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

Shah, Jigesh A.; Patel, Madhukar S.; Elias, Nahel; Navarro-Alvarez, Nalú; Rosales, Ivy A.; Wilkinson, Robert A.; Louras, Nathan; Hertl, Martin; Fishman, Jay A.; Colvin, Robert B.; Cosimi, A. Benedict; Markmann, James F.; Sachs, David H.; Vagefi, Parsia A.

doi:10.1111/ajt.14341

Cited by 87 publications

(95 citation statements)

References 27 publications

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“…With these modifications, four additional pig-to-baboon LXT experiments were performed using a continuous infusion of hPCC and immunosuppression consisting of anti-thymocyte globulin induction and maintenance therapy with FK-506, methylprednisone and either belatacept (n=3) or anti-CD40 monoclonal antibody (mAb) (n=1). (9, 10) All four recipients demonstrated a significant reduction in blood transfusion requirements post-operatively and spontaneous recovery of platelet counts beginning as early as POD 4, with peak platelet counts of 614,000 and 709,000 in the POD 25 and POD 29 surviving animals, respectively. (10) This degree of platelet count recovery was likely associated with the post-splenectomy state, with subsequent normalization of this reactive thrombocytosis in the weeks following splenectomy.…”

Section: Laboratory Experience With Liver Xenotransplantationmentioning

confidence: 92%

“…(9, 10) All four recipients demonstrated a significant reduction in blood transfusion requirements post-operatively and spontaneous recovery of platelet counts beginning as early as POD 4, with peak platelet counts of 614,000 and 709,000 in the POD 25 and POD 29 surviving animals, respectively. (10) This degree of platelet count recovery was likely associated with the post-splenectomy state, with subsequent normalization of this reactive thrombocytosis in the weeks following splenectomy.…”

Section: Laboratory Experience With Liver Xenotransplantationmentioning

confidence: 96%

“…(7) Until recently, challenges related to the consistent development of lethal coagulopathy has troubled progress in the field of pig-to-NHP LXT, however, reports suggesting prolonged survival of nearly a month have reinvigorated interest (FIGURE 1). (8–10) In this review, progress in the field of orthotopic pig-to-NHP LXT will be discussed as it pertains to laboratory developments in large animal models that have informed clinical trials which are under consideration.…”

Section: Introductionmentioning

confidence: 99%

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Liver xenotransplantation

Patel¹,

Louras

Vagefi³

2017

Current Opinion in Organ Transplantation

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Purpose of Review There continues to be inadequate organ supply, and lack of effective temporary support, for patients with liver failure. The purpose of this review is to discuss recent progress in the field of orthotopic pig-to-nonhuman primate (NHP) liver xenotransplantation (LXT). Recent Findings From 1968 to 2012, survival in pig-to-NHP LXT has been limited to 9 days, initially due to hyperacute rejection which has been ameliorated through use of genetically engineered donor organs, but ultimately due to profound thrombocytopenia, thrombotic microangiopathy (TMA), and bleeding. More recently, demise secondary to lethal coagulopathy was avoided with LXT of α(1,3)-galactosyltransferase (GT) knockout (GTKO), CMV-negative porcine xenografts into baboons receiving exogenous administration of coagulation factors and co-stimulation blockade, establishing that a porcine liver is capable of supporting NHP life for nearly a month. Summary Continued consistent achievement of pig-to-NHP LXT survival beyond two weeks justifies consideration of a clinical application as a bridge to allotransplantation for patients with acute hepatic failure. Further genetic modifications to the donor, as well as additional studies, are required in order to apply LXT as destination therapy.

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Section: Laboratory Experience With Liver Xenotransplantationmentioning

confidence: 92%

Section: Laboratory Experience With Liver Xenotransplantationmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Liver xenotransplantation

Patel¹,

Louras

Vagefi³

2017

Current Opinion in Organ Transplantation

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“…However, because of additional coagulation dysfunction, the current results of pig liver xenotransplantation in NHPs are poor in comparison with those of heart and kidney transplantation, with survival extending to approximately one month [24]. Further genetic modification of the pig is required.…”

Section: Initial Clinical Trials Of Xenotransplantationmentioning

confidence: 99%

Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation

et al. 2018

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Background: There is a continuing critical shortage of organs from deceased human donors for transplantation, particularly for patients awaiting kidney transplantation. Efforts are being made to resolve the donor kidney shortage by the transplantation of kidneys from genetically-engineered pigs. Summary: This review outlines the pathobiological barriers to pig organ xenotransplantation in primates, which include (i) antibody-dependent complement-mediated rejection, (ii) a T cell-mediated elicited antibody and cellular response, (iii) coagulation dysregulation between pigs and primates, and (iv) a persistent inflammatory response. As a result of increasing genetic manipulation of the pig and the introduction of novel immunosuppressive agents, pig kidney graft survival has increased from minutes to months, and even to >1 year in some cases. Aspects of the selection of the patients for a first clinical trial are discussed. Although there would appear to be some cross-reactivity between anti-human leukocyte antigen (HLA) antibodies and swine leukocyte antigens expressed in pigs, some HLA-sensitized patients will be at no disadvantage if they receive a pig kidney. Furthermore, the current limited evidence is that, even if the patient becomes sensitized to pig antigens (after a pig organ transplant), this would not be detrimental to a subsequent allotransplant. The potential risk of infection with a pig microorganism, and the function of a pig kidney in a primate are also discussed. Key Message: The recent encouraging results of pig kidney transplantation in nonhuman primates suggest the likelihood of a successful (and safe) initial clinical trial, with graft survival for months or possibly years.

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“…The Boston group increased survival to 29 days by the exogenous administration of human coagulation factors using the same model [26]. They reported two GTKO pig liver xenografts that survived >25 days (longest 29 days) (Figure 2), with immunosuppressive therapy consisting of anti-CD40mAb or belatacept [27]. Although there remain problems with this regimen, clinical trials of bridging to allotransplantation with a pig liver graft might become a possibility [28].…”

Section: Introductionmentioning

confidence: 99%

Xenotransplantation

Ekser

Li²,

Cooper³

2017

Current Opinion in Organ Transplantation

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Purpose of review To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. Recent findings Starting from early 2000, with the introduction of Gal-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to nonGal antigens continue to be the hurdle to overcome. The production of genetically-engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently CRISPR technology made the production of genetically-engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached >900 days, >400 days, and >600 day, respectively. The availability of multiple-gene pigs (5 or 6 genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus. Summary Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

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

Cited by 87 publications

References 27 publications

Liver xenotransplantation

Liver xenotransplantation

Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation

Xenotransplantation

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