., et al. Pig-to-monkey islet xenotransplantation using multi-transgenic pigs. Am. J. Transplant. 2014, 14, 2275–2287, doi:10.1111/ajt.12868
Hering, B. J., Wijkstrom M., Graham M. L., et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat. Med. 2006, 12, 301–303, doi:10.1038/nm1369
Lei, J., Zhang A., Deng H., et al. Intrapleural transplantation of allogeneic pancreatic islets achieves glycemic control in a diabetic non-human primate. Am. J. Transplant. 2022, 22, 966–972, doi:10.1111/ajt.16875
Markmann, J. F. Isolated Pancreatic Islet Transplantation: A Coming of Age. Am. J. Transplant. 2016, 16, 381–382, doi:10.1111/ajt.13538
Lai, L., Kolber-Simonds D., Park K. W., et al. Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 2002, 295, 1089–1092, doi:10.1126/science.1068228
Cooper, D. K. C., Hara, H. Xenotransplantation-A Basic Science Perspective. Kidney360 2023, 4, 1147–1149, doi:10.34067/KID.0000000000000173
Deng, J., Yang, L., Wang, Z., et al. Advance of genetically modified pigs in xeno-transplantation. Front. Cell Dev. Biol. 2022, 10, 1033197, doi:10.3389/fcell.2022.1033197
Meier, R. P. H., Longchamp A., Mohiuddin M., et al. Recent progress and remaining hurdles toward clinical xenotransplantation. Xenotransplantation 2021, 28, e12681, doi:10.1111/xen.12681
Girani, L., Xie X., Lei T., et al. Xenotransplantation in Asia. Xenotransplantation 2019, 26, e12493, doi:10.1111/xen.12493
Carrier, A. N., Verma A., Mohiuddin M., et al. Xenotransplantation: A New Era. Front. Immunol. 2022, 13, 900594, doi:10.3389/fimmu.2022.900594
Pan, W., Zhang W., Zheng B., et al. Cellular dynamics in pig-to-human kidney xenotransplantation. Med. 2024, 5, 1016–1029.e1014, doi:10.1016/j.medj.2024.05.003
Igaz, P. Recent strategies to overcome the hyperacute rejection in pig to human xenotransplantation. Yale J. Biol. Med. 2001, 74, 329–340
Loupy, A., Goutaudier V., Giarraputo A., et al. Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study. Lancet 2023, 402, 1158–1169, doi:10.1016/s0140-6736(23)01349-1
Lian, Y., Gao C., Wu Y., et al. Suppression of Delayed Xenograft Rejection by Resveratrol in a Hamster-to-Rat Cardiac Transplantation Model. Transplant. Proc. 2017, 49, 1483–1491, doi:10.1016/j.transproceed.2017.03.091
Zhou, Q., Li T., Wang K., et al. Current status of xenotransplantation research and the strategies for preventing xenograft rejection. Front. Immunol. 2022, 13, 928173, doi:10.3389/fimmu.2022.928173
Bach, F. H., Winkler, H., Ferran, C., et al. Delayed xenograft rejection. Immunology Today 1996, 17, 379– 384, doi:10.1016/0167-5699(96)10024-4
Spitzer, T. R., Sachs, D. H. Transplantation Tolerance through Hematopoietic Chimerism. N. Engl. J. Med. 2022, 386, 2332–2333, doi:10.1056/NEJMe2204651
Kawai, T., Sachs, D. H. Tolerance induction: hematopoietic chimerism. Curr. Opin. Organ Transplant. 2013, 18, 402–407, doi:10.1097/MOT.0b013e328363621d
Sachs, D. H., Kawai, T., Sykes, M. Induction of tolerance through mixed chimerism. Cold Spring Harb. Perspect. Med. 2014, 4, a015529, doi:10.1101/cshperspect.a015529
Yamada, K., Sykes, M., Sachs, D. H. Tolerance in xenotransplantation. Curr. Opin. Organ Transplant. 2017, 22, 522–528, doi:10.1097/MOT.0000000000000466
Zuber, J., Sykes, M. Mechanisms of Mixed Chimerism-Based Transplant Tolerance. Trends. Immunol. 2017, 38, 829–843, doi:10.1016/j.it.2017.07.008
Porrett, P. M., Orandi B. J., Kumar V., et al. First clinical-grade porcine kidney xenotransplant using a human decedent model. Am. J. Transplant. 2022, 22, 1037–1053, doi:10.1111/ajt.16930
O'Connell, P. J. Thrombotic microangiopathy: the next big hurdle for xenotransplantation. J. Am. Soc. Nephrol. 2005, 16, 2529–2530, doi:10.1681/asn.2005070735
Liu, Y., Niu Y., Ma X., et al. Porcine endogenous retrovirus: classification, molecular structure, regulation, function, and potential risk in xenotransplantation. Funct. Integr. Genomics 2023, 23, 60, doi:10.1007/s10142-023-00984-7
Cooper, D. K. C. Advancing Xenotransplantation to the Clinic: How Relevant Is the Pig-to-nonhuman Primate Kidney Transplantation Model Today? Transplantation 2022, 106, 1717–1719, doi:10.1097/TP.0000000000004097
Montgomery, R.A., Stern J. M., Lonze B. E., et al. Results of Two Cases of Pig-to-Human Kidney Xenotransplantation. N. Engl. J. Med. 2022, 386, 1889– 1898, doi:10.1056/NEJMoa2120238
Griffith, B. P., Goerlich C. E., Singh A. K., et al. Genetically Modified Porcine-to-Human Cardiac Xenotransplantation. N. Engl. J. Med. 2022, 387, 35–44, doi:10.1056/NEJMoa2201422
Tao, K. S., Yang Z. X., Zhang X., et al. Gene-modified pig-to-human liver xenotransplantation. Nature 2025, 641, 1029–1036, doi:10.1038/s41586-025-08799-1
Zhang, X., Li X., Yang Z., et al. A review of pig liver xenotransplantation: Current problems and recent progress. Xenotransplantation 2019, 26, e12497, doi:10.1111/xen.12497
Gao, B. Basic liver immunology. Cell. Mol. Immunol. 2016, 13, 265–266, doi:10.1038/cmi.2016.09
Jenne, C. N., Kubes, P. Immune surveillance by the liver. Nat. Immunol. 2013, 14, 996–1006, doi:10.1038/ni.2691
Thorgersen, E. B., Barratt-Due A., Haugaa H., et al. The Role of Complement in Liver Injury, Regeneration, and Transplantation. Hepatology 2019, 70, 725–736, doi:10.1002/hep.30508
Cross-Najafi, A. A., Lopez K., Isidan A., et al. Current Barriers to Clinical Liver Xenotransplantation. Front. Immunol. 2022, 13, 827535, doi:10.3389/fimmu.2022.827535
Deng, S., Zhang, Y., Shen, S., et al. Immunometabolism of Liver Xenotransplantation and Prospective Solutions. Adv. Sci. (Weinh) 2025, 12, e2407610, doi:10.1002/advs.202407610
Sykes, M. Developing pig-to-human organ transplants. Science 2022, 378, 135–136, doi:10.1126/science.abo7935
Morticelli, L., Rossdam C., Cajic S., et al. Genetic knockout of porcine GGTA1 or CMAH/GGTA1 is associated with the emergence of neo-glycans. Xenotransplantation 2023, 30, e12804, doi:10.1111/xen.12804
Fang, B., Wang C., Yuan Y., et al. Generation and characterization of genetically modified pigs with GGTA1/beta4GalNT2/CMAH knockout and human CD55/CD47 expression for xenotransfusion studies. Sci. Rep. 2024, 14, 29870, doi:10.1038/s41598-024-81730-2
Byrne, G., Ahmad-Villiers, S., Du, Z., et al. B4GALNT2 and xenotransplantation: A newly appreciated xenogeneic antigen. Xenotransplantation 2018, 25, e12394, doi:10.1111/xen.12394
Yoon, S., Lee S., Park C., et al. An Efficacious Transgenic Strategy for Triple Knockout of Xeno-Reactive Antigen Genes GGTA1, CMAH, and B4GALNT2 from Jeju Native Pigs. Vaccines (Basel) 2022, 10, 1503, doi:10.3390/vaccines10091503
Mallapaty, S. First pig liver transplanted into a person lasts for 10 days. Nature 2024, 627, 710–711, doi:10.1038/d41586-024-00853-8
Mallapaty, S. First pig-to-human liver transplant recipient 'doing very well'. Nature 2024, 630, 18. doi:10.1038/d41586-024-01613-4
Ekser, B., Burlak C., Waldman J. P., et al. Immunobiology of liver xenotransplantation. Expert Rev. Clin. Immunol. 2012, 8, 621–634, doi:10.1586/eci.12.56
Connolly, M. R., Kuravi K., Burdorf L., et al. Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models. Xenotransplantation 2021, 28, e12712, doi:10.1111/xen.12712
Gaca, J. G., Lesher A., Aksoy O., et al. The role of the porcine von Willebrand factor: baboon platelet interactions in pulmonary xenotransplantation. Transplantation 2002, 74, 1596–1603, doi:10.1097/00007890-200212150-00018
Burlak, C., Paris L. L., Chihara R. K., et al. The fate of human platelets perfused through the pig liver: implications for xenotransplantation. Xenotransplantation 2010, 17, 350–361, doi:10.1111/j.1399-3089.2010.00605.x
Peng, Q., Yeh H., Wei L., et al. Mechanisms of xenogeneic baboon platelet aggregation and phagocytosis by porcine liver sinusoidal endothelial cells. PloS One 2012, 7, e47273, doi:10.1371/journal.pone.0047273
Platt, J. L., Holzknecht, Z. E. Porcine platelet antigens recognized by human xenoreactive natural antibodies. Transplantation 1994, 57, 327–335, doi:10.1097/00007890-199402150-00003
Royo, T., Vidal, M., Badimon, L. Porcine platelet von Willebrand antigen II (vW AgII): inhibitory effect on collagen-induced aggregation and comparative distribution with human platelets. Thromb. Haemost 1998, 80, 677–685
Shah, J. A., Navarro-Alvarez N., DeFazio M., et al. A Bridge to Somewhere: 25-day Survival After Pig-to-Baboon Liver Xenotransplantation. Ann. Surg. 2016, 263, 1069–1071, doi:10.1097/sla.0000000000001659
Jiang, Y., Que, W., Zhu, P. et al. The Role of Diverse Liver Cells in Liver Transplantation Tolerance. Front. Immunol. 2020, 11, 1203, doi:10.3389/fimmu.2020.01203
Poisson, J., Lemoinne S., Boulanger C., et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J. Hepatol. 2017, 66, 212–227, doi:10.1016/j.jhep.2016.07.009
Paris, L. L., Chihara R. K., Reyes L. M., et al. ASGR1 expressed by porcine enriched liver sinusoidal endothelial cells mediates human platelet phagocytosis in vitro. Xenotransplantation 2011, 18, 245–251, doi:10.1111/j.1399-3089.2011.00639.x
Chihara, R. K., Paris L. L., Reyes L. M., et al. Primary porcine Kupffer cell phagocytosis of human platelets involves the CD18 receptor. Transplantation 2011, 92, 739–744, doi:10.1097/TP.0b013e31822bc986
Cowan, P. J., Robson, S. C. Progress towards overcoming coagulopathy and hemostatic dysfunction associated with xenotransplantation. Int. J. Surg. 2015, 23, 296–300, doi:10.1016/j.ijsu.2015.07.682
Ekser, B., Lin C. C., Long C., et al. Potential factors influencing the development of thrombocytopenia and consumptive coagulopathy after genetically modified pig liver xenotransplantation. Transpl. Int. 2012, 25, 882–896, doi:10.1111/j.1432-2277.2012.01506.x
Huai, G., Wang Y., Du J., et al. The generation and evaluation of TKO/hCD55/hTM/hEPCR gene-modified pigs for clinical organ xenotransplantation. Front. Immunol. 2024, 15, 1488552, doi:10.3389/fimmu.2024.1488552
Miura, S., Habibabady Z. A., Pollok F., et al. Effects of human TFPI and CD47 expression and selectin and integrin inhibition during GalTKO.hCD46 pig lung perfusion with human blood. Xenotransplantation 2022, 29, e12725, doi:10.1111/xen.12725
Cowan, P. J., Robson, S. C., d'Apice, A. J. Controlling coagulation dysregulation in xenotransplantation. Curr. Opin. Organ Transplant. 2011, 16, 214–221, doi:10.1097/MOT.0b013e3283446c65
Rubinstein, J., Lane, A., Luebbering, N., et al. CD40 Ligand Levels in Pediatric Cohorts Correlate with Baseline Platelet Count and Transplant-Associated Mortality but Not with Endothelial Injury. Biology of Blood and Marrow Transplantation 2019, 25, S133–S134, doi:10.1016/j.bbmt.2018.12.420
Ji, H., Li X., Yue S., et al. Pig BMSCs Transfected with Human TFPI Combat Species Incompatibility and Regulate the Human TF Pathway in Vitro and in a Rodent Model. Cell. Physiol. Biochem. 2015, 36, 233–249, doi:10.1159/000374067
Ide, K., Wang H., Tahara H., et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc. Natl. Acad. Sci. U S A. 2007, 104, 5062–5066, doi:10.1073/pnas.0609661104
Linares-Cervantes, I., Echeverri J., Cleland S., et al. Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts. Am. J. Transplant. 2019, 19, 2991–3005, doi:10.1111/ajt.15395
Liu, Q., Nassar A., Farias K., et al. Comparing Normothermic Machine Perfusion Preservation With Different Perfusates on Porcine Livers From DonorsAfter Circulatory Death. Am. J. Transplant. 2016, 16, 794–807, doi:10.1111/ajt.13546
Bond, A., Bruno, V., Johnson, J., et al. Development and Preliminary Testing of Porcine Blood-Derived Endothelial-like Cells for Vascular Tissue Engineering Applications: Protocol Optimisation and Seeding of Decellularised Human Saphenous Veins. Int. J. Mol. Sci. 2022, 23, 6633, doi:10.3390/ijms23126633
Goto, T., Noguchi Y., Linares I., et al. Indocyanine green fluorescence quantification during normothermic ex situ perfusion for the assessment of porcine liver grafts after circulatory death. Liver Transpl. 2024, 30, 907–917, doi:10.1097/lvt.0000000000000416
Roozen, E. A., Lomme, R. M., Calon, N. U., et al. Validity of a novel ex vivo porcine liver perfusion model for studying haemostatic products. Lab. Anim. 2023, 57, 319– 331, doi:10.1177/00236772221138398
Becker, D. Hefti M., Schuler M. J., et al. Model Assisted Analysis of the Hepatic Arterial Buffer Response During Ex Vivo Porcine Liver Perfusion. IEEE transactions on bio-medical engineering 2020, 67, 667–678, doi:10.1109/tbme.2019.2919413
Ekser, B., Markmann, J. F., Tector, A. J. Current status of pig liver xenotransplantation. Int. J. Surg. 2015, 23, 240– 246, doi:10.1016/j.ijsu.2015.06.083
Mohiuddin, M. M., Singh A. K., Corcoran P. C., et al. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nat. Commun. 2016, 7, 11138, doi:10.1038/ncomms11138
Längin, M., Mayr T., Reichart B., et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 2018, 564, 430–433, doi:10.1038/s41586-018-0765-z
Mohiuddin, M. M., Goerlich C. E., Singh A. K., et al. Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months. Xenotransplantation 2022, 29, e12744, doi:10.1111/xen.12744
Eisenson, D. L., Hisadome, Y., Yamada, K. Progress in Xenotransplantation: Immunologic Barriers, Advances in Gene Editing, and Successful Tolerance Induction Strategies in Pig-To-Primate Transplantation. Front. Immunol. 2022, 13, 899657, doi:10.3389/fimmu.2022.899657
Tseng, Y. L., Kuwaki K., Dor F. J., et al. alpha1,3- Galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation 2005, 80, 1493–1500, doi:10.1097/01.tp.0000181397.41143.fa
Burdorf, L., Gao Z., Riner A., et al. Expression of human thrombomodulin by GalTKO.hCD46 pigs modulates coagulation cascade activation by endothelial cells and during ex vivo lung perfusion with human blood. 2023, 30, e12828, doi:10.1111/xen.12828
Goerlich, C. E., Kaczorowski D., Singh A., et al. Human Thrombomodulin Transgene Expression Prevents Intracardiac Thrombus in Life Supporting Pig-to-Baboon Cardiac Xenotransplantation. The Journal of Heart and Lung Transplantation 2020, 39, S145, doi:10.1016/j.healun.2020.01.1069
Perrin, S., Magill, M. The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis. Front. Immunol. 2022, 13, 861471, doi:10.3389/fimmu.2022.861471
Bender, M., Abicht J. M., Reichart B., et al. Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation. Biomedicines 2024, 12, 1927, doi:10.3390/biomedicines12081927
Griffith, B. P., Grazioli A., Singh A. K., et al. Transplantation of a genetically modified porcine heart into a live human. Nat. Med. 2025, 31, 589–598, doi:10.1038/s41591-024-03429-1
Fu, R., Fang M., Xu K., et al. Generation of GGTA1-/- β2M-/-CIITA-/- Pigs Using CRISPR/Cas9 Technology to Alleviate Xenogeneic Immune Reactions. Transplantation 2010, 104, 1566–1573, doi:10.1097/tp.0000000000003205
Phelps, C. J., Koike C., Vaught T. D., et al. Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 2003, 299, 411–414, doi:10.1126/science.1078942
Petersen, B., Frenzel A., Lucas-Hahn A., et al. Efficient production of biallelic GGTA1 knockout pigs by cytoplasmic microinjection of CRISPR/Cas9 into zygotes. Xenotransplantation 2016, 23, 338–346, doi:10.1111/xen.12258
Ierino, F. L., Sandrin, M. S. Spectrum of the early xenograft response: from hyperacute rejection to delayed xenograft injury. Crit. Rev. Immunol. 2007, 27, 153–166, doi:10.1615/critrevimmunol.v27.i2.30
Chaban, R., McGrath G., Habibabady Z., et al. Increased human complement pathway regulatory protein gene dose is associated with increased endothelial expression and prolonged survival during ex-vivo perfusion of GTKO pig lungs with human blood. Xenotransplantation 2023, 30, e12812, doi:10.1111/xen.12812
Milusev, A., Ren J., Despont A., et al. Glycocalyx dynamics and the inflammatory response of genetically modified porcine endothelial cells. Xenotransplantation 2023, 30, e12820, doi:10.1111/xen.12820
Ramackers, W., Rataj D., Werwitzke S., et al. Expression of human thrombomodulin on porcine endothelial cells can reduce platelet aggregation but did not reduce activation of complement or endothelium - an experimental study. Transpl. Int. 2020, 33, 437–449, doi:10.1111/tri.13573
Burdorf, L., Laird C. T., Harris D. G., et al. Pig-to-baboon lung xenotransplantation: Extended survival with targeted genetic modifications and pharmacologic treatments. Am. J. Transplant. 2022, 22, 28–45, doi:10.1111/ajt.16809
Lee, K. F., Lu B., Roussel J. C., et al. Protective effects of transgenic human endothelial protein C receptor expression in murine models of transplantation. Am. J. Transplant. 2012, 12, 2363–2372, doi:10.1111/j.1600-6143.2012.04122.x
Dwyer, K. M., Robson S. C., Nandurkar H. H., et al. Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation. J. Clin. Invest. 2004, 113, 1440–1446, doi:10.1172/jci19560
Espié, P., He Y., Koo P., et al. First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am. J. Transplant. 2020, 20, 463–473, doi:10.1111/ajt.15661
Choi, H. J., Lee J.J., Kim D.H., et al. Blockade of CD40-CD154 costimulatory pathway promotes long-term survival of full-thickness porcine corneal grafts in nonhuman primates: clinically applicable xenocorneal transplantation. Am. J. Transplant. 2015, 15, 628–641, doi:10.1111/ajt.13057
Pengam, S., Durand J., Usal C., et al. SIRPα/CD47 axis controls the maintenance of transplant tolerance sustained by myeloid-derived suppressor cells. Am. J. Transplant. 2019, 19, 3263–3275, doi:10.1111/ajt.15497
Schneider, M. K, Seebach, J. D. Current cellular innate immune hurdles in pig-to-primate xenotransplantation. Curr. Opin. Organ Transplant. 2008, 13, 171–177, doi:10.1097/MOT.0b013e3282f88a30
Goerlich, C. E., Griffith B. P., Shah A., et al. A Standardized Approach to Orthotopic (Life-supporting) Porcine Cardiac Xenotransplantation in a Nonhuman Primate Model. Transplantation 2023, 107, 1718–1728, doi:10.1097/tp.0000000000004508
Längin, M., Bender, M., Schmoeckel, M., et al. Progress in Orthotopic Pig Heart Transplantation in Nonhuman Primates. Transpl. Int. 2024, 37, 13607, doi:10.3389/ti.2024.13607
Garry, D. J., Weiner, J. I., Greising, S. M., et al. Cardiac Xenotransplantation: Clinical Impact of Science and Discovery. Circulation 2022, 146, 961–963, doi:10.1161/circulationaha.122.059191
Stalder, M., Tye T., Lam T. T., et al. Improved assessment of graft function by echocardiography in cynomolgus monkey recipients of hDAF-transgenic pig cardiac xenografts. J. Heart Lung Transplant. 2005, 24, 215–221, doi:10.1016/j.healun.2003.09.041
Mohiuddin, M. M., Singh A. K., Scobie L., et al. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report. Lancet 2023, 402, 397–410, doi:10.1016/s0140-6736(23)00775-4
Olymbios, M., Kwiecinski, J., Berman, D. S. et al. Imaging in Heart Transplant Patients. JACC. Cardiovasc. Imaging 2018, 11, 1514–1530, doi:10.1016/j.jcmg.2018.06.019
Mastrobuoni, S., Dell'aquila A. M., Arraiza M., et al. Allograft morphology and function in heart transplant recipients surviving more than 15 years by magnetic resonance imaging and dual-source computed tomography. Eur. J. Cardiothorac. Surg. 2011, 40, e62– 66, doi:10.1016/j.ejcts.2011.02.055
Londoño, M. C., Souza L. N., Lozano J. J., et al. Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients. J. Hepatol. 2018, 69, 626–634, doi:10.1016/j.jhep.2018.04.012
Sablik, K. A., Jordanova, E. S., Pocorni, N., et al. Immune Cell Infiltrate in Chronic-Active Antibody-Mediated Rejection. Front. Immunol. 2019, 10, 3106, doi:10.3389/fimmu.2019.03106
Cadili, A., Kneteman, N. The role of macrophages in xenograft rejection. Transplant. Proc. 2008, 40, 3289– 3293, doi:10.1016/j.transproceed.2008.08.125
Fox, A., Mountford, J., Braakhuis, A., et al. Innate and adaptive immune responses to nonvascular xenografts: evidence that macrophages are direct effectors of xenograft rejection. J. Immunol. 2001, 166, 2133–2140, doi:10.4049/jimmunol.166.3.2133
Hu, M., Hawthorne, W. J., Yi, S., et al. Cellular Immune Responses in Islet Xenograft Rejection. Front. Immunol. 2022, 13, 893985, doi:10.3389/fimmu.2022.893985
Cooper, D. K. C., Ekser, B., Tector, A. J. Immunobiological barriers to xenotransplantation. Int. J. Surg. 2015, 23, 211–216, doi:10.1016/j.ijsu.2015.06.068
Matter-Reissmann, U. B., Forte P., Schneider M. K., et al. Xenogeneic human NK cytotoxicity against porcine endothelial cells is perforin/granzyme B dependent and not inhibited by Bcl-2 overexpression. Xenotransplantation 2002, 9, 325–337, doi:10.1034/j.1399-3089.2002.01074.x
Puga Yung, G., Schneider, M. K. J., Seebach, J. D. The Role of NK Cells in Pig-to-Human Xenotransplantation. J. Immunol. Res. 2017, 2017, 4627384, doi:10.1155/2017/4627384
Cross-Najafi, A. A., Farag K., Isidan A., et al. Co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells attenuates human NK cell-mediated degranulation. Front. Immunol. 2023, 14, 1217809, doi:10.3389/fimmu.2023.1217809
Lilienfeld, B. G., Crew, M. D., Forte, P., et al. Transgenic expression of HLA-E single chain trimer protects porcine endothelial cells against human natural killer cell-mediated cytotoxicity. Xenotransplantation 2007, 14, 126–134, doi:10.1111/j.1399-3089.2007.00378.x
Anderson, D. J., Jones-Carr M., Perry J., et al. Genetically Modified Porcine Kidneys Have Sufficient Tissue Integrity for Use in Pig-to-Human Xenotransplantation. Ann. Surg. 2024, 280, 374–382, doi:10.1097/sla.0000000000006380
Kawai, T., Williams W. W., Elias N., et al. Xenotransplantation of a Porcine Kidney for End-Stage Kidney Disease. The New England journal of medicine 2025, 392, 1933–1940, doi:10.1056/NEJMoa2412747
Sykes, M., Griesemer, A. D. Transplantation tolerance in nonhuman primates and humans. Bone Marrow Transplant. 2019, 54, 815–821, doi:10.1038/s41409-019-0620-3
Sykes, M., Sachs, D. H. Progress in xenotransplantation: overcoming immune barriers. Nat. Rev. Nephrol. 2022, 18, 745–761, doi:10.1038/s41581-022-00624-6
Cheung, M. D., Asiimwe R., Erman E. N., et al. Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant. Nat. Commun. 2024, 15, 3140, doi:10.1038/s41467-024-47454-7
Locke, J. E., Kumar, V., Anderson, D. et al. Normal Graft Function After Pig-to-Human Kidney Xenotransplant. JAMA Surg. 2023, 158, 1106–1108, doi:10.1001/jamasurg.2023.2774
Firl, D. J., Markmann, J. F. Measuring success in pig to non-human-primate renal xenotransplantation: Systematic review and comparative outcomes analysis of 1051 life-sustaining NHP renal allo- and xeno-transplants. Am. J. Transplant. 2022, 22, 1527–1536, doi:10.1111/ajt.16994
Manook, M., Olaso D., Anwar I., et al. Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig. Sci. Transl. Med. 2024, 16, eadk6152, doi:10.1126/scitranslmed.adk6152
Pintore, L., Paltrinieri S., Vadori M., et al. Clinicopathological findings in non-human primate recipients of porcine renal xenografts: quantitative and qualitative evaluation of proteinuria. Xenotransplantation 2013, 20, 449–457, doi:10.1111/xen.12063
Cozzi, E., Bhatti F., Schmoeckel M., et al. Long-term survival of nonhuman primates receiving life-supporting transgenic porcine kidney xenografts. Transplantation 2000, 70, 15–21
Kim, S. C., Mathews D. V., Breeden C. P., et al. Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion. Am. J. Transplant. 2019, 19, 2174–2185, doi:10.1111/ajt.15329
Iwase, H., Klein, E. C., Cooper, D. K. Physiologic Aspects of Pig Kidney Transplantation in Nonhuman Primates. Comp. Med. 2018, 68, 332–340, doi:10.30802/aalas-cm-17-000117
Foote, J. B., Jagdale A., Yamamoto T., et al. Histopathology of pig kidney grafts with/without expression of the carbohydrate Neu5Gc in immunosuppressed baboons. Xenotransplantation 2021, 28, e12715, doi:10.1111/xen.12715
Aoyagi, T., Yamashita K., Suzuki T., et al. A human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys: induction and maintenance therapy. Am. J. Transplant. 2009, 9, 1732– 1741, doi:10.1111/j.1600-6143.2009.02693.x
Garcia, B., Sun H. T., Yang H. J., et al. Xenotransplantation of human decay accelerating factor transgenic porcine kidney to non-human primates: 4 years experience at a Canadian center. Transplant. Proc. 2004, 36, 1714–1716, doi:10.1016/j.transproceed.2004.06.018
Allison, A. C., Eugui, E. M. Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 2005, 80, S181–190, doi:10.1097/01.tp.0000186390.10150.66
Naganuma, Y., Maeda M., Nakamura K., et al. Impacts of dosing and drug withdrawal period on tacrolimus-based triple therapy in a non-human primate renal transplantation model. Transpl. Immunol. 2022, 75, 101704, doi:10.1016/j.trim.2022.101704
Cowan, P. J., Cooper, D. K., d'Apice, A. J. Kidney xenotransplantation. Kidney international 2014, 85, 265– 275, doi:10.1038/ki.2013.381
Kinoshita, K., Maenaka A., Rosales I. A., et al. Novel factors potentially initiating acute antibody-mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen. Xenotransplantation 2024, 31, e12859, doi:10.1111/xen.12859
Habibabady, Z., McGrath G., Kinoshita K., et al. Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed? Xenotransplantation 2023, 30, e12816, doi:10.1111/xen.12816
Zheng, J., Guo H., Gong H. L., et al. Donor-specific antibodies, glomerulitis, and human leukocyte antigen B eplet mismatch are risk factors for peritubular capillary C4d deposition in renal allografts. Chin. Med. J. (Engl). 2021, 134, 2874–2881, doi:10.1097/cm9.0000000000001685
Böhmig, G. A., Exner M., Habicht A., et al. Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury. J. Am. Soc. Nephrol. 2002, 13, 1091–1099, doi:10.1681/asn.V1341091
Shimizu, A., Yamada, K., Robson, S. C., et al. Pathologic characteristics of transplanted kidney xenografts. J. Am. Soc. Nephrol. 2012, 23, 225–235, doi:10.1681/asn.2011040429
Ladowski, J. M., Tector M., Martens G., et al. Late graft failure of pig-to-rhesus renal xenografts has features of glomerulopathy and recipients have anti-swine leukocyte antigen class I and class II antibodies. Xenotransplantation 2024, 31, e12862, doi:10.1111/xen.12862
Cimeno, A., Kuravi K., Sorrells L., et al. hEPCR.hTBM.hCD47.hHO-1 with donor clodronate and DDAVP treatment improves perfusion and function of GalTKO.hCD46 porcine livers perfused with human blood. Xenotransplantation 2022, 29, e12731, doi:10.1111/xen.12731
Shimizu, A., Yamada K., Yamamoto S., et al. Thrombotic microangiopathic glomerulopathy in human decay accelerating factor-transgenic swine-to-baboon kidney xenografts. J. Am. Soc. Nephrol. 2005, 16, 2732–2745, doi:10.1681/asn.2004121148
Takeuchi, K., Ariyoshi Y., Shimizu A., et al. Expression of human CD47 in pig glomeruli prevents proteinuria and prolongs graft survival following pig-to-baboon xenotransplantation. Xenotransplantation 2021, 28, e12708, doi:10.1111/xen.12708
Ko, N., Shim J., Kim H. J., et al. A desirable transgenic strategy using GGTA1 endogenous promoter-mediated knock-in for xenotransplantation model. Sci. Rep. 2022, 12, 9611, doi:10.1038/s41598-022-13536-z
Butler, J. R., Martens G. R., Li P., et al. The fate of human platelets exposed to porcine renal endothelium: a single-pass model of platelet uptake in domestic and genetically modified porcine organs. J. Surg. Res. 2016, 200, 698– 706, doi:10.1016/j.jss.2015.08.034
Nghiem, D. D. Technical Considerations in the Pig-To-Human Kidney Xenotransplant: A Historical Perspective. Transplant. Proc. 2024, 56, 721–722, doi:10.1016/j.transproceed.2024.01.018
Bolignano, D., Donato V., Coppolino G., et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am. J. Kidney. Dis. 2008, 52, 595–605, doi:10.1053/j.ajkd.2008.01.020
Clerico, A., Galli, C., Fortunato, A., et al. Neutrophil gelatinase-associated lipocalin (NGAL) as biomarker of acute kidney injury: a review of the laboratory characteristics and clinical evidences. Clin. Chem. Lab. Med. 2012, 50, 1505–1517, doi:10.1515/cclm-2011-0814
Kielar, M., Dumnicka P., Gala-Błądzińska A., et al. Urinary NGAL Measured after the First Year Post Kidney Transplantation Predicts Changes in Glomerular Filtration over One-Year Follow-Up. J. Clin. Med. 2020, 10, 43, doi:10.3390/jcm10010043
Makris, K., Markou N., Evodia E., et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of acute kidney injury in critically ill multiple trauma patients. Clin. Chem. Lab. Med. 2009, 47, 79–82, doi:10.1515/cclm.2009.004
Heyne, N., Kemmner S., Schneider C., et al. Urinary neutrophil gelatinase-associated lipocalin accurately detects acute allograft rejection among other causes of acute kidney injury in renal allograft recipients. Transplantation 2012, 93, 1252–1257, doi:10.1097/TP.0b013e31824fd892
Kanter, J., Beltran S., Molina D., et al. Urinary neutrophil gelatinase-associated lipocalin after kidney transplantation: is it a good biomarker to assess delayed graft function? Transplant. Proc. 2013, 45, 1368–1370, doi:10.1016/j.transproceed.2013.01.019
Abdulhadi, T., Alrata L., Dubrawka C., et al. Donor-derived cell free DNA as a biomarker in kidney transplantation. Pharmacogenomics 2023, 24, 771–780, doi:10.2217/pgs-2023-0138
Aubert, O., Ursule-Dufait C., Brousse R., et al. Cell-free DNA for the detection of kidney allograft rejection. Nat. Med. 2024, 30, 2320–2327, doi:10.1038/s41591-024-03087-3
Stites, E., Kumar D., Olaitan O., et al. High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury. Am. J. Transplant. 2020, 20, 2491–2498, doi:10.1111/ajt.15822
Oellerich, M., Sherwood K., Keown P., et al. Liquid biopsies: donor-derived cell-free DNAfor the detection of kidney allograft injury. Nat. Rev. Nephrol. 2021, 17, 591– 603, doi:10.1038/s41581-021-00428-0
Oellerich, M., Shipkova M., Asendorf T., et al. Absolute quantification of donor-derived cell-free DNAas a marker of rejection and graft injury in kidney transplantation: Results from a prospective observational study. Am. J. Transplant. 2019, 19, 3087–3099, doi:10.1111/ajt.15416
Ghonge, N. P., Goyal, N., Vohra, S. et al. Renal transplant evaluation: multimodality imaging of post-transplant complications. Br. J. Radiol. 2021, 94, 20201253, doi:10.1259/bjr.20201253
Sugi, M. D., Joshi, G., Maddu, K. K., et al. Imaging of Renal Transplant Complications throughout the Life of the Allograft: Comprehensive Multimodality Review. Radiographics 2019, 39, 1327–1355, doi:10.1148/rg.2019190096
Fernández, T., Sebastià C., Paño B., et al. Contrast-enhanced US in Renal Transplant Complications: Overview and Imaging Features. Radiographics 2024, 44, e230182, doi:10.1148/rg.230182
Sharfuddin, A. Renal relevant radiology: imaging in kidney transplantation. Clin. J. Am. Soc. Nephrol. 2014, 9, 416–429, doi:10.2215/cjn.02960313
Danobeitia, J. S., Zens T. J., Chlebeck P. J., et al. Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation. Am. J. Transplant. 2020, 20, 1513–1526, doi:10.1111/ajt.15777
Kervella, D., Le Bas-Bernardet, S., Bruneau, S., et al. Protection of transplants against antibody-mediated injuries: from xenotransplantation to allogeneic transplantation, mechanisms and therapeutic insights. Front. Immunol. 2022, 13, 932242, doi:10.3389/fimmu.2022.932242
Ezzelarab, M. B., Cooper, D. K. C. Systemic inflammation in xenograft recipients (SIXR): A new paradigm in pig-to-primate xenotransplantation? Int. J. Surg. 2015, 23, 301–305, doi:10.1016/j.ijsu.2015.07.643
Stewart, A. G., Fishman, J. A. Surveillance and prevention of infection in clinical xenotransplantation. Clin. Microbiol. Rev. 2025, 38, e0015023, doi:10.1128/cmr.00150-23
Yamada, K., Tasaki M., Sekijima M., et al. Porcine cytomegalovirus infection is associated with early rejection of kidney grafts in a pig to baboon xenotransplantation model. Transplantation 2014, 98, 411–418, doi:10.1097/tp.0000000000000232
Briski, O., La Motta G. E., Ratner L. D., et al. Comparison of ICSI, IVF, and in vivo derived embryos to produce CRISPR-Cas9 gene-edited pigs for xenotransplantation. Theriogenology 2024, 220, 43–55, doi:10.1016/j.theriogenology.2024.02.028
Beaton, B. P., Kwon D. N., Choi Y. J., et al. Inclusion of homologous DNA in nuclease-mediated gene targeting facilitates a higher incidence of bi-allelically modified cells. Xenotransplantation 2015, 22, 379–390, doi:10.1111/xen.12194
Kang, J. T., Kwon D. K., Park A. R., et al. Production of α1,3-galactosyltransferase targeted pigs using transcription activator-like effector nuclease-mediated genome editing technology. J. Vet. Sci. 2016, 17, 89–96, doi:10.4142/jvs.2016.17.1.89
Yilmaz, S., Sahin, T., Saglam, K. What Are the Immune Obstacles to Liver Xenotransplantation Which Is Promising for Patients with Hepatocellular Carcinoma? J. Gastrointest. Cancer 2020, 51, 1209–1214, doi:10.1007/s12029-020-00495-9
Wang, Y., Chen G., Pan D., et al. Pig-to-human kidney xenotransplants using genetically modified minipigs. Cell Rep. Med. 2024, 5, 101744, doi:10.1016/j.xcrm.2024.101744
Duca, M., Malagolini, N., Dall'Olio, F. The story of the Sd(a) antigen and of its cognate enzyme B4GALNT2: What is new? Glycoconj. J. 2023, 40, 123–133, doi:10.1007/s10719-022-10089-1
Martens, G. R., Reyes, L. M., Butler, J. R., et al. Humoral Reactivity of Renal Transplant-Waitlisted Patients to Cells From GGTA1/CMAH/B4GalNT2, and SLA Class I Knockout Pigs. Transplantation 2017, 101, e86–e92, doi:10.1097/tp.0000000000001646
Fischer, K., Rieblinger B., Hein R., et al. Viable pigs after simultaneous inactivation of porcine MHC class I and three xenoreactive antigen genes GGTA1, CMAH and B4GALNT2. Xenotransplantation 2020, 27, e12560, doi:10.1111/xen.12560
Song, M., Fitch Z. W., Samy K. P., et al. Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation. Xenotransplantation 2021, 28, e12680, doi:10.1111/xen.12680
Ramírez, P., Montoya M. J., Ríos A., et al. Prevention of hyperacute rejection in a model of orthotopic liver xenotransplantation from pig to baboon using polytransgenic pig livers (CD55, CD59, and H-transferase). Transplant. Proc. 2005, 37, 4103–4106, doi:10.1016/j.transproceed.2005.09.186
Le Bas-Bernardet, S., Tillou X., Poirier N., et al. Xenotransplantation of galactosyl-transferase knockout, CD55, CD59, CD39, and fucosyl-transferase transgenic pig kidneys into baboons. Transplant. Proc. 2011, 43, 3426–3430, doi:10.1016/j.transproceed.2011.09.024
Cooper, D. K., Ezzelarab M. B., Hara H., et al. The pathobiology of pig-to-primate xenotransplantation: a historical review. Xenotransplantation 2016, 23, 83–105, doi:10.1111/xen.12219
Maeda, A., Kogata S., Toyama C., et al. The Innate Cellular Immune Response in Xenotransplantation. Front. Immunol. 2022, 13, 858604, doi:10.3389/fimmu.2022.858604
Gollackner, B., Goh S. K., Qawi I., et al. Acute vascular rejection of xenografts: roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activity. Transplantation 2004, 77, 1735–1741, doi:10.1097/01.tp.0000131167.21930.b8
Ramsoondar, J. J., Macháty Z., Costa C., et al. Production of alpha 1,3-galactosyltransferase-knockout cloned pigs expressing human alpha 1,2-fucosylosyltransferase. Biol. Reprod. 2003, 69, 437–445, doi:10.1095/biolreprod.102.014647
Candinas, D., Belliveau S., Koyamada N., et al. T cell independence of macrophage and natural killer cell infiltration, cytokine production, and endothelial activation during delayed xenograft rejection. Transplantation 1996, 62, 1920–1927, doi:10.1097/00007890-199612270-00042
Lee, J. H., Lee H. J., Nahm K. M., et al. Effects of combined expression of human complement regulatory proteins and H-transferase on the inhibition of complement-mediated cytolysis in porcine embryonic fibroblasts. Transplant. Proc. 2006, 38, 1618–1621, doi:10.1016/j.transproceed.2006.02.129
Bennet, W., Björkland A., Sundberg B., et al. Expression of complement regulatory proteins on islets of Langerhans: a comparison between human islets and islets isolated from normal and hDAF transgenic pigs. Transplantation 2001, 72, 312–319, doi:10.1097/00007890-200107270-00026
Cowan, P. J., d'Apice, A. J. The coagulation barrier in xenotransplantation: incompatibilities and strategies to overcome them. Curr. Opin. Organ Transplant. 2008, 13, 178–183, doi:10.1097/MOT.0b013e3282f63c74
Zidan, A., El-Sherbini, A. H., Noureldin, A., et al. Characterizing coagulation responses in humans and nonhuman primates following kidney xenotransplantation-A narrative review. Am. J. Hematol. 2025, 100, 285–295, doi:10.1002/ajh.27506
Bühler, L., Basker M., Alwayn I. P., et al. Coagulation and thrombotic disorders associated with pig organ and hematopoietic cell transplantation in nonhuman primates. Transplantation 2000, 70, 1323–1331, doi:10.1097/00007890-200011150-00010
Cooper, D. K. C., Hara H., Iwase H., et al. Justification of specific genetic modifications in pigs for clinical organ xenotransplantation. Xenotransplantation 2019, 26, e12516, doi:10.1111/xen.12516
Wuensch, A., Baehr A., Bongoni A. K., et al. Regulatory sequences of the porcine THBD gene facilitate endothelial-specific expression of bioactive human thrombomodulin in single- and multitransgenic pigs. Transplantation 2014, 97, 138–147, doi:10.1097/TP.0b013e3182a95cbc
Tena, A., Kurtz J., Leonard D. A., et al. Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation. Am. J. Transplant. 2014, 14, 2713–2722, doi:10.1111/ajt.12918
Matlung, H. L., Szilagyi, K., Barclay, N. A., et al. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol. Rev. 2017, 276, 145–164, doi:10.1111/imr.12527
Maeda, A., Lo P. C., Sakai R., et al. A Strategy for Suppressing Macrophage-mediated Rejection in Xenotransplantation. Transplantation 2020, 104, 675– 681, doi:10.1097/tp.0000000000003024
Zhang, R., Wang Y., Chen L., et al. Reducing immunoreactivity of porcine bioprosthetic heart valves by genetically-deleting three major glycan antigens, GGTA1/β4GalNT2/CMAH. Acta Biomater. 2018, 72, 196–205, doi:10.1016/j.actbio.2018.03.055
Milland, J., Christiansen D., Lazarus B. D., et al. The molecular basis for galalpha(1,3)gal expression in animals with a deletion of the alpha1,3galactosyltransferase gene. J. Immunol. 2006, 176, 2448–2454, doi:10.4049/jimmunol.176.4.2448
Peri, S., Kulkarni, A., Feyertag, F., et al. Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc. Genome Biol. Evol. 2018, 10, 207– 219, doi:10.1093/gbe/evx251
Shim, J., Ko N., Kim H. J., et al. Human immune reactivity of GGTA1/CMAH/A3GALT2 triple knockout Yucatan miniature pigs. Transgenic Res. 2021, 30, 619– 634, doi:10.1007/s11248-021-00271-w
Ma, D., Hirose T., Lassiter G., et al. Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques. Am. J. Transplant. 2022, 22, 46–57, doi:10.1111/ajt.16780
Meehan, S. M., Kremer J., Ali F. N., et al. Thrombotic microangiopathy and peritubular capillary C4d expression in renal allograft biopsies. Clin. J. Am. Soc. Nephrol. 2011, 6, 395–403, doi:10.2215/cjn.05870710
Lu, T. Y., Xu X. L., Du X. G., et al. Advances in Innate Immunity to Overcome Immune Rejection during Xenotransplantation. Cells 2022, 11, 3865, doi:10.3390/cells11233865
Griesemer, A., Yamada, K., Sykes, M. Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol. Rev. 2014, 258, 241– 258, doi:10.1111/imr.12152
Fecke, W., Long, J., Richards, A., et al. Protection of hDAF-transgenic porcine endothelial cells against activation by human complement: role of the membrane attack complex. Xenotransplantation 2002, 9, 97–105, doi:10.1034/j.1399-3089.2002.1o012.x
Bongoni, A. K., Lu B., Salvaris E. J., et al. Overexpression of Human CD55 and CD59 or Treatment with Human CD55 Protects against Renal Ischemia-Reperfusion Injury in Mice. J. Immunol. 2017, 198, 4837–4845, doi:10.4049/jimmunol.1601943
Dalmasso, A. P., Benson, B. A., Johnson, J. S., et al. Resistance against the membrane attack complex of complement induced in porcine endothelial cells with a Gal alpha(1-3)Gal binding lectin: up-regulation of CD59 expression. J. Immunol. 2000, 164, 3764–3773, doi:10.4049/jimmunol.164.7.3764
Lin, C. C., Cooper, D. K., Dorling, A. Coagulation dysregulation as a barrier to xenotransplantation in the primate. Transpl. Immunol. 2009, 21, 75–80, doi:10.1016/j.trim.2008.10.008
Siegel, J. B., Grey S. T., Lesnikoski B. A., et al. Xenogeneic endothelial cells activate human prothrombin. Transplantation 1997, 64, 888–896, doi:10.1097/00007890-199709270-00017
Salvaris, E. J., Moran C. J., Roussel J. C., et al. Pig endothelial protein C receptor is functionally compatible with the human protein C pathway. Xenotransplantation 2020, 27, e12557, doi:10.1111/xen.12557
Budorf, L., Rybak, E., Zhang, T., et al. Human EPCR Expression in GalTKO.hCD46 Lungs Extends Survival Time and Lowers PVR in a Xenogenic Lung Perfusion Model. J. Heart Lung Transplant. 2013, 32, S137, doi:10.1016/j.healun.2013.01.307
Qawi, I., Robson, S. C. New developments in anti-platelet therapies: potential use of CD39/vascular ATP diphosphohydrolase in thrombotic disorders. Curr. Drug Targets. 2000, 1, 285–296
Akinleye A., Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J. Hematol. Oncol. 2019, 12, 92, doi:10.1186/s13045-019-0779-5
Iyer R. F., Verweij M. C., Nair S. S., et al. CD8(+) T cell targeting of tumor antigens presented by HLA-E. Sci. Adv. 2024, 10, eadm7515, doi:10.1126/sciadv.adm7515
Liu X., Song J., Zhang H., et al. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer Cell 2023, 41, 272–287, doi:10.1016/j.ccell.2023.01.001
Fisher, J. G., Doyle, A. D. P., Graham, L. V., et al. Disruption of the NKG2A:HLA-E Immune Checkpoint Axis to Enhance NK Cell Activation against Cancer. Vaccines 2022, 10, 1993, doi:10.3390/vaccines10121993
Dammeijer F., van Gulijk M., Mulder E. E., et al. The PD- 1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes. Cancer Cell 2020, 38, 685–700, doi:10.1016/j.ccell.2020.09.001
Yi, M., Zheng X., Niu M., et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol. Cancer 2022, 21, 28, doi:10.1186/s12943-021-01489-2
Li, S., Zou, D. "Please don't lyse me": Programmed cell death ligand-1 expression on neonatal islet cells promotes xenotransplant acceptance. Am. J. Transplant. 2024, 24, 1093–1094, doi:10.1016/j.ajt.2024.02.002
Waffarn E. E., Khosravi-Maharlooei M., Vecchione A., et al. Mixed xenogeneic porcine chimerism tolerizes human anti-pig natural antibody-producing cells in a humanized mouse model. Xenotransplantation 2021, 28, e12691, doi:10.1111/xen.12691
Forte P., Baumann B. C., Weiss E. H., et al. HLA-E expression on porcine cells: protection from human NK cytotoxicity depends on peptide loading. Am. J. Transplant. 2005, 5, 2085–2093, doi:10.1111/j.1600-6143.2005.00987.x
Ding, Q., Lu, L., Zhou, X., et al. Human PD-L1-overexpressing porcine vascular endothelial cells induce functionally suppressive human CD4+CD25hiFoxp3+ Treg cells. J. Leukoc. Biol. 2011, 90, 77–86, doi:10.1189/jlb.1210691
Ma, D., Hirose T., Lassiter G., et al. Kidney transplantation from triple‐knockout pigs expressing multiple human proteins in cynomolgus macaques. Am. J. Transplant. 2022, 22, 46–57
Iwase, H., Hara H., Ezzelarab M., et al. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation 2017, 24, e12293, doi:10.1111/xen.12293
Denner, J. Porcine Endogenous Retroviruses and Xenotransplantation, 2021. Viruses 2021, 13, 2156, doi:10.3390/v13112156
Quereda, J. J., Herrero-Medrano J. M., Abellaneda J. M., et al. Porcine endogenous retrovirus copy number in different pig breeds is not related to genetic diversity. Zoonoses Public Health 2012, 59, 401–407, doi:10.1111/j.1863-2378.2012.01467.x
Specke, V., Rubant, S., Denner, J. Productive infection of human primary cells and cell lines with porcine endogenous retroviruses. Virology 2001, 285, 177–180, doi:10.1006/viro.2001.0934
Fishman, J. A. Assessment of infectious risk in clinical xenotransplantation: the lessons for clinical allotransplantation. Xenotransplantation 2014, 21, 307– 308, doi:10.1111/xen.12118
Chung, H. C., Nguyen, V. G., Moon, H. J., et al. Regulation of porcine endogenous retrovirus by dual LTR1+2 (Long Terminal Region) miRNA in primary porcine kidney cells. J. Vet. Sci. 2019, 20, e50, doi:10.4142/jvs.2019.20.e50
Denner, J. Risk of pathogenic virus transmission by somatic cell nuclear transfer: implications for xenotransplantation. Biol. Reprod. 2022, 107, 717–722, doi:10.1093/biolre/ioac120
Yue, Y., Xu W., Kan Y., et al. Extensive germline genome engineering in pigs. Nat. Biomed. Eng. 2021, 5, 134–143, doi:10.1038/s41551-020-00613-9
Güell, M., Niu D., Kan Y., et al. PERV inactivation is necessary to guarantee absence of pig-to-patient PERVs transmission in xenotransplantation. Xenotransplantation 2017, 24, e12366, doi:10.1111/xen.12366
Güell, M. Genome-Wide PERV Inactivation in Pigs Using CRISPR/Cas9. Methods Mol. Biol. 2020, 2110, 139–149, doi:10.1007/978-1-0716-0255-3_10
Ma, D. H., Sasaki, H., Hirose, T., et al. Successful Long-Term TMA- and Rejection-Free Survival of a Kidney Xenograft with Triple Xenoantigen Knockout Plus Insertion of Multiple Human Transgenes. Available online: https://atcmeetingabstracts.com/abstract/successful-long-term-tma-and-rejection-free-survival-of-a-kidney-xenograft-with-triple-xenoantigen-knockout-plus-insertion-of-multiple-human-transgenes/ (accessed on 22 July 2025)
Egerer, S., Fiebig U., Kessler B., et al. Early weaning completely eliminates porcine cytomegalovirus from a newly established pig donor facility for xenotransplantation. Xenotransplantation 2018, 25, e12449, doi:10.1111/xen.12449
Denner, J. Virus Safety of Xenotransplantation. Viruses 2022, 14, 1926, doi:10.3390/v14091926
Xi, J., Zheng W., Chen M., et al. Genetically engineered pigs for xenotransplantation: Hopes and challenges. Front. Cell Dev. Biol. 2022, 10, 1093534, doi:10.3389/fcell.2022.1093534
Anand, R. P., Layer J. V., Heja D., et al. Design and testing of a humanized porcine donor for xenotransplantation. Nature 2023, 622, 393–401, doi:10.1038/s41586-023-06594-4
Yang, L., Güell M., Niu D., et al. Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science 2015, 350, 1101–1104, doi:10.1126/science.aad1191
Yuan, Y., Cui Y., Zhao D., et al. Complement networks in gene-edited pig xenotransplantation: enhancing transplant success and addressing organ shortage. J. Transl. Med. 2024, 22, 324, doi:10.1186/s12967-024-05136-4
Wolf, E., Kemter, E., Klymiuk, N., et al. Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation. Anim. Front. 2019, 9, 13–20, doi:10.1093/af/vfz014
Oriol, R., Ye, Y., Koren, E., et al. Carbohydrate antigens of pig tissues reacting with human natural antibodies as potential targets for hyperacute vascular rejection in pig-to-man organ xenotransplantation. Transplantation 1993, 56, 1433–1442, doi:10.1097/00007890-199312000-00031
Lu, J., Kishore, U. C1 Complex:An Adaptable Proteolytic Module for Complement and Non-Complement Functions. Front. Immunol. 2017, 8, 592, doi:10.3389/fimmu.2017.00592
Rollins, S. A., Matis, L. A., Springhorn, J. P., et al. Monoclonal antibodies directed against human C5 and C8 block complement-mediated damage of xenogeneic cells and organs. Transplantation 1995, 60, 1284–1292
Wright, K., Dziuk, R., Mital, P., et al. Xenotransplanted Pig Sertoli Cells Inhibit Both the Alternative and Classical Pathways of Complement-Mediated Cell Lysis While Pig Islets Are Killed. Cell Transplant. 2016, 25, 2027–2040, doi:10.3727/096368916x692032
Boksa, M., Zeyland, J., Słomski, R., et al. Immune modulation in xenotransplantation. Arch. Immunol. Ther. Exp. (Warsz) 2015, 63, 181–192, doi:10.1007/s00005-014-0317-7
Ghebremariam, Y. T., Smith, S. A., Anderson, J. B., et al. Intervention strategies and agents mediating the prevention of xenorejection. Ann. N. Y. Acad. Sci. 2005, 1056, 123–143, doi:10.1196/annals.1352.028
Tomasi, R., Tariq M., Hübner M., et al. T-Cell Response in a Cardiac Xenotransplant Model. Exp. Clin. Transplant. 2021, 19, 708–716, doi:10.6002/ect.2020.0359
Bishop, G. A., Hostager, B. S. The CD40-CD154 interaction in B cell-T cell liaisons. Cytokine Growth Factor Rev. 2003, 14, 297–309, doi:10.1016/s1359-6101(03)00024-8
Laman, J. D., Claassen, E., Noelle, R. J. Functions of CD40 and Its Ligand, gp39 (CD40L). Crit. Rev. Immunol. 2017, 37, 371–420, doi:10.1615/CritRevImmunol.v37.i2-6.100
Elster, E. A., Xu H., Tadaki D. K., et al. Treatment with the humanized CD154-specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates. Transplantation 2001, 72, 1473– 1478, doi:10.1097/00007890-200111150-00001
Miura, S., Habibabady Z. A., Pollok F., et al. TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival. Am. J. Transplant. 2023, 23, 1182–1193, doi:10.1016/j.ajt.2023.03.025
Michaels, A. J., Stoppato, M., Flores, W. J., et al. Anti-CD40 antibody 2C10 binds to a conformational epitope at the CD40-CD154 interface that is conserved among primate species. Am. J. Transplant. 2020, 20, 298–305, doi:10.1111/ajt.15574
Iwase, H., Liu H., Wijkstrom M., et al. Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date. Xenotransplantation 2015, 22, 302–309, doi:10.1111/xen.12174
Badell, I. R., La Muraglia G. M. 2nd, Liu D., et al. Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig. Am. J. Transplant. 2018, 18, 89–101, doi:10.1111/ajt.14400
Latek, R., Fleener C., Lamian V., et al. Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation. Transplantation 2009, 87, 926–933, doi:10.1097/TP.0b013e31819b5a58
Oura, T., Hotta K., Rosales I., et al. Addition of Anti-CD40 Monoclonal Antibody to Nonmyeloablative Conditioning With Belatacept Abrogated Allograft Tolerance Despite Induction of Mixed Chimerism. Transplantation 2019, 103, 168–176, doi:10.1097/TP.0000000000002417
Dalle, J.-H., Menezes, J., Wagner, E., et al. Anti-Thymocyte Globulin Increases Dramatically Natural Killer Cell Interferon Gamma Production While Respecting Other Functionnal Aspects of These Cells. Blood 2004, 104, 4957, doi:10.1182/blood.V104.11.4957.4957
Ruzek, M. C., Neff K. S., Luong M., et al. In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. Transplantation 2009, 88, 170–179, doi:10.1097/TP.0b013e3181abc061
Scott, L. J., McKeage, K., Keam, S. J., et al. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003, 63, 1247–1297, doi:10.2165/00003495-200363120-00006
Tian, M., Lv Y., Zhai C., et al. Alternative immunomodulatory strategies for xenotransplantation: CD80/CD86-CTLA4 pathway-modified immature dendritic cells promote xenograft survival. PloS One 2013, 8, e69640, doi:10.1371/journal.pone.0069640
Lan, P., Wang L., Diouf B., et al. Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism. Blood 2004, 103, 3964–3969, doi:10.1182/blood-2003-10-3697
Arce-Sillas, A., Álvarez-Luquín D. D., Tamaya-Domínguez B., et al. Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation. J. Immunol. Res. 2016, 2016, 1720827, doi:10.1155/2016/1720827
Li, X. C., Turka, L. A. An update on regulatory T cells in transplant tolerance and rejection. Nat. Rev. Nephrol. 2010, 6, 577–583, doi:10.1038/nrneph.2010.101
Wang, L., Wang Z., Han R., et al. Donor bone-marrow CXCR4+ Foxp3+ T-regulatory cells are essential for costimulation blockade-induced long-term survival of murine limb transplants. Sci. Rep. 2020, 10, 9292, doi:10.1038/s41598-020-66139-x
Podestà, M. A., Remuzzi, G., Casiraghi, F. Mesenchymal Stromal Cells for Transplant Tolerance. Front. Immunol. 2019, 10, 1287, doi:10.3389/fimmu.2019.01287