A Bridge to Somewhere

Shah, Jigesh A.; Navarro-Alvarez, Nalú; Defazio, Matthew W.; Rosales, Ivy A.; Elias, Nahel; Yeh, Heidi; Colvin, Robert B.; Cosimi, A. Benedict; Markmann, James F.; Hertl, Martin; Sachs, David H.; Vagefi, Parsia A.

doi:10.1097/sla.0000000000001659

Cited by 51 publications

(34 citation statements)

References 7 publications

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“…Baboon recipients of galactose-α(1,3)-galactose knockout (GalT-KO) miniature swine livers showed spontaneous resolution of initial thrombocytopenia, markedly decreased transfusion requirements and avoidance of TMA (4). Although survival was initially limited to 7-days with this protocol, the addition of co-stimulation blockade to the protocol appeared to improve LXT survival from 9-days to 25-days in a single recipient (5). Here we present our experience using this protocol in a series of four pig-to-baboon LXT experiments.…”

Section: Introductionmentioning

confidence: 99%

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

Shah

Patel

Elias

et al. 2017

American Journal of Transplantation

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Since the first attempt in 1968, survival following pig-to-primate liver xenotransplantation (LXT) has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous post-transplant infusion of human prothrombin concentrate complex and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone and co-stimulation blockade (belatacept, n=3 or anti-CD40mAb, n=1) to extend survival. Baboon #1 remained well until POD25 when euthanasia was required due to cholestasis and plantar ulcers. Baboon #2 was euthanized following a seizure on POD5, despite normal LFTs and no apparent pathology. Baboon # 3 demonstrated initial stable liver function, but was euthanized on POD8 due to worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis and a focal CMV inclusion. Baboon # 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations as well as rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation or TMA. Thus, nearly one-month rejection-free survival has been achieved following LXT in 2 of 4 continuous recipients, demonstrating that the porcine liver can support life in primates for several weeks and is encouraging for potential clinical application of LXT as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

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Section: Introductionmentioning

confidence: 99%

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

Shah

Patel

Elias

et al. 2017

American Journal of Transplantation

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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%

“…(8, 9) This emphasizes that a NHP can be maintained with the hepatic metabolism of a porcine liver, and holds promise at this early stage for consideration of initial clinical application of LXT as a bridge to allotransplantation in patients with acute hepatic failure.…”

Section: Laboratory Experience With Liver Xenotransplantationmentioning

confidence: 99%

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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“…The most recent report 27 documented 25-day survival of a GTKO pig liver graft in a baboon treated with a human prothrombinase concentrate complex. Immunosuppressive therapy included induction with antithymocyte globulin and cobra venom factor, with maintenance with belatacept, tacrolimus, and methylprednisolone.…”

Section: Introductionmentioning

confidence: 99%

“…Although it requires native splenectomy, the Xi’an technique has the advantage that none of the native liver needs to be excised as the graft fits comfortably into the splenic fossa. (Ekser et al 17 , Navarro-Alvarez et al 26 , Yeh et al 25 , and Shah et al 27 all performed splenectomy in order to reduce thrombocytopenia. However, whether splenectomy is immunologically beneficial to the outcome is uncertain, but there was no definitive evidence for this in the early studies of pig heart or kidney xenotransplantation [reviewed in 29 .…”

Section: Introductionmentioning

confidence: 99%

Pig Liver Xenotransplantation

et al. 2016

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Experience with clinical liver xenotransplantation has largely involved the transplantation of livers from nonhuman primates. Experience with pig livers has been scarce. This brief review will be restricted to assessing the potential therapeutic impact of pig liver xenotransplantation in acute liver failure and the remaining barriers that currently do not justify clinical trials. A relatively new surgical technique of heterotopic pig liver xenotransplantation is described that might play a role in bridging a patient with acute liver failure until either the native liver recovers or a suitable liver allograft is obtained. Other topics discussed include the possible mechanisms for the development of the thrombocytopenis that rapidly occurs after pig liver xenotransplantation in a primate, the impact of pig complement on graft injury, the potential infectious risks, and potential physiologic incompatibilities between pig and human. There is cautious optimism that all of these problems can be overcome by judicious genetic manipulation of the pig. If liver graft survival could be achieved in the absence of thrombocytopenia or rejection for a period of even a few days, there may be a role for pig liver transplantation as a bridge to allotransplantation in carefully selected patients.

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A Bridge to Somewhere

Cited by 51 publications

References 7 publications

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

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

Liver xenotransplantation

Pig Liver Xenotransplantation

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