Mechanisms of Injury in Porcine Livers Perfused With Blood of Patients With Fulminant Hepatic Failure

Collins, Bradley H.; Chari, Ravi S.; Magee, John C.; Harland, Robert C.; Lindman, Bonnie J.; Logan, John S.; Bollinger, R. Randal; Meyers, William C.; Platt, Jeffrey L.

doi:10.1097/00007890-199412000-00004

Cited by 21 publications

(36 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, acute vascular rejection is seen when the complement system is inhibited, a condition in which hyperacute vascular rejection is never seen. Based on these considerations, as well as the concept that the histologic features shared by hyperacute and acute vascular rejection can be seen in non-immunologic conditions (Busch et al 1975, Cerra et al 1977, Collins et al 1994a, we proposed that the pathogenesis of acute vascular rejection differs from the pathogenesis of hyperacute rejection. If hyperacute rejection can be characterized by a global loss of endothelial functions, acute vascular rejection is probably best characterized as a lesion arising as a consequence of the acquisition of new endothelial functions.…”

Section: Pathophysiology Of Acute Vascular Rejectionmentioning

confidence: 93%

“…The accumulation of these cells appears to depend on antibody binding to xenogeneic endothelial cells and is probably linked to endothelial cell damage (Inverardi et al 1992). We have used immunohistochemistry in an attempt to detect natural killer cells in hyperacute xenograft rejection in guinea pig-to-rat and porcine-to-primate models (Leventhal et al 1993b, Collins et al 1994a). Substantial numbers of these cells have not been seen.…”

Section: Mechanisms Of Immunorecognition Leading To Hyperacute Xenogrmentioning

confidence: 99%

See 1 more Smart Citation

A Perspective on Xenograft Rejection and Accommodation¹

Platt

1994

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

There is increasing interest in the potential clinical application of xenotransplantation. This interest derives in part from the need to identify a more abundant source of organs for transplantation and in part from rapid progress in understanding the cellular and molecular events that contribute to xenograft rejection. Recent areas of progress include the characterization of xenoreactive antibodies which would initiate the rejection of porcine organs transplanted into primates. These antibodies consist predominantly of IgM and their binding is characterized by high avidity and surprising uniformity. Xenoreactive antibodies recognize porcine glycoproteins of the integrin family; the determinants residing on N-linked substitutions. The predominant substitution has a terminal alpha Gal residue. Antibody binding initiates activation of complement through the classical pathway triggering a number of effector mechanisms. These mechanisms may include loss of heparan sulfate from endothelial cells mediated by C5a and xenoreactive antibody; a change in endothelial cell shape mediated by C5b-7 or the membrane-attack complex; procoagulant changes mediated by the membrane-attack complex; and neutrophil adhesion mediated by iC3b. If hyperacute rejection is prevented by the depletion of xenoreactive antibody and/or the inhibition of complement, acute vascular rejection may be seen some days later. Acute vascular rejection is characterized by prominent evidence of thrombosis and neutrophil infiltration. The cause of acute vascular rejection is unknown, but may reflect profound alterations in the function of endothelial cells lining blood vessels in the graft. In some cases, when recipients of xenografts are modified by depletion of xenoreactive antibodies, acute vascular rejection does not occur; rather, a process called accommodation allows the xenograft to survive despite the return to the circulation of xenoreactive antibodies and complement. The mechanism for accommodation is not known. New therapeutic strategies including the development of specific immunoabsorbants, identification of preferred donor animals expressing low levels of antigen and the development of transgenic donor animals expressing human complement regulatory proteins are among the strategies which may bring xenotransplantation closer to the clinical arena.

show abstract

Section: Pathophysiology Of Acute Vascular Rejectionmentioning

confidence: 93%

Section: Mechanisms Of Immunorecognition Leading To Hyperacute Xenogrmentioning

confidence: 99%

A Perspective on Xenograft Rejection and Accommodation¹

Platt

1994

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

show abstract

“…Endothelial damage and dysfunction may then lead to the deposition of fibrin and formation of platelet thrombi. 7,24 In case 1, fibrin deposition along endothelial surfaces was found in the perfused porcine liver graft. This fibrin might directly damage baboon erythrocytes, resulting in intravascular hemolysis.…”

Section: Discussionmentioning

confidence: 94%

“…Thus, ECLP now is being reevaluated as a therapeutic modality of intervention in patients with acute hepatic failure. [7][8][9] However, to date, there have been no preclinical studies that evaluated the safety of ECLP in nonhuman primates.…”

mentioning

confidence: 99%

Influence of extracorporeal porcine liver perfusion on nonhuman primates: Minimizing hemolysis improves subsequent survival

Nishitai¹

2001

Liver Transplantation

View full text Add to dashboard Cite

The aim of this study is to detect and analyze risk factors of direct cross-circulation between porcine liver and nonhuman primates before a clinical application of extracorporeal liver perfusion (ECLP) as a liver-assist method. Porcine livers were perfused with baboon blood in an ECLP system. Six healthy baboons were directly connected to the ECLP system with continuous prostaglandin E 1 administration. Cross-circulation was terminated in the following circumstances: (1) E xtracorporeal liver perfusion (ECLP) is a temporary liver-assist method. First reported by Otto et al, 1 it was studied extensively during the 1960s to 1980s. 2-5 ECLP was found to improve the neurological status of patients with acute hepatic failure by facilitating the removal of such toxic substances as ammonia and bilirubin. 6 Since the 1980s, orthotopic liver transplantation has become the established treatment of choice for severe acute hepatic failure, and ECLP was not studied for a time. However, a chronic shortage of human livers available for transplantation and the possibility that the need for transplantation might be averted encouraged renewed interest in liver-assist methods. Thus, ECLP now is being reevaluated as a therapeutic modality of intervention in patients with acute hepatic failure. 7-9 However, to date, there have been no preclinical studies that evaluated the safety of ECLP in nonhuman primates.We developed a new ECLP system using a whole porcine liver as a liver-assist device. The administration of prostaglandin E 1 , which ameliorates injury mediated by xenogeneic humoral factors, has enabled the xenoperfused porcine liver to be kept viable for 9 hours in a closed circuit. [10][11][12][13] The metabolic capacity of this ECLP system has been pharmacokinetically analyzed using galactose-, lidocaine-, and ammonia-loading tests and documented to maintain functional capacity similar to that of in situ porcine livers for up to 9 hours. 14 Before an application of the ECLP system in the clinical arena, a preclinical assessment using nonhuman primates is a prerequisite. Because symptoms of acute hepatic failure vary, it is difficult to distinguish potential complications of ECLP from complications of the underlying liver disease. In this preclinical study, healthy baboons were used to investigate the influences of the ECLP system on primates.

show abstract

“…108,109 Because FH patients have a very low complement level, clinical and experimental data tend to show that xenogenic liver perfusion is associated with minimal or no hyperacute rejection, providing that patients do not receive blood or blood derivative immediately before or during xenoperfusion. 110,111 The clinical application of porcine ECLP was also subjected to the same physiologic, immunologic, and virologic restrictions of the xenograft.…”

Section: Extracorporeal Whole Liver Perfusionmentioning

confidence: 99%

Extracorporeal Liver Support: Waiting for the Deciding Vote

Adham

2003

ASAIO Journal

View full text Add to dashboard Cite

Because acute liver cell failure is associated with an exceedingly high mortality, liver support has been proposed since the 1950s to improve patient outcome. Early devices, including hemodialysis, hemofiltration, exchange transfusion, plasmapheresis, hemoperfusion, plasma and cross-hemodialysis or cross-circulation, appeared inefficient. Meanwhile, documented results of extracorporeal liver perfusion (ECLP) suggested its superiority over conventional treatment. These devices were abandoned with the development of liver transplantation (LT), which allowed a better outcome and longer survival rate. In the present day, the fact that patients die while waiting for LT because of organ shortage led to a renewed interest in liver support as bridge to LT or regeneration. These devices can be classified according to the presence or lack of hepatocytes, whereas biologic devices refers to the presence of cells or other organic and biochemical component. The absence of individual success of early models led to the development of combined hepatocyte free devices, or artificial liver, which are based upon the hemodiabsorption principle (Biologic-DT) or on the "albumin bound toxin hypothesis" (Molecular Adsorbents Recirculating System) with encouraging results. Meanwhile, hepatocyte based bioartificial liver devices (BLD) were conceived for a global "metabolic support." BLD were developed with the use of human hepatoma cell line (C3A) or primary or cryopreserved porcine hepatocytes. Preliminary experience gave promising results bridging patients to LT. Based upon the same principle of global hepatocyte metabolic support, ECLP regained interest, particularly with the development of transgenic pigs. Several concerns were raised about these devices. Artificial livers lacked any metabolic synthetic activity, the use of human liver for ECLP seems hardly acceptable because of organ shortage, and the accepted use of borderline livers for transplantation is pending trials for the use of xenogenic livers. For BLD, the concerns were the low hepatocyte mass, the absence of accessory liver cells, and the potential risk of seeding tumor cells into patient with the use of human hepatoma cell line. The use of porcine hepatocytes (BLD or ECLP) raised physiologic and immunologic concerns and particularly the fear of a possible transfer of porcine viral material. Although recent studies clearly demonstrate clinical improvement of patients with the use of recently developed liver support devices, most of reported prospective, controlled, or randomized trials had a small number of patients. To give the deciding vote and avoid previous pitfalls, trials need to be developed with a larger number of patients based upon statistically significant models with the following characteristics: 1) comprehensive understanding of the acute liver cell failure mechanisms, 2) world wide classification of conditions that require liver support, and 3) a clear definition of treatment success pending patients to LT or recovery without transplantation. There has not y...

show abstract

Mechanisms of Injury in Porcine Livers Perfused With Blood of Patients With Fulminant Hepatic Failure

Cited by 21 publications

References 0 publications

A Perspective on Xenograft Rejection and Accommodation¹

A Perspective on Xenograft Rejection and Accommodation¹

Influence of extracorporeal porcine liver perfusion on nonhuman primates: Minimizing hemolysis improves subsequent survival

Extracorporeal Liver Support: Waiting for the Deciding Vote

Contact Info

Product

Resources

About

Mechanisms of Injury in Porcine Livers Perfused With Blood of Patients With Fulminant Hepatic Failure

Cited by 21 publications

References 0 publications

A Perspective on Xenograft Rejection and Accommodation1

A Perspective on Xenograft Rejection and Accommodation1

Influence of extracorporeal porcine liver perfusion on nonhuman primates: Minimizing hemolysis improves subsequent survival

Extracorporeal Liver Support: Waiting for the Deciding Vote

Contact Info

Product

Resources

About

A Perspective on Xenograft Rejection and Accommodation¹

A Perspective on Xenograft Rejection and Accommodation¹