Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade

J. A. Shah, M. S. Patel, N. Elias, N. Navarro-Alvarez, I. Rosales, R. A. Wilkinson, N. J. Louras, M. Hertl, J. A. Fishman, R. B. Colvin, A. B. Cosimi, J. F. Markmann, D. H. Sachs, P. A. Vagefi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti–thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

Original languageEnglish (US)
Pages (from-to)2178-2185
Number of pages8
JournalAmerican Journal of Transplantation
Volume17
Issue number8
DOIs
StatePublished - Aug 2017
Externally publishedYes

Fingerprint

Heterologous Transplantation
Blood Coagulation Factors
Papio
Liver Function Tests
Primates
Swine
Euthanasia
Survival
Liver
Pathology
Thrombotic Microangiopathies
Foot Ulcer
Galactosyltransferases
Antilymphocyte Serum
Acute Liver Failure
Cholestasis
Tacrolimus
Cytomegalovirus
Immunosuppression
Seizures

Keywords

  • basic (laboratory) research/science
  • coagulation and hemostasis
  • fusion proteins and monoclonal antibodies: costimulation molecule specific
  • graft survival
  • immunosuppressant
  • immunosuppressive regimens
  • xenotransplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade. / Shah, J. A.; Patel, M. S.; Elias, N.; Navarro-Alvarez, N.; Rosales, I.; Wilkinson, R. A.; Louras, N. J.; Hertl, M.; Fishman, J. A.; Colvin, R. B.; Cosimi, A. B.; Markmann, J. F.; Sachs, D. H.; Vagefi, P. A.

In: American Journal of Transplantation, Vol. 17, No. 8, 08.2017, p. 2178-2185.

Research output: Contribution to journalArticle

Shah, JA, Patel, MS, Elias, N, Navarro-Alvarez, N, Rosales, I, Wilkinson, RA, Louras, NJ, Hertl, M, Fishman, JA, Colvin, RB, Cosimi, AB, Markmann, JF, Sachs, DH & Vagefi, PA 2017, 'Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade', American Journal of Transplantation, vol. 17, no. 8, pp. 2178-2185. https://doi.org/10.1111/ajt.14341
Shah, J. A. ; Patel, M. S. ; Elias, N. ; Navarro-Alvarez, N. ; Rosales, I. ; Wilkinson, R. A. ; Louras, N. J. ; Hertl, M. ; Fishman, J. A. ; Colvin, R. B. ; Cosimi, A. B. ; Markmann, J. F. ; Sachs, D. H. ; Vagefi, P. A. / Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade. In: American Journal of Transplantation. 2017 ; Vol. 17, No. 8. pp. 2178-2185.
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abstract = "Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti–thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.",
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