Skip to main content

Advertisement

SpringerLink
Log in

Porcine Islet Xenografts: a Clinical Source of ß-Cell Grafts

  • Immunology, Transplantation, and Regenerative Medicine (L Piemonti and V Sordi, Section Editors)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Diabetes is medical and social burden affecting millions around the world. Despite intensive therapy, insulin fails to maintain adequate glucose homeostasis and often results in episodes of hypoglycemic unawareness. Islet transplantation is a propitious replacement therapy, and incremental improvements in islet isolation and immunosuppressive drugs have made this procedure a feasible option. Shortage of donors, graft loss, and toxic immunosuppressive agents are few of many hurdles against making human allogenic islet transplantation a routine procedure.

Recent Findings

Xenografts—especially pig islets—offer a logical alternative source for islets. Current preclinical studies have revealed problems such as optimal islet source, zoonosis, and immune rejection. These issues are slowing clinical application.

Summary

Genetically modified pigs, encapsulation devices, and new immune-suppressive regimens can confer graft protection. In addition, extrahepatic transplant sites are showing promising results. Notwithstanding few approved clinical human trials, and available data from non-human primates, recent reports indicate that porcine islets are closer to be the promising solution to cure diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care 2016:39 Suppl 1:S22. doi: 10.2337/dc16-S005.

  2. International Diabetes Federation. IDF diabetes atlas—7th edition. IDF 2015.

  3. Beagley J, Guariguata L, Weil C, Motala AA. Global estimates of undiagnosed diabetes in adults. Diabetes Res Clin Pract. 2014;103:150. doi:10.1016/j.diabres.2013.11.001.

    Article  PubMed  Google Scholar 

  4. Da Rocha Fernandes J, Ogurtsova K, Linnenkamp U, Guariguata L, Seuring T, Zhang P. Diabetes Atlas estimates of 2014 global health expenditures on diabetes. Diabetes Res Clin Pract. 2014;2016(117):48–54. doi:10.1016/j.diabres.2016.04.016.

    Google Scholar 

  5. Orloff MJ, Yamanaka N, Greenleaf GE, Huang YT, Huang DG, Leng XS. Reversal of mesangial enlargement in rats with long-standing diabetes by whole pancreas transplantation. Diabetes. 1986;35:347–54. doi:10.2337/diabetes.35.3.347.

    Article  CAS  PubMed  Google Scholar 

  6. Kelly WB, Lillehei RC, Merkel FK, Idezuki Y, Goetz FC. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Transplantation. 1968;6:145. doi:10.1097/00007890-196801000-00034.

    Article  Google Scholar 

  7. Squifflet J, Gruessner RWG, Sutherland DER. The history of pancreas transplantation: past, present and future. Acta Chir Belg. 2008;108:367–78. doi:10.1080/00015458.2008.11680243.

    Article  PubMed  Google Scholar 

  8. Wisel SA, Braun HJ, Stock PG. Current outcomes in islet versus solid organ pancreas transplant for β-cell replacement in type 1 diabetes. Curr Opin Organ Transplant. 2016;21:399–404. doi:10.1097/MOT.0000000000000332.

    Article  CAS  PubMed  Google Scholar 

  9. Gruessner AC. 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the international pancreas transplant registry (IPTR). Rev Diabet Stud. 2011;8:6–16. doi:10.1900/RDS.2011.8.6.

    Article  PubMed  PubMed Central  Google Scholar 

  10. • Dholakia S, Oskrochi Y, Easton G, Papalois V. Advances in pancreas transplantation. J R Soc Med. 2016;109:141–6. doi:10.1177/0141076816636369. This review is very informative and demonstrates history and recent advances in pancreas transplantation.

    Article  PubMed  Google Scholar 

  11. Brendel M, Hering B, Schulz A, Bretzel R. International Islet Transplant Registry report #8. Germany, University of Giessen. 1999: 1–20.

  12. Warnock GL, Kneteman NM, Ryan E, Seelis RE, Rabinovitch A, Rajotte RV. Normoglycaemia after transplantation of freshly isolated and cryopreserved pancreatic islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1991;34:55–8. doi:10.1007/BF00404026.

    Article  CAS  PubMed  Google Scholar 

  13. Warnock GL, Kneteman NM, Ryan EA, Rabinovitch A, Rajotte RV. Long-term follow-up after transplantation of insulin-producing pancreatic islets into patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1992;35:89–95. doi:10.1007/BF00400857.

    Article  CAS  PubMed  Google Scholar 

  14. Warnock GL, Kneteman NM, Ryan EA, Evans MG, Seelis RE, Halloran PF, et al. Continued function of pancreatic islets after transplantation in type I diabetes. Lancet (London, England). 1989;2:570. doi:10.1016/S0140-6736(89)90701-0.

    Article  CAS  Google Scholar 

  15. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343:230–8. doi:10.1056/NEJM200007273430401.

    Article  CAS  PubMed  Google Scholar 

  16. Ryan EA, Lakey JR, Rajotte RV, Korbutt GS, Kin T, Imes S, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes. 2001;50:710–9. doi:10.2337/diabetes.50.4.710.

    Article  CAS  PubMed  Google Scholar 

  17. Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes. 2002;51:2148–57. doi:10.2337/diabetes.51.7.2148.

    Article  CAS  PubMed  Google Scholar 

  18. Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. Jama. 2005;293:830–5. doi:10.1001/jama.293.7.830.

    Article  CAS  PubMed  Google Scholar 

  19. Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355:1318–30. doi:10.1056/NEJMoa061267.

    Article  CAS  PubMed  Google Scholar 

  20. Warnock GL, Meloche RM, Thompson D, Shapiro RJ, Fung M, Ao Z, et al. Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus. Arch Surg. 2005;140:735–44. doi:10.1001/archsurg.140.8.735.

    Article  PubMed  Google Scholar 

  21. Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016;39:1230–40. doi:10.2337/dc15-1988.

    Article  PubMed  Google Scholar 

  22. Brennan DC, Kopetskie HA, Sayre PH, Alejandro R, Cagliero E, Shapiro AMJ, et al. Long-term follow-up of the Edmonton protocol of islet transplantation in the United States. Am J Transplant. 2016;16:509–17. doi:10.1111/ajt.13458.

    Article  CAS  PubMed  Google Scholar 

  23. World Health Organization. Statement from the xenotransplantation advisory consultation. 2005.

  24. Cooper DKC, Ekser B, Tector AJ. A brief history of clinical xenotransplantation. Int J Surg (London, England). 2015;23:205–10. doi:10.1016/j.ijsu.2015.06.060.

    Article  Google Scholar 

  25. Wright AD, Walsh CH, Fitzgerald MG, Malins JM. Very pure porcine insulin in clinical practice. British Med J. 1979;1:25–7. doi:10.1136/bmj.1.6155.25.

    Article  CAS  Google Scholar 

  26. Mykén PSU, Bech-Hansen O. A 20-year experience of 1712 patients with the biocor porcine bioprosthesis. J Thorac Cardiovasc Surg. 2009;137:76–81. doi:10.1016/j.jtcvs.2008.05.068.

    Article  PubMed  Google Scholar 

  27. Wong BS, Yamada K, Okumi M, Weiner J, O’Malley PE, Tseng YL, et al. Allosensitization does not increase the risk of xenoreactivity to alpha1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists. Transplantation. 2006;82:314–9. doi:10.1097/01.tp.0000228907.12073.0b.

    Article  CAS  PubMed  Google Scholar 

  28. Maki T, O’Neil JJ, Porter J, Mullon C, Solomon BA, Monaco AP. Porcine islets for xenotransplantation. Transplantation. 1996;62:136–8. doi:10.1097/00007890-199607150-00028.

    Article  CAS  PubMed  Google Scholar 

  29. Kirchhof N, Shibata S, Wijkstrom M, Kulick DM, Salerno CT, Clemmings SM, et al. Reversal of diabetes in non-immunosuppressed rhesus macaques by intraportal porcine islet xenografts precedes acute cellular rejection. Xenotransplantation. 2004;11:396–407. doi:10.1111/j.1399-3089.2004.00157.x.

    Article  PubMed  Google Scholar 

  30. Hårdstedt M, Finnegan CP, Kirchhof N, Hyland KA, Wijkstrom M, Murtaugh MP, et al. Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts. Xenotransplantation. 2005;12:293–302. doi:10.1111/j.1399-3089.2005.00228.x.

    Article  PubMed  Google Scholar 

  31. Hering BJ, Wijkstrom M, Graham ML, Hårdstedt M, Aasheim TC, Jie T, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med. 2006;12:301–3. doi:10.1038/nm1369.

    Article  CAS  PubMed  Google Scholar 

  32. Jin SM, Lee HS, Oh SH, Park HJ, Park JB, Kim JH, et al. Adult porcine islet isolation using a ductal preservation method and purification with a density gradient composed of histidine-tryptophan-ketoglutarate solution and iodixanol. Transplant Proc. 2014;46:1628–32. doi:10.1016/j.transproceed.2014.03.004.

    Article  CAS  PubMed  Google Scholar 

  33. Shin JS, Kim JM, Kim JS, Min BH, Kim YH, Kim HJ, et al. Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets. Am J Transplant. 2015;15:2837–50. doi:10.1111/ajt.13345.

    Article  CAS  PubMed  Google Scholar 

  34. Korbutt GS, Elliott JF, Ao Z, Smith DK, Warnock GL, Rajotte RV. Large scale isolation, growth, and function of porcine neonatal islet cells. J Clin Invest. 1996;97:2119–29. doi:10.1172/JCI118649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kin T, Korbutt GS, Kobayashi T, Dufour JM, Rajotte RV. Reversal of diabetes in pancreatectomized pigs after transplantation of neonatal porcine islets. Diabetes. 2005;54:1032–9. doi:10.2337/diabetes.54.4.1032.

    Article  CAS  PubMed  Google Scholar 

  36. Cardona K, Pearson TC, Korbutt GS, Lyon J, Milas Z, Rajotte RV, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006;12:304–6. doi:10.1038/nm1375.

    Article  CAS  PubMed  Google Scholar 

  37. Thompson P, Cardona K, Russel M, Korbutt G, Cano J, Rajotte R, et al. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant. 2011;11:947–57. doi:10.1111/j.1600-6143.2011.03509.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Emamaullee JA, Shapiro AM, Rajotte RV, Korbutt G, Elliott JF. Neonatal porcine islets exhibit natural resistance to hypoxia-induced apoptosis. Transplantation. 2006;82:945–52. doi:10.1097/01.tp.0000238677.00750.32.

    Article  PubMed  Google Scholar 

  39. Harb G, Toreson J, Dufour J, Korbutt G. Acute exposure to streptozotocin but not human proinflammatory cytokines impairs neonatal porcine islet insulin secretion in vitro but not in vivo. Xenotransplantation. 2007;14:580–90. doi:10.1111/j.1399-3089.2007.00427.x.

    Article  PubMed  Google Scholar 

  40. Kin T, Korbutt GS. Delayed functional maturation of neonatal porcine islets in recipients under strict glycemic control. Xenotransplantation. 2007;14:333–8. doi:10.1111/j.1399-3089.2007.00414.x.

    Article  PubMed  Google Scholar 

  41. Potter KJ, Abedini A, Marek P, Klimek AM, Butterworth S, Driscoll M, et al. Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts. Proc Natl Acad Sci U S A. 2010;107:4305–10. doi:10.1073/pnas.0909024107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Arefanian H, Tredget EB, Rajotte RV, Gill RG, Korbutt GS, Rayat GR. Short-term administrations of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies induce tolerance to neonatal porcine islet xenografts in mice. Diabetes. 2010;59:958–66. doi:10.2337/db09-0413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Groth CG, Tibell A, Tollemar J, Bolinder J, Östman J, Möller E, et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet. 1994;344:1402–4. doi:10.1016/S0140-6736(94)90570-3.

    Article  CAS  PubMed  Google Scholar 

  44. Reinholt FP, Hultenby K, Tibell A, Korsgren O, Groth CG. Survival of fetal porcine pancreatic islet tissue transplanted to a diabetic patient: findings by ultrastructural immunocytochemistry. Xenotransplantation. 1998;5:222–5. doi:10.1111/j.1399-3089.1998.tb00031.x.

    Article  CAS  PubMed  Google Scholar 

  45. Heneine W, Tibell A, Switzer WM, Sandstrom P, Rosales GV, Mathews A, et al. No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts. Lancet. 1998;352:695–9. doi:10.1016/S0140-6736(98)07145-1.

    Article  CAS  PubMed  Google Scholar 

  46. Tibell A, Groth CG. No viral disease after xenotransplantation. Nature. 1998;392:646. doi:10.1038/33517.

    Article  CAS  PubMed  Google Scholar 

  47. Elliott RB. Microencapsulated neonatal porcine islet implants alleviate unaware hypoglycaemia without immune suppression. In communication to 23th World Congress of IPITA. Prague, Czech Republic. 2011.

  48. Garkavenko O, Wynyard S, Nathu D, Quane T, Durbin K, Denner J, et al. The first clinical xenotransplantation trial in New Zealand: efficacy and safety. Xenotransplantation. 2012;19:6–7. doi:10.1111/j.1399-3089.2011.00680_3.x.

    Article  Google Scholar 

  49. Bennet W, Groth C, Larsson R, Nilsson B, Korsgren O. Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes. Ups J Med Sci. 2000;105:125–33. doi:10.1517/03009734000000059.

    Article  CAS  PubMed  Google Scholar 

  50. Moberg L, Johansson H, Lukinius A, Berne C, Foss A, Källen R, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002;360:2039–45. doi:10.1016/S0140-6736(02)12020-4.

    Article  CAS  PubMed  Google Scholar 

  51. Liuwantara D, Chew YV, Favaloro EJ, Hawkes JM, Burns HL, O’Connell PJ, et al. Characterizing the mechanistic pathways of the instant blood-mediated inflammatory reaction in xenogeneic neonatal islet cell transplantation. Transplant Direct. 2016;2:e77. doi:10.1097/TXD.0000000000000590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hawthorne WJ, Salvaris EJ, Phillips P, Hawkes J, Liuwantara D, Burns H, et al. Control of IBMIR in neonatal porcine islet xenotransplantation in baboons. Am J Transplant. 2014;14:1300–9. doi:10.1111/ajt.12722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vogel C, Fritzinger DC, Hew BE, Thorne M, Bammert H. Recombinant cobra venom factor. Mol Immunol. 2004;41:191–9. doi:10.1016/S0161-5890(04)00073-2.

    Article  CAS  PubMed  Google Scholar 

  54. Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B. Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes. 2002;51:1779–84. doi:10.2337/diabetes.51.6.1779.

    Article  CAS  PubMed  Google Scholar 

  55. Yonekawa Y, Matsumoto S, Okitsu T, Arata T, Iwanaga Y, Noguchi H, et al. Effective islet isolation method with extremely high islet yields from adult pigs. Cell Transplant. 2005;14:757–62. doi:10.3727/000000005783982512.

    Article  PubMed  Google Scholar 

  56. Ricordi C, Socci C, Davalli AM, Staudacher C, Baro P, Vertova A, et al. Isolation of the elusive pig islet. Surgery. 1990;107:688.

    CAS  PubMed  Google Scholar 

  57. Pepper AR, Gall C, Mazzuca DM, Melling CWJ, White DJG. Diabetic rats and mice are resistant to porcine and human insulin: flawed experimental models for testing islet xenografts. Xenotransplantation. 2009;16:502–10. doi:10.1111/j.1399-3089.2009.00548.x.

    Article  PubMed  Google Scholar 

  58. Mandel TE. Fetal islet xenotransplantation in rodents and primates. J Mol Med. 1999;77:155–60. doi:10.1007/s001090050326.

    Article  CAS  PubMed  Google Scholar 

  59. • Krishnan R, Buder B, Alexander M, Foster CE, Lakey JR. Juvenile porcine islets can restore euglycemia in diabetic athymic nude mice after xenotransplantation. Transplantation. 2015;99:710–6. doi:10.1097/TP.0000000000000667. A great recent report regarding the juvenile porcine islets and their potential benefits.

    Article  CAS  PubMed  Google Scholar 

  60. Mueller KR, Balamurugan AN, Cline GW, Pongratz RL, Hooper RL, Weegman BP, et al. Differences in glucose-stimulated insulin secretion in vitro of islets from human, nonhuman primate, and porcine origin. Xenotransplantation. 2013;20:75–81. doi:10.1111/xen.12022.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sun Y, Ma X, Zhou D, Vacek I, Sun AM. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J Clin Invest. 1996;98:1417–22. doi:10.1172/JCI118929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dufrane D, Goebbels RM, Saliez A, Guiot Y, Gianello P. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation. 2006;81:1345–53. doi:10.1097/01.tp.0000208610.75997.20.

    Article  PubMed  Google Scholar 

  63. Cardona K, Milas Z, Strobert E, Cano J, Jiang W, Safley SA, et al. Engraftment of adult porcine islet xenografts in diabetic nonhuman primates through targeting of costimulation pathways. Am J Transplant. 2007;7:2260–8. doi:10.1111/j.1600-6143.2007.01933.x.

    Article  CAS  PubMed  Google Scholar 

  64. van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C, He J, et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant. 2009;9:2716–26. doi:10.1111/j.1600-6143.2009.02850.x.

    Article  PubMed  Google Scholar 

  65. Dufrane D, Goebbels RM, Gianello P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation. 2010;90:1054–62. doi:10.1097/TP.0b013e3181f6e267.

    Article  PubMed  Google Scholar 

  66. Vériter S, Gianello P, Igarashi Y, Beaurin G, Ghyselinck A, Aouassar N, et al. Improvement of subcutaneous bioartificial pancreas vascularization and function by coencapsulation of pig islets and mesenchymal stem cells in primates. Cell Transplant. 2014;23:1349–64. doi:10.3727/096368913X663550.

    Article  PubMed  Google Scholar 

  67. Bottino R, Wijkstrom M, van der Windt DJ, Hara H, Ezzelarab M, Murase N. Pig-to-monkey islet xenotransplantation using multi-transgenic pigs. Am J Transplant. 2014;14:2275–87. doi:10.1111/ajt.12868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Elliott RB, Escobar L, Tan PLJ, Garkavenko O, Calafiore R, Basta P, et al. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc. 2005;37:3505–8. doi:10.1016/j.transproceed.2005.09.038.

    Article  CAS  PubMed  Google Scholar 

  69. Thompson P, Badell IR, Lowe M, Cano J, Song M, Leopardi F, et al. Islet xenotransplantation using Gal-deficient neonatal donors improves engraftment and function. Am J Transplant. 2011;11:2593–602. doi:10.1111/j.1600-6143.2011.03720.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thompson P, Badell IR, Lowe M, Turner A, Cano J, Avila J, et al. Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival. Am J Transplant. 2012;12:1765–75. doi:10.1111/j.1600-6143.2012.04031.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rayat GR, Rajotte RV, Elliott JF, Korbutt GS. Expression of gal alpha(1,3)gal on neonatal porcine islet beta-cells and susceptibility to human antibody/complement lysis. Diabetes. 1998;47:1406–11. doi:10.2337/diabetes.47.9.1406.

    Article  CAS  PubMed  Google Scholar 

  72. Bennet W, Bjorkland A, Sundberg B, Davies H, Liu J, Holgersson J, et al. A comparison of fetal and adult porcine islets with regard to gal (1, 3) gal expression and the role of human immunoglobulins and complement in islet cell cytotoxicity. Transplantation. 2000;69:1711–7.

    Article  CAS  PubMed  Google Scholar 

  73. Rayat GR, Rajotte RV, Hering BJ, Binette TM, Korbutt GS. In vitro and in vivo expression of galalpha-(1, 3) gal on porcine islet cells is age dependent. J Endocrinol. 2003;177:127–35. doi:10.1677/joe.0.1770127.

    Article  CAS  PubMed  Google Scholar 

  74. 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. doi:10.1126/science.1078942.

    Article  CAS  PubMed  Google Scholar 

  75. World Health Organization. Second WHO global consultation on regulatory requirements for xenotransplantation clinical trials. WHO 2011.

  76. Takeuchi Y, Patience C, Magre S, Weiss RA, Banerjee PT, Tissier PL, et al. Host range and interference studies of three classes of pig endogenous retrovirus. J Virol. 1998;72:9986–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med. 1997;3:282–6.

    Article  CAS  PubMed  Google Scholar 

  78. Specke V, Rubant S, Denner J. Productive infection of human primary cells and cell lines with porcine endogenous retroviruses. Virology. 2001;285:177–80. doi:10.1006/viro.2001.0934.

    Article  CAS  PubMed  Google Scholar 

  79. Valdes-Gonzalez RA, Dorantes LM, Garibay GN, Bracho-Blanchet E, Mendez AJ, Davila-Perez R, et al. Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. Eur J Endocrinol 2005:153:419–27. DOI: 153/3/419.

  80. Denner J. Is porcine endogenous retrovirus (PERV) transmission still relevant? Transplant Proc. 2008;40:587–9. doi:10.1016/j.transproceed.2007.12.026.

    Article  CAS  PubMed  Google Scholar 

  81. Valdes-Gonzalez R, Dorantes LM, Bracho-Blanchet E, Rodríguez-Ventura A, White DJG. No evidence of porcine endogenous retrovirus in patients with type 1 diabetes after long-term porcine islet xenotransplantation. J Med Virol. 2010;82:331–4. doi:10.1002/jmv.21655.

    Article  CAS  PubMed  Google Scholar 

  82. Cheng M. Islet xeno/transplantation and the risk of contagion: local responses from Canada and Australia to an emerging global technoscience. Life Sci Soc Policy. 2015;11:1–23. doi:10.1186/s40504-015-0030-2.

    Article  CAS  Google Scholar 

  83. Fishman JA, Scobie L, Takeuchi Y. Xenotransplantation-associated infectious risk: a WHO consultation. Xenotransplantation. 2012;19:72–81. doi:10.1111/j.1399-3089.2012.00693.x.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Chatenoud L. Chemical immunosuppression in islet transplantation: friend or foe? N Engl J Med. 2008;358:1192–3. doi:10.1056/NEJMcibr0708067.

    Article  CAS  PubMed  Google Scholar 

  85. Gala-Lopez BL, Pepper AR, Pawlick RL, O’Gorman D, Kin T, Bruni A, et al. Antiaging glycopeptide protects human islets against tacrolimus-related injury and facilitates engraftment in mice. Diabetes. 2016;65:451–62. doi:10.2337/db15-0764.

    Article  CAS  PubMed  Google Scholar 

  86. Chick WL, Perna JJ, Lauris V, Low D, Galletti PM, Panol G, et al. Artificial pancreas using living beta cells: effects on glucose homeostasis in diabetic rats. Science. 1977;197:780–2. doi:10.1126/science.407649.

    Article  CAS  PubMed  Google Scholar 

  87. Elliott RB, Escobar L, Calafiore R, Basta G, Garkavenko O, Vasconcellos A, et al. Transplantation of micro- and macroencapsulated piglet islets into mice and monkeys. Transplant Proc. 2005;37:466–9. doi:10.1016/j.transproceed.2004.12.198.

    Article  CAS  PubMed  Google Scholar 

  88. Kumagai-Braesch M, Jacobson S, Mori H, Jia X, Takahashi T, Wernerson A, et al. The TheraCyte™ device protects against islet allograft rejection in immunized hosts. Cell Transplant. 2013:22:1137. doi: 0.3727/096368912X657486.

  89. Chang TM. Semipermeable microcapsules. Science. 1964;146:524–5. doi:10.1126/science.146.3643.524.

    Article  CAS  PubMed  Google Scholar 

  90. Lim F, Sun AM. Microencapsulated islets as bioartificial endocrine pancreas. Science. 1980;210:908–10. doi:10.1126/science.6776628.

    Article  CAS  PubMed  Google Scholar 

  91. Elliott RB, Escobar L, Tan PLJ, Muzina M, Zwain S, Buchanan C. Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation. 2007;14:157–61. doi:10.1111/j.1399-3089.2007.00384.x.

    Article  PubMed  Google Scholar 

  92. Korbutt GS, Elliott JF, Ao Z, Flashner M, Warnock GL, Rajotte RV. Microencapsulation of neonatal porcine islets: long-term reversal of diabetes in nude mice and in vitro protection from human complement mediated cytolysis. Transplant Proc. 1997;29:2128. doi:10.1016/S0041-1345(97)00259-5.

    Article  CAS  PubMed  Google Scholar 

  93. Rayat GR, Rajotte RV, Ao Z, Korbutt GS. Microencapsulation of neonatal porcine islets: protection from human antibody/complement-mediated cytolysis in vitro and long-term reversal of diabetes in nude mice. Transplantation. 2000;69:1084–90.

    Article  CAS  PubMed  Google Scholar 

  94. Vegas AJ, Veiseh O, Guertler M, Millman JR, Pagliuca FW, Bader AR, et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 2016;22:306–11. doi:10.1038/nm.4030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. de Groot M, Keizer PPM, de Haan BJ, Schuurs TA, Leuvenink HGD, van Schilfgaarde R, et al. Microcapsules and their ability to protect islets against cytokine-mediated dysfunction. Transplant Proc. 2001;33:1711–2. doi:10.1016/S0041-1345(00)02653-1.

    Article  PubMed  Google Scholar 

  96. • Veiseh O, Doloff JC, Ma M, Vegas AJ, Tam HH, Bader AR, et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat Mater. 2015;14:643–51. doi:10.1038/nmat4290. An interesting report debating the old concept of minimizing the capsule size to increase oxygen diffusion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Villiger P, Ryan EA, Owen R, O’Kelly K, Oberholzer J, Saif FA, et al. Prevention of bleeding after islet transplantation: lessons learned from a multivariate analysis of 132 cases at a single institution. Am J Transplant. 2005;5:2992–8. doi:10.1111/j.1600-6143.2005.01108.x.

    Article  CAS  PubMed  Google Scholar 

  98. Bhargava R, Senior PA, Ackerman TE, Ryan EA, Paty BW, Lakey JR, et al. Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. Diabetes. 2004;53:1311–7. doi:10.2337/diabetes.53.5.1311.

    Article  CAS  PubMed  Google Scholar 

  99. Markmann JF, Rosen M, Siegelman ES, Soulen MC, Deng S, Barker CF, et al. Magnetic resonance-defined periportal steatosis following intraportal islet transplantation: a functional footprint of islet graft survival? Diabetes. 2003;52:1591–4. doi:10.2337/diabetes.52.7.1591.

    Article  CAS  PubMed  Google Scholar 

  100. Korsgren O, Lundgren T, Felldin M, Foss A, Isaksson B, Permert J, et al. Optimising islet engraftment is critical for successful clinical islet transplantation. Diabetologia. 2008;51:227–32. doi:10.1007/s00125-007-0868-9.

    Article  CAS  PubMed  Google Scholar 

  101. Buitinga M, Truckenmuller R, Engelse MA, Moroni L, Ten Hoopen HW, van Blitterswijk CA, et al. Microwell scaffolds for the extrahepatic transplantation of islets of Langerhans. PLoS One. 2013;8:e64772. doi:10.1371/journal.pone.0064772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Nyitray CE, Chavez MG, Desai T. Compliant 3D microenvironment improves β-cell cluster insulin expression through mechanosensing and β-catenin signaling. Tissue Eng A. 2014;20:1888–95. doi:10.1089/ten.tea.2013.0692.

    Article  CAS  Google Scholar 

  103. Sionov RV, Finesilver G, Sapozhnikov L, Soroker A, Zlotkin-Rivkin E, Saad Y, et al. Beta cells secrete significant and regulated levels of insulin for long periods when seeded onto acellular micro-scaffolds. Tissue Eng A. 2015;21:2691–702. doi:10.1089/ten.tea.2014.0711.

    Article  CAS  Google Scholar 

  104. Dufour JM, Rajotte RV, Zimmerman M, Rezania A, Kin T, Dixon D, et al. Development of an ectopic site for islet transplantation, using biodegradable scaffolds. Tissue Eng. 2005;11:1323–31. doi:10.1089/ten.2005.11.1323.

    Article  CAS  PubMed  Google Scholar 

  105. Ellis C, Suuronen E, Yeung T, Seeberger K, Korbutt G. Bioengineering a highly vascularized matrix for the ectopic transplantation of islets. Islets. 2013;5:216–25. doi:10.4161/isl.27175.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ellis CE, Ellis LK, Korbutt RS, Suuronen EJ, Korbutt GS. Development and characterization of a collagen-based matrix for vascularization and cell delivery. BioResearch Open Access. 2015;4:188–97. doi:10.1089/biores.2015.0007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pepper AR, Gala-Lopez B, Pawlick R, Merani S, Kin T, Shapiro AMJ. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol. 2015;33:518–23. doi:10.1038/nbt.3211.

    Article  CAS  PubMed  Google Scholar 

  108. Pepper A, Pawlick R, Bruni A, Gala-Lopez B, Wink J, Rafiei Y, et al. Harnessing the foreign body reaction in marginal mass device-less subcutaneous islet transplantation in mice. Transplantation. 2016;100:1474–9. doi:10.1097/TP.0000000000001162.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University of Alberta, 5.002 Li Ka Shing Bldg, 8602 112 Street, Edmonton, AB, T6G 2E1, Canada

    Bassem F. Salama & Gregory S. Korbutt

  2. Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada

    Bassem F. Salama & Gregory S. Korbutt

Authors
  1. Bassem F. Salama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory S. Korbutt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregory S. Korbutt.

Ethics declarations

Conflict of Interest

Bassem F. Salama and Gregory S. Korbutt declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Immunology, Transplantation, and Regenerative Medicine

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salama, B.F., Korbutt, G.S. Porcine Islet Xenografts: a Clinical Source of ß-Cell Grafts. Curr Diab Rep 17, 14 (2017). https://doi.org/10.1007/s11892-017-0846-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-017-0846-7

Keywords

Search

Navigation