Immunopathological Observations After Xenogeneic Liver Perfusions Using Donor Pigs Transgenic for Human Decay-Accelerating Factor1,2

Pascher, Andreas; Poehlein, Christian; Storck, M.; Prestel, R.; Mueller-Hoecker, Josef; White, David J.; Abendroth, D.; Hammer, C.

doi:10.1097/00007890-199708150-00002

Cited by 41 publications

(17 citation statements)

References 20 publications

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“…The earliest type of rejection seen in a pig-to-primate xenograft is hyperacute rejection, which occurs within minutes to hours of transplantation (1)(2)(3) and is initiated by xenoreactive antibodies that bind to the endothelial lining of the graft vasculature, activating the complement system (2,3). Hyperacute rejection can now be overcome by depletion of antidonor antibodies or inhibition of complement (3)(4)(5). When hyperacute rejection is averted, especially by inhibition of the recipient's complement system, the xenograft becomes subject to acute vascular rejection that destroys the graft over a period of hours to days (6,7).…”

Section: Introductionmentioning

confidence: 99%

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Lin

Weidner²,

Byrne³

et al. 1998

J. Clin. Invest.

259

161

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Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens. (

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Section: Introductionmentioning

confidence: 99%

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Lin

Weidner²,

Byrne³

et al. 1998

J. Clin. Invest.

259

161

View full text Add to dashboard Cite

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“…Immunologic modulations, such as the use of liver grafts from transgenic pigs expressing human complement regulatory proteins on the endothelial cell surface or immunoadsorption of patients before cross-circulation, could be effective in maintaining critically important endothelial function of the isolated liver grafts. 30,31 In addition, systemic inhibition of the complement cascade by the administration of soluble human complement-regulatory proteins may be another effective strategy to reduce humoral factor-mediated endothelial injury. 24 Although both complement activity and absolute levels of individual complement components were maintained through the experiments in this study, complement activity in patients with acute hepatic failure may be low as a result of impaired synthesis of complement components and increased consumption of complements.…”

Section: Discussionmentioning

confidence: 99%

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

Nishitai¹

2001

Liver Transplantation

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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.

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“…Next, the liver was harvested and transferred to the perfusion machine based on the previously described method with some modifications [14]. Fresh human blood from two healthy donors of identical blood type (A, B, or 0) and Rh factor was diluted with lactate Ringer's solution to a hematocrit level of 25%.…”

Section: Xenoperfusionmentioning

confidence: 99%

“…Recently, the first successful xenogeneic liver transplantation was reported by Ramirez et al, in which two livers from decay-accelerating factor (DAF) transgenic pigs were transplanted into baboons and survived 4 and 8 days without HAR [17]. In other papers, however, these transgenic livers could not sustain their functions for more than a few hours, even in the xenogeneic liver perfusion [lo, 14,161. These facts thus indicated that such transgenic livers still need to be improved before xenogeneic perfusion and eventually xenogeneic liver transplantation can be successfully performed.…”

Section: Introductionmentioning

confidence: 99%

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Adenovirus-mediated gene transfer of triple human complement regulating proteins (DAF, MCP and CD59) in the xenogeneic porcine-to-human transplantation model. Part II: xenogeneic perfusion of the porcine liver in vivo

et al. 2002

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In this study, the adenovirus-mediated gene transfer of triple human complement regulating proteins was investigated in xenogeneic pig liver perfusion. The porcine liver was perfused in situ at 4 "C under a pump-driven veno-venous shunt of the portal vein and inferior vena cava, with 5 to 1 5~1 0~' plaqueforming units (pfu) of adenovirus vector (group 1: AxCALacZ; 2: Ax-CADAF; 4: AxCACD59 + AxCADAF + AxCAMCP) for 1 h (for each, n=3). The livers were harvested 24 h after gene transfer and then were reperfused ex-vivo with fresh human blood for 2 h. In immunohistochemical staining, each complement regulating protein (CRP) showed a distribution similar to that of the LacZ expression. The CACD59; 3: AxCACD59 + AX-C3 levels in the perfusate were also maintained at higher levels in group 4 from 60 to 120 min after reperfusion (C3: 85% to 95% of the initial level) than in groups 1 to 3 (C3: 80% to 90% of the initial level) from 60 to 120 min after reperfusion. The complement deposition on the porcine liver [C3, membrane attack component (MAC)] decreased significantly more in group 4 than in groups 1 to 3. In conclusion, the adenovirus-mediated multiple gene transfer of human CRPs (hCRPs) was found to effectively suppress the complement activation in xenogeneic pig liver perfusion.

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Immunopathological Observations After Xenogeneic Liver Perfusions Using Donor Pigs Transgenic for Human Decay-Accelerating Factor1,2

Abstract: These results confirm that the transgenic expression of the human complement regulatory protein hDAF reduces complement activation and prevents hyperacute rejection in a xenogeneic liver perfusion model over the 3-hr evaluation period used in this study.

Cited by 41 publications

References 20 publications

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

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

Adenovirus-mediated gene transfer of triple human complement regulating proteins (DAF, MCP and CD59) in the xenogeneic porcine-to-human transplantation model. Part II: xenogeneic perfusion of the porcine liver in vivo

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