Skip to main content

Advertisement

SpringerLink
Log in

What Are the Immune Obstacles to Liver Xenotransplantation Which Is Promising for Patients with Hepatocellular Carcinoma?

  • Review Article
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Purpose

Liver transplantation is the most important achievement in the twentieth and twenty-first century. It is the gold standard treatment for hepatocellular carcinoma. However, it provides the best results when performed under strict selection criteria. Nevertheless, organ supply is overwhelmed by the number of patients on the waiting list. There are certain strategies to expand the donor pool such as split liver transplantation, use of extended criteria donors, and living donor liver transplantation. Xenotransplantation can also be a strategy in decreasing the organ shortage. We reviewed the current status of xenotransplantation.

Methods

We evaluated the historical attempts of xenotransplantation to humans and also made a summary of the preclinical studies in the field.

Results

Molecular biology and genetic engineering are developing with an incredible speed. There are great achievements made in cell therapy, 3D bioprinting of the organs, and ultimately xenotransplantation. There is a vast amount of problems to be handled before evaluating the efficacy of xenotransplantation in the treatment of hepatocellular carcinoma. Major problems include antibody-mediated rejection to antigens such as galactose ⍺1-3 galactose, N- glycolylneuraminic acid, β1,4-N-acetylgalactosaminyltransferase, lethal thrombocytopenia, and erythrocyte sequestration. Antibody mediated rejection to these specific antigens are addressed using gene editing technology including CRISPR Cas9, TALEN and other recombination methods. Although hyperacute rejection is reduced, long-term survival could not be achieved in experimental models.

Conclusion

The future is yet to come, there are developments made in the field of genetic editing, immunosuppressive medication, and pretransplant desensitization techniques. Therefore, we believe that xenotransplantation will be in clinical practice, at least for treatment of critically ill patients.

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

Data Availability

Not applicable.

Abbreviations

AFP:

Alpha fetoprotein

AMR:

Antibody-mediated rejection

ATG:

Thymoglobulin

β4GalNT2:

Acetylgalactosaminyl transferase

Gal ⍺1-3 Gal:

Galactose ⍺1-3 galactose

GPC-3:

Glypican-3

HCC:

Hepatocellular carcinoma

HIV:

Human immunodeficiency virus

hTERT:

Human telomerase reverse transcriptase

LTx:

Liver transplantation

KO:

Knockout

MAGE-A:

Melanoma antigen gene A

MDSC:

Myeloid-derived suppressor cells

NY-ESO-1 (CTAG1B):

Cancer testis antigen 1B

Neu5Gc:

N-glycolylneuraminic acid antigen

SSX-2:

Synovial sarcoma, X 2

References

  1. Zarrinpar A, Busuttil RW. Liver transplantation: past, present and future. Nat Rev Gastroenterol Hepatol. 2013;10:434–40. https://doi.org/10.1038/nrgastro.2013.88.

    Article  CAS  Google Scholar 

  2. O’Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg. 1988;207:373–9. https://doi.org/10.1097/00000658-198804000-00002.

    Article  PubMed  Google Scholar 

  3. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–9. https://doi.org/10.1056/NEJM199603143341104.

    Article  CAS  PubMed  Google Scholar 

  4. Sapisochin G, Goldaracena N, Laurence JM, Dib M, Barbas A, Ghanekar A, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: a prospective validation study. Hepatology. 2016;64:2077–88. https://doi.org/10.1002/hep.28643.

    Article  Google Scholar 

  5. Ince V, Akbulut AS, Otan E, Ersan V, Karakas S, Sahin TT, et al. Liver transplantation for hepatocellular carcinoma: Malatya experience and proposals for expanded criteria. J Gastrointest Cancer. 2020;51:998–1005. https://doi.org/10.1007/s12029-020-00424-w.

    Article  CAS  Google Scholar 

  6. Taniguchi S, Cooper DK. Clinical xenotransplantation: past, present and future. Ann R Coll Surg Engl. 1997;79:13–9.

    CAS  PubMed  Google Scholar 

  7. Starzl TE, Fung J, Tzakis A, Todo S, Demetris AJ, Marino IR, et al. Baboon-to-human liver transplantation. Lancet. 1993;341:65–71. https://doi.org/10.1016/0140-6736(93)92553-6.

    Article  CAS  PubMed  Google Scholar 

  8. Hato T, Goyal L, Greten TF, Duda DG, Zhu AX. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology. 2014;60:1776–82. https://doi.org/10.1002/hep.27246.

    Article  CAS  PubMed  Google Scholar 

  9. Shiina S, Tagawa K, Unuma T, Takanashi R, Yoshiura K, Komatsu Y, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study. Cancer. 1991;68:1530. https://doi.org/10.1002/1097-0142(19911001)68:7<1524::AID-CNCR2820680711>3.0.CO;2-O.

    Article  Google Scholar 

  10. Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatology. 1998;27:67–72. https://doi.org/10.1002/hep.510270112.

    Article  CAS  Google Scholar 

  11. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res. 2004;10:4332–41. https://doi.org/10.1158/1078-0432.CCR-04-0181.

    Article  CAS  Google Scholar 

  12. Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology. 2014;59:1415–26. https://doi.org/10.1002/hep.26731.

    Article  CAS  PubMed  Google Scholar 

  13. Rushfeldt C, Sveinbjørnsson B, Seljelid R, Smedsrød B. Early events of hepatic metastasis formation in mice: role of Kupffer and NK-cells in natural and interferon-γ-stimulated defense. J Surg Res. 1999;82:209–15. https://doi.org/10.1006/jsre.1998.5532.

    Article  CAS  Google Scholar 

  14. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93. https://doi.org/10.1200/JCO.2006.09.4565.

    Article  Google Scholar 

  15. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+CD25+Foxp3+ T cells. Gastroenterology. 2008;135:234–43. https://doi.org/10.1053/j.gastro.2008.03.020.

    Article  CAS  Google Scholar 

  16. Zimmerman MA, Ghobrial RM, Tong MJ, Hiatt JR, Cameron AM, Hong J, et al. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008;143:182–8. https://doi.org/10.1001/archsurg.2007.39.

    Article  Google Scholar 

  17. Shah JA, Navarro-Alvarez N, DeFazio M, Rosales IA, Elias N, Yeh H, et al. A bridge to somewhere: 25-day survival after pig-to-baboon liver xenotransplantation. Ann Surg. 2016;263:1069–71. https://doi.org/10.1097/SLA.0000000000001659.

    Article  Google Scholar 

  18. Kim K, Schuetz C, Elias N, Veillette GR, Wamala I, Varma M, et al. Up to 9-day survival and control of thrombocytopenia following alpha1,3-galactosyl transferase knockout swine liver xenotransplantation in baboons. Xenotransplantation. 2012;19:256–64. https://doi.org/10.1111/j.1399-3089.2012.00717.x.

    Article  PubMed  Google Scholar 

  19. Boksa M, Zeyland J, Słomski R, Lipiński D. Immune modulation in xenotransplantation. Arch Immunol Ther Exp. 2015;63:181–92. https://doi.org/10.1007/s00005-014-0317-7.

    Article  CAS  Google Scholar 

  20. Powelson J, Cosimi AB, Austen W, Bailen M, Colvin R, Gianello P, et al. Porcine-to-primate orthotopic liver transplantation. Transplant Proc. 1994;26:1353–4.

    CAS  PubMed  Google Scholar 

  21. Calne RY, White HJ, Herbertson BM, Millard PR, Davis DR, Salaman JR, et al. Pig-to-baboon liver xenografts. Lancet. 1968;291:1176–8. https://doi.org/10.1016/S0140-6736(68)91869-2.

    Article  Google Scholar 

  22. Zhang Z, Li X, Zhang H, Zhang X, Chen H, Pan D, et al. Cytokine profiles in Tibetan macaques following α-1,3-galactosyltransferase-knockout pig liver xenotransplantation. Xenotransplantation. 2017;24:1–11. https://doi.org/10.1111/xen.12321.

    Article  Google Scholar 

  23. 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. https://doi.org/10.1111/xen.12161.

    Article  PubMed  Google Scholar 

  24. 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. https://doi.org/10.1111/xen.12019.

    Article  PubMed  Google Scholar 

  25. Li P, Estrada JL, Burlak C, Montgomery J, Butler JR, Santos RM, et al. Efficient generation of genetically distinct pigs in a single pregnancy using multiplexed single-guide RNA and carbohydrate selection. Xenotransplantation. 2015;22:20–31. https://doi.org/10.1111/xen.12131.

    Article  PubMed  Google Scholar 

  26. Starzl TE, Rao AS, Murase N, Demetris AJ, Thomson A, Fung JJ. Chimerism and xenotransplantation: new concepts. Surg Clin North Am. 1999;79:191–205. https://doi.org/10.1016/S0039-6109(05)70014-1.

    Article  CAS  PubMed  Google Scholar 

  27. Makowka L, Cramer DV, Hoffman A, Breda M, Sher L, Eiras-Hreha G, et al. The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure. Transplantation. 1995;59:1654–9. https://doi.org/10.1097/00007890-199506270-00002.

    Article  Google Scholar 

  28. Zaidi A, Schmoeckel M, Bhatti F, Waterworth P, Tolan M, Cozzi E, et al. Life-supporting pig-to-primate renal xenotransplantation using genetically modified donors. Transplantation. 1998;65:1584–90. https://doi.org/10.1097/00007890-199806270-00008.

    Article  CAS  PubMed  Google Scholar 

  29. Schmoeckel M, Bhatti FNK, Zaidi A, Cozzi E, Waterworth PD, Tolan MJ, et al. Orthotopic heart transplantation in a transgenic pig-to-primate model. Transplantation. 1998;65:1570–7. https://doi.org/10.1097/00007890-199806270-00006.

    Article  CAS  PubMed  Google Scholar 

  30. Ramirez P, Chavez R, Majado M, Munitiz V, Muñoz A, Hernandez Q, et al. Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days. Transplantation. 2000;70:989–98. https://doi.org/10.1097/00007890-200010150-00001.

    Article  CAS  Google Scholar 

  31. Ramirez P, Chavez R, Majado M, Munitiz V, Muñoz A, Hernandez Q, et al. The porcine liver supports metabolic homeostasis in the nonhuman primate: experimental study in a model of orthotopic liver transplantation from h-DAF transgenic pig to baboon. Transplant Proc. 2000;32:1112–3. https://doi.org/10.1016/S0041-1345(00)01150-7.

    Article  CAS  Google Scholar 

  32. Ekser B, Long C, Echeverri GJ, Hara H, Ezzelarab M, Lin CC, et al. Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants. Am J Transplant. 2010;10:273–85. https://doi.org/10.1111/j.1600-6143.2009.02945.x.

    Article  CAS  Google Scholar 

  33. Yeh H, Machaidze Z, Wamala I, Fraser JW, Navarro-Alvarez N, Kim K, et al. Increased transfusion-free survival following auxiliary pig liver xenotransplantation. Xenotransplantation. 2014;21:454–64. https://doi.org/10.1111/xen.12111.

    Article  Google Scholar 

  34. Kolber-Simonds D, Lai L, Watt SR, Denaro M, Arn S, Augenstein ML, et al. Production of α-1,3-galactosyltransferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations. Proc Natl Acad Sci U S A. 2004;101:7335–40. https://doi.org/10.1073/pnas.0307819101.

    Article  CAS  PubMed  Google Scholar 

  35. Fu J, Zuber J, Shonts B, Obradovic A, Lau S, Waffarn E, et al. Role of graft-derived graft-versus-host T cells in facilitating multilineage blood chimerism after human intestinal transplantation. Transplantation. 2018;102:S419–20. https://doi.org/10.1097/01.tp.0000543197.33598.e5.

    Article  Google Scholar 

  36. Fung J, Rao A, Starzl T. Clinical trials and projected future of liver xenotransplantation. World J Surg. 1997;21:956–61. https://doi.org/10.1007/s002689900333.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, 244280, Malatya, Turkey

    Sezai Yilmaz, Tolga Sahin & Kutay Saglam

  2. Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km, 44280, Malatya, Turkey

    Sezai Yilmaz

Authors
  1. Sezai Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tolga Sahin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kutay Saglam
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to the manuscript.

Corresponding author

Correspondence to Sezai Yilmaz.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Code Availability

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yilmaz, S., Sahin, T. & Saglam, K. What Are the Immune Obstacles to Liver Xenotransplantation Which Is Promising for Patients with Hepatocellular Carcinoma?. J Gastrointest Canc 51, 1209–1214 (2020). https://doi.org/10.1007/s12029-020-00495-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-020-00495-9

Keywords

Search

Navigation