Ex vivo lung model of pig-to-human hyperacute xenograft rejection

Macchiarini, Paolo; Mazmanian, Guy-Michel; Oriol, Rafaël; Montpréville, Vincent de; Dulmet, Élisabeth; Fattal, Soly; Libert, Jacques; Doubine, Sylvie; Nochy, Dominique; Rieben, Robert; Dartevelle, Philippe

doi:10.1016/s0022-5223(97)70175-2

Cited by 34 publications

(34 citation statements)

References 26 publications

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“…Subsequent deposition of IgM, IgG, C1q, C3, C4, C9 will lead to the rapid failure of xenograft [3,18]. However, whether xenoreactive antibodies actually remain bound to swine endothelium is not certain [19].…”

Section: Discussionmentioning

confidence: 99%

Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient☆

Kang

Lee

Kim

et al. 2005

European Journal of Cardio-Thoracic Surgery

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Objective: Unlike cardiac or renal xenotransplants, the depletion of complement using cobra venom factor (CVF) does not improve pulmonary xenograft survival. Several cases suggest that the swine von Willebrand factor (vWF) may play a major role in presenting a different pathogenesis of pulmonary xenograft dysfunction from other organs. To evaluate the role of vWF and the complement system in mediating hyperacute vascular injury of pulmonary xenografts and elucidate pathogenesis of the injury, we performed swine-to-canine orthotropic single lung xenotransplantation after pre-treatment of 1-deamino-8-D-arginine vasopressin (DDAVP) and CVF. Methods: We set up three groups for lung xenotransplantation: group I served as the control group; group II, recipients pre-treated with CVF; group III, donors pre-treated with DDAVP (9 mg/kg, 3 days)/recipients pre-treated with CVF (60 u/kg). Hemodynamic data, coagulation and complement system parameters, and grafted lung pathologies were examined serially for 3 h after transplantation. Results: DDAVP infusion reduced the vWF content in swine lung tissue in vivo (7.7G2.4 AU/mg vs 16.0G5.6 AU/mg, P!0.0001). Infusion of CVF 24 h prior to transplantation effectively depleted the recipient's serum C3 and complement hemolytic activity below the detectable range. Regardless of the use of CVF, both groups I and II transplanted with unmodified grafts showed an immediate drop in leukocytes and platelet counts after transplantation. However, in group III, in recipients transplanted with DDAVP pre-treated swine lung, the platelet count did not decrease after transplantation (PZ0.0295). The decrease of plasma antithrombin and fibrinogen tended to be attenuated in group III. Light microscopic examination revealed extensive vascular thromboses in both capillary and larger vessels, as well as early pulmonary parenchymal damage in groups I and II, but were rarely observed in group III. Conclusions: Complement inhibition alone was not enough to alleviate intravascular thrombosis, the main pathology in pulmonary xenotransplantation. Pre-infusion of DDAVP to the donor animal was effective in preventing platelet sequestration and attenuated intravascular thrombosis. It is suggested that the strategies targeting vWF would be promising for successful pulmonary xenotransplantation.

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Section: Discussionmentioning

confidence: 99%

Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient☆

Kang

Lee

Kim

et al. 2005

European Journal of Cardio-Thoracic Surgery

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“…11,[15][16][17] The mechanisms of hemolysis in organ xenoperfusion have not yet been fully elucidated. Two factors may be implicated in hemolysis during cross-circulation with xenogeneic ECLP.…”

Section: Discussionmentioning

confidence: 99%

“…27 It is reported that loss of anticoagulant functions of the endothelium leads to platelet aggregation and subsequent fibrin formation, which may then lead to erythrocyte fragmentation or microhemolysis. 25,28 Macchiarini et al 15 reported severe hemolysis in relation to intravascular thrombi of fibrin and platelet in extracorporeal pig lung perfusion with human blood. Moreover, RBC fragmentation promotes thrombus formation.…”

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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“…121). In an attempt to overcome this incompatibility problem, transgenic pigs have been engineered that express human complement-regulatory proteins such as decay-accelerating factor (DAF) and CD59.…”

Section: Risks and Incompatibilities Associated With Using Pig Organsmentioning

confidence: 99%

Islet cell transplantation for insulin-dependent diabetes mellitus: perspectives from the present and prospects for the future

Gray

Titus

Badet

2000

Expert Rev. Mol. Med.

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The long-term complications of insulin-dependent diabetes mellitus have become a major health care problem, and it is now clear that they arise from inadequate homeostatic control of blood glucose by injected replacement insulin. Transplantation of pancreatic islets is arguably the most logical approach to restoring metabolic homeostasis in people with diabetes. This review looks at the current status of human islet transplantation and the problems that remain. These include: (1) the limited supply of human islet tissue available for transplantation; (2) the adverse effects of current immunosuppressive protocols on diabetic patients; (3) the problems of primary nonfunction of the transplanted islets; (4) the rejection of islets; and (5) the recurrence of autoimmune diabetic disease. Some of the approaches that might solve these problems are then examined: (1) immune modulation to reduce or prevent immune attack by the recipient's immune system; (2) immunoisolation to prevent recognition of the islet graft; (3) induction of tolerance; (4) xenotransplantation using islets derived from animals; and (5) gene therapy.

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Ex vivo lung model of pig-to-human hyperacute xenograft rejection

Abstract: This pig-to-human xenograft model suggests that the pig lung perfused with human blood has an early and violent hyperacute rejection that results in irreversible pulmonary dysfunction and failure within approximately 150 minutes of reperfusion.

Cited by 34 publications

References 26 publications

Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient☆

Pre-treatment of donor with 1-deamino-8-d-arginine vasopressin could alleviate early failure of porcine xenograft in a cobra venom factor treated canine recipient☆

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

Islet cell transplantation for insulin-dependent diabetes mellitus: perspectives from the present and prospects for the future

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