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Open Access 11-05-2024 | Heart Transplantation | Review Article

How should cardiac xenotransplantation be initiated in Japan?

Authors: Shunsuke Saito, Shuji Miyagawa, Takuji Kawamura, Daisuke Yoshioka, Masashi Kawamura, Ai Kawamura, Yusuke Misumi, Takura Taguchi, Takashi Yamauchi, Shigeru Miyagawa

Published in: Surgery Today

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Abstract

The world's first clinical cardiac xenotransplantation, using a genetically engineered pig heart with 10 gene modifications, prolonged the life of a 57-year-old man with no other life-saving options, by 60 days. It is foreseeable that xenotransplantation will be introduced in clinical practice in the United States. However, little clinical or regulatory progress has been made in the field of xenotransplantation in Japan in recent years. Japan seems to be heading toward a "device lag", and the over-importation of medical devices and technology in the medical field is becoming problematic. In this review, we discuss the concept of pig-heart xenotransplantation, including the pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental heart overgrowth, as well as genetic modification strategies in pigs to prevent or minimize these problems. Moreover, we summarize the necessity for and current status of xenotransplantation worldwide, and future prospects in Japan, with the aim of initiating xenotransplantation in Japan using genetically modified pigs without a global delay. It is imperative that this study prompts the initiation of preclinical xenotransplantation research using non-human primates and leads to clinical studies.
Literature
1.
Griffith BP, Goerlich CE, Singh AK, Rothblatt M, Lau CL, Shah A, et al. Genetically modified porcine-to-human cardiac xenotransplantation. N Engl J Med. 2022;387:35–44.PubMedPubMedCentralCrossRef
2.
Montgomery RA, Stern JM, Lonze BE, Tatapudi VS, Mangiola M, Wu M, et al. Results of two cases of pig-to-human kidney xenotransplantation. N Engl J Med. 2022;386:1889–98.PubMedCrossRef
3.
Mohiuddin MM, Goerlich CE, Singh AK, Zhang T, Tatarov I, Lewis B, et al. Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months. Xenotransplantation. 2022;29: e12744.PubMedPubMedCentralCrossRef
4.
Adams AB, Lovasik BP, Faber DA, Burlak C, Breeden C, Estrada JL, et al. Anti-C5 antibody tesidolumab reduces early antibody-mediated rejection and prolongs survival in renal xenotransplantation. Ann Surg. 2021;274:473–80.PubMedCrossRef
5.
Miyagawa S, Murakami H, Takahagi Y, Nakai R, Yamada M, Murase A, et al. Remodeling of the major pig xenoantigen by N-acetylglucosaminyltransferase III in transgenic pig. J Biol Chem. 2001;276:39310–9.PubMedCrossRef
6.
Fujita T, Miyagawa S, Ezoe K, Saito T, Sato N, Takahagi Y, et al. Skin graft of double transgenic pigs of N-acetylglucosaminyltransferase III (GnT-III) and DAF (CD55) genes survived in cynomolgus monkey for 31 days. Transpl Immunol. 2004;13:259–64.PubMedCrossRef
7.
Komoda H, Miyagawa S, Omori T, Takahagi Y, Murakami H, Shigehisa T, et al. Survival of adult islet grafts from transgenic pigs with N-acetylglucosaminyltransferase-III (GnT-III) in cynomolgus monkeys. Xenotransplantation. 2005;12:209–16.PubMedCrossRef
8.
Miyagawa S, Maeda A, Toyama C, Kogata S, Okamatsu C, Yamamoto R, et al. Aspects of the complement system in new era of xenotransplantation. Front Immunol. 2022;13: 860165.PubMedPubMedCentralCrossRef
9.
Maeda A, Kogata S, Toyama C, Lo PC, Okamatsu C, Yamamoto R, et al. The innate cellular immune response in xenotransplantation. Front Immunology. 2022;13: 858604.CrossRef
10.
Murakami M, Suzuki Y, Tominaga T. Rapid globalization of medical device clinical development programs in Japan—the case of drug-eluting stents. Circ J. 2018;82:636–43.PubMedCrossRef
11.
12.
13.
Jorde UP, Saeed O, Koehl D, Morris AA, Wood KL, Meyer DM, et al. The society of thoracic surgeons interagency registry for mechanically sssisted circulatory support 2023 annual report: focus on magnetically levitated devices. Ann Thorac Surg. 2023;117:33–44.PubMedCrossRef
14.
Hsich E, Singh TP, Cherikh WS, Harhay MO, Hayes D Jr, Perch M, et al. The international thoracic organ transplant registry of the international society for heart and lung transplantation: Thirty-ninth adult heart transplantation report-2022; focus on transplant for restrictive heart disease. J Heart Lung Transplant. 2022;41:1366–75.PubMedPubMedCentralCrossRef
15.
16.
17.
18.
McNamara N, Narroway H, Williams M, Brookes J, Farag J, Cistulli D, et al. Contemporary outcomes of continuous-flow left ventricular assist devices-a systematic review. Ann Cardiothorac Surgery. 2021;10(2):186–208.CrossRef
19.
Mehra MR, Uriel N, Naka Y, Cleveland JC Jr, Yuzefpolskaya M, Salerno CT, et al. A fully magnetically levitated left ventricular assist device-Final report. N Engl J Med. 2019;380:1618–27.PubMedCrossRef
20.
Saito S, Toda K, Nakamura T, Miyagawa S, Yoshikawa Y, Hata H, et al. Rescuing patients with severe biventricular failure in the era of continuous-flow left ventricular assist device. Circ J. 2019;83:379–85.PubMedCrossRef
21.
Saito S, Sakaguchi T, Miyagawa S, Yoshikawa Y, Yamauchi T, Ueno T, et al. Biventricular support using implantable continuous-flow ventricular assist devices. J Heart Lung Transplant. 2011;30:475–8.PubMedCrossRef
22.
Saito S, Sakaguchi T, Sawa Y. Clinical report of long-term support with dual Jarvik 2000 biventricular assist device. J Heart Lung Transplant. 2011;30:845–7.PubMedCrossRef
23.
Marasco S, Simon AR, Tsui S, Schramm R, Eifert S, Hagl CM, et al. International experience using a durable, centrifugal-flow ventricular assist device for biventricular support. J Heart Lung Transplant. 2020;39:1372–9.PubMedCrossRef
24.
Farag J, Woldendorp K, McNamara N, Bannon PG, Marasco SF, Loforte A, et al. Contemporary outcomes of continuous-flow biventricular assist devices. Ann Cardiothorac Surg. 2021;10:311–28.PubMedPubMedCentralCrossRef
25.
Arabía FA, Cantor RS, Koehl DA, Kasirajan V, Gregoric I, Moriguchi JD, et al. Interagency registry for mechanically assisted circulatory support report on the total artificial heart. J Heart Lung Transplant. 2018;37:1304–12.PubMedCrossRef
26.
Miyagawa S, Sawa Y. Building a new strategy for treating heart failure using Induced Pluripotent Stem Cells. J Cardiol. 2018;72:445–8.PubMedCrossRef
27.
Miyagawa S, Kainuma S, Kawamura T, Suzuki K, Ito Y, Iseoka H, et al. Case report: Transplantation of human induced pluripotent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy. Front Cardiovasc Med. 2022;9: 950829.PubMedPubMedCentralCrossRef
28.
Liu N, Ye X, Yao B, Zhao M, Wu P, Liu G, et al. Advances in 3D bioprinting technology for cardiac tissue engineering and regeneration. Bioact Mater. 2021;6:1388–401.PubMed
29.
Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J. 1967;41:1271–4.PubMed
30.
Hardy JD, Kurrus FD, Chavez CM, Neely WA, Eraslan S, Turner MD, et al. Heart transplantation in man. Developmental studies and report of a case. JAMA. 1964;188:1132–40.PubMedCrossRef
31.
Taniguchi S, Cooper DK. Clinical xenotransplantation: past, present and future. Ann R Col Surg Engl. 1997;79:13–9.
32.
Cooley DA, Hallman GL, Bloodwell RD, Nora JJ, Leachman RD. Human heart transplantation. Experience with twelve cases. Am J Cardiol. 1968;22:804–10.PubMedCrossRef
33.
Dureau, Fradin, Gonin, Michaud, Mikaeloff. Heart and liver transplantations (in French). Lyon Med. 1969;222:585–6.
34.
Barnard CN, Wolpowitz A, Losman JG. Heterotopic cardiac transplantation with a xenograft for assistance of the left heart in cardiogenic shock after cardiopulmonary bypass. S Afr Med J. 1977;52:1035–8.PubMed
35.
Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA. 1985;254:3321–9.PubMedCrossRef
36.
Czaplicki J, Blońska B, Religa Z. The lack of hyperacute xenogeneic heart transplant rejection in a human. J Heart Lung Transplant. 1992;11:393–7.PubMed
37.
38.
39.
Reichart B, Langin M, Denner J, Schwinzer R, Cowan PJ, Wolf E. Pathways to clinical cardiac xenotransplantation. Transplantation. 2021;105:1930–43.PubMedCrossRef
40.
Lexer G, Cooper DK, Rose AG, Wicomb WN, Rees J, Keraan M, et al. Hyperacute rejection in a discordant (pig to baboon) cardiac xenograft model. J Heart Transplant. 1986;5:411–8.PubMed
41.
Rose AG, Cooper DK, Human PA, Reichenspurner H, Reichart B. Histopathology of hyperacute rejection of the heart: experimental and clinical observations in allografts and xenografts. J Heart Lung Transplant. 1991;10:223–34.PubMed
42.
Rose AG, Cooper DK. A histopathologic grading system of hyperacute (humoral, antibody-mediated) cardiac xenograft and allograft rejection. J Heart Lung Transplant. 1996;15:804–17.PubMed
43.
Rose AG, Cooper DK. Venular thrombosis is the key event in the pathogenesis of antibody-mediated cardiac rejection. Xenotransplantation. 2000;7:31–41.PubMedCrossRef
44.
Galili U, Shohet SB, Kobrin E, Stults CL, Macher BA. Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. J Biol Chem. 1988;263:17755–62.PubMedCrossRef
45.
Galili U, Mandrell RE, Hamadeh RM, Shohet SB, Griffiss JM. Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora. Infect Immun. 1988;56:1730–7.PubMedPubMedCentralCrossRef
46.
Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, et al. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci USA. 1998;95(20):11751–6.PubMedPubMedCentralCrossRef
47.
Salama A, Evanno G, Harb J, Soulillou JP. Potential deleterious role of anti-Neu5Gc antibodies in xenotransplantation. Xenotransplantation. 2015;22:85–94.PubMedCrossRef
48.
Miwa Y, Kobayashi T, Nagasaka T, Liu D, Yu M, Yokoyama I, et al. Are N-glycolylneuraminic acid (Hanganutziu-Deicher) antigens important in pig-to-human xenotransplantation? Xenotransplantation. 2004;11:247–53.PubMedCrossRef
49.
Byrne G, Ahmad-Villiers S, Du Z, McGregor C. B4GALNT2 and xenotransplantation: a newly appreciated xenogeneic antigen. Xenotransplantation. 2018;25: e12394.PubMedPubMedCentralCrossRef
50.
51.
Lo PC, Eguchi H, Sakai R, Maeda A, Kogata S, Toyama C, et al. Reactions to porcine cells with or without β4GalNT2. Transplant Proc. 2020;52:1916–8.PubMedCrossRef
52.
Komoda H, Miyagawa S, Kubo T, Kitano E, Kitamura H, Omori T, et al. A study of the xenoantigenicity of adult pig islets cells. Xenotransplantation. 2004;11:237–46.PubMedCrossRef
53.
Fukuta D, Miyagawa S, Kubo T, Matsunami K, Shirasu A, Hattori H, et al. Effect of hybrid complement regulatory proteins on xenogeneic cells. Biochem Biophys Res Commun. 2003;306:476–82.PubMedCrossRef
54.
Tanemura M, Miyagawa S, Koyota S, Koma M, Matsuda H, Tsuji S, et al. Reduction of the major swine xenoantigen, the alpha-galactosyl epitope by transfection of the alpha2,3-sialyltransferase gene. J Biol Chem. 1998;273:16421–5.PubMedCrossRef
55.
Dai Y, Vaught TD, Boone J, Chen SH, Phelps CJ, Ball S, et al. Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat Biotechnol. 2002;20:251–5.PubMedCrossRef
56.
Phelps CJ, Koike C, Vaught TD, Boone J, Wells KD, Chen SH, et al. Production of alpha 1,3-galactosyltransferase-deficient pigs. Science. 2003;299:411–4.PubMedCrossRef
57.
58.
Lutz AJ, Li P, Estrada JL, Sidner RA, Chihara RK, Downey SM, et al. Double knockout pigs deficient in N-glycolylneuraminic acid and galactose α-1,3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation. 2013;20:27–35.PubMedCrossRef
59.
Estrada JL, Martens G, Li P, Adams A, Newell KA, Ford ML, et al. Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/β4GalNT2 genes. Xenotransplantation. 2015;22:194–202.PubMedPubMedCentralCrossRef
60.
Li Q, Hara H, Banks CA, Yamamoto T, Ayares D, Mauchley DC, et al. Anti-pig antibody in infants: can a genetically engineered pig heart bridge to allotransplantation? Ann Thorac Surg. 2020;109:1268–73.PubMedCrossRef
61.
Matsunami K, Kusama T, Okura E, Shirakura R, Fukuzawa M, Miyagawa S. Involvement of position-147 for HLA-E expression. Biochem Biophys Res Commun. 2006;347:692–7.PubMedCrossRef
62.
Weiss EH, Lilienfeld BG, Müller S, Müller E, Herbach N, Kessler B, et al. HLA-E/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation. 2009;87:35–43.PubMedCrossRef
63.
Ide K, Wang H, Tahara H, Liu J, Wang X, Asahara T, et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci U S A. 2007;104:5062–6.PubMedPubMedCentralCrossRef
64.
Maeda A, Lo PC, Sakai R, Noguchi Y, Kodama T, Yoneyama T, et al. A strategy for suppressing macrophage-mediated rejection in xenotransplantation. Transplantation. 2020;104:675–81.PubMedCrossRef
65.
Esquivel EL, Maeda A, Eguchi H, Asada M, Sugiyama M, Manabe C, et al. Suppression of human macrophage-mediated cytotoxicity by transgenic swine endothelial cell expression of HLA-G. Transpl Immunol. 2015;32:109–15.PubMedCrossRef
66.
Maeda A, Kawamura T, Ueno T, Usui N, Eguchi H, Miyagawa S. The suppression of inflammatory macrophage-mediated cytotoxicity and proinflammatory cytokine production by transgenic expression of HLA-E. Transpl Immunol. 2013;29:76–81.PubMedCrossRef
67.
Sakai R, Maeda A, Choi TV, Lo PC, Jiaravuthisan P, Shabri AM, et al. Human CD200 suppresses macrophage-mediated xenogeneic cytotoxicity and phagocytosis. Surg Today. 2018;48:119–26.PubMedCrossRef
68.
Noguchi Y, Maeda A, Lo PC, Takakura C, Haneda T, Kodama T, et al. Human TIGIT on porcine aortic endothelial cells suppresses xenogeneic macrophage-mediated cytotoxicity. Immunobiology. 2019;224:605–13.PubMedCrossRef
69.
Ladowski JM, Hara H, Cooper DKC. The role of SLAs in xenotransplantation. Transplantation. 2021;105:300–7.PubMedCrossRef
70.
Hammer SE, Ho CS, Ando A, Rogel-Gaillard C, Charles M, Tector M, et al. Importance of the major histocompatibility complex (swine leukocyte antigen) in swine health and biomedical research. Annu Rev Anim Biosci. 2020;8:171–98.PubMedCrossRef
71.
Samy KP, Butler JR, Li P, Cooper DKC, Ekser B. The role of costimulation blockade in solid organ and islet xenotransplantation. J Immunol Res. 2017;2017:8415205.PubMedPubMedCentralCrossRef
72.
Mohiuddin MM, Singh AK, Corcoran PC, Thomas Iii ML, Clark T, Lewis BG, 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.PubMedPubMedCentralCrossRef
73.
Längin M, Mayr T, Reichart B, Michel S, Buchholz S, Guethoff S, et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature. 2018;564:430–3.PubMedCrossRef
74.
Cowan PJ, Robson SC. Progress towards overcoming coagulopathy and hemostatic dysfunction associated with xenotransplantation. Int J Surg. 2015;23:296–300.PubMedCrossRef
75.
Bühler L, Basker M, Alwayn IP, Goepfert C, Kitamura H, Kawai T, et al. Coagulation and thrombotic disorders associated with pig organ and hematopoietic cell transplantation in nonhuman primates. Transplantation. 2000;70:1323–31.PubMedCrossRef
76.
Shimizu A, Hisashi Y, Kuwaki K, Tseng YL, Dor FJ, Houser SL, et al. Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons. Am J Pathol. 2008;172:1471–81.PubMedPubMedCentralCrossRef
77.
Mohiuddin MM, Corcoran PC, Singh AK, Azimzadeh A, Hoyt RF Jr, Thomas ML, et al. B-cell depletion extends the survival of GTKO.hCD46Tgpig heart xenografts in baboons for up to 8 months. Am J Transplant. 2012;12:763–71.PubMedCrossRef
78.
Iwase H, Ekser B, Satyananda V, Bhama J, Hara H, Ezzelarab M, et al. Pig-to-baboon heterotopic heart transplantation–exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens. Xenotransplantation. 2015;22:211–20.PubMedPubMedCentralCrossRef
79.
Salvaris EJ, Moran CJ, Roussel JC, Fisicaro N, Robson SC, Cowan PJ. Pig endothelial protein C receptor is functionally compatible with the human protein C pathway. Xenotransplantation. 2020;27: e12557.PubMedCrossRef
80.
Oropeza M, Petersen B, Carnwath JW, Lucas-Hahn A, Lemme E, Hassel P, et al. Transgenic expression of the human A20 gene in cloned pigs provides protection against apoptotic and inflammatory stimuli. Xenotransplantation. 2009;16:522–34.PubMedCrossRef
81.
Petersen B, Ramackers W, Lucas-Hahn A, Lemme E, Hassel P, Queisser AL, et al. Transgenic expression of human heme oxygenase-1 in pigs confers resistance against xenograft rejection during ex vivo perfusion of porcine kidneys. Xenotransplantation. 2011;18:355–68.PubMedCrossRef
82.
Iwase H, Ball S, Adams K, Eyestone W, Walters A, Cooper DKC. Growth hormone receptor knockout: relevance to xenotransplantation. Xenotransplantation. 2021;28: e12652.PubMedCrossRef
83.
Hinrichs A, Riedel EO, Klymiuk N, Blutke A, Kemter E, Längin M, et al. Growth hormone receptor knockout to reduce the size of donor pigs for preclinical xenotransplantation studies. Xenotransplantation. 2021;28: e12664.PubMedCrossRef
84.
Goerlich CE, Griffith B, Hanna P, Hong SN, Ayares D, Singh AK, et al. The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors. J Thorac Cardiovasc Surg. 2023;165:e69–81.PubMedCrossRef
85.
86.
Fishman JA. Prevention of infection in xenotransplantation: Designated pathogen-free swine in the safety equation. Xenotransplantation. 2020;27: e12595.PubMedCrossRef
87.
88.
89.
Denner J, Längin M, Reichart B, Krüger L, Fiebig U, Mokelke M, et al. Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival. Sci Rep. 2020;10:17531.PubMedPubMedCentralCrossRef
90.
Mohiuddin MM, Singh AK, Scobie L, Goerlich CE, Grazioli A, Saharia K, et al. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report. Lancet. 2023;402:397–410.PubMedCrossRef
91.
Denner J. Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? Retrovirology. 2018;15:28.PubMedPubMedCentralCrossRef
92.
Wynyard S, Nathu D, Garkavenko O, Denner J, Elliott R. Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. Xenotransplantation. 2014;21:309–23.PubMedCrossRef
93.
Morozov VA, Wynyard S, Matsumoto S, Abalovich A, Denner J, Elliott R. No PERV transmission during a clinical trial of pig islet cell transplantation. Virus Res. 2017;227:34–40.PubMedCrossRef
94.
Yang L, Güell M, Niu D, George H, Lesha E, Grishin D, et al. Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science. 2015;350:1101–4.PubMedCrossRef
95.
Niu D, Wei HJ, Lin L, George H, Wang T, Lee IH, et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science. 2017;357:1303–7.PubMedPubMedCentralCrossRef
96.
Shimoda M, Matsumoto S. Update regarding xenotransplantation in Japan. Xenotransplantation. 2019;26: e12491.PubMedCrossRef
97.
Kobayashi T, Miyagawa S. Current activity of xenotransplantation in Japan. Xenotransplantation. 2019;26: e12487.PubMedCrossRef
98.
Kobayashi T. Status of Preparation for Clinical Application of Xenotransplantation (in Japanese). Jinkouzouki (Jpn J Artif Organs). 2023;52:215–20.
Metadata
Title
How should cardiac xenotransplantation be initiated in Japan?
Authors
Shunsuke Saito
Shuji Miyagawa
Takuji Kawamura
Daisuke Yoshioka
Masashi Kawamura
Ai Kawamura
Yusuke Misumi
Takura Taguchi
Takashi Yamauchi
Shigeru Miyagawa
Publication date
11-05-2024
Publisher
Springer Nature Singapore
Published in
Surgery Today
Print ISSN: 0941-1291
Electronic ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-024-02861-7