Immunopathology of Hyperacute Xenograft Rejection in a Swine-to-Primate Model

Platt, Jeffrey L.; Fischel, Richard; Matas, Arthur J.; Reif, Sally; Bolman, R. Morton; Bach, Fritz H.

doi:10.1097/00007890-199108000-00006

Cited by 425 publications

(199 citation statements)

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“…In heart and kidney xenotransplantation, the same antibody-and complement-mediated endothelial injury results in graft destruction because of microvascular thrombosis. 19 Our results shed light on the nature of this hemorrhage. This study shows that activities of clotting factors V, IX, and X, as well as fibrinogen levels, decrease throughout the intraoperative and postoperative course.…”

Section: Discussionmentioning

confidence: 65%

Aberrations in hemostasis and coagulation in untreated discordant hepatic xenotransplantation: Studies in the dog-to-pig model

Tector

Fridell

Elias

et al. 2002

Liver Transplantation

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Discordant liver xenotransplantation is a poorly explored entity. Data from the few large animal studies of hepatic xenotransplantation suggest that severe hemorrhage is encountered. The purpose of the studies described here is to characterize the nature of the hemorrhage that accompanies liver xenotransplantation. Canine livers were transplanted into porcine recipients, and lethal hemorrhage was encountered. Analysis of recipient blood showed that factors V, IX, and X were present in adequate levels until after the hemorrhage appeared, suggesting that coagulation factor loss was the result and not the cause of hemorrhage. Platelet counts decreased dramatically in recipients within minutes of graft reperfusion. There also was no evidence of clotting activity in the blood of recipients of liver xenografts within minutes of graft reperfusion. This loss of clotting activity was specific to liver xenografts, was not seen in renal xenografts with or without venovenous bypass, and also was absent in pig-to-pig liver allografts. In brief, the hemorrhage that accompanies liver xenotransplantation occurs because of a decrease in the number and function of circulating platelets in the recipient.

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Section: Discussionmentioning

confidence: 65%

Aberrations in hemostasis and coagulation in untreated discordant hepatic xenotransplantation: Studies in the dog-to-pig model

Tector

Fridell

Elias

et al. 2002

Liver Transplantation

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“…Esto se traduce en una disminución brusca de plaquetas por la formación de trombos al inicio de la perfusión 26 . A nivel microscópico observamos un rechazo hiperagudo indistinguible del observado in vivo 25 , con trombosis glomerular extensa, hemorragia tubular e intersticial multifocal, con focos de isquemia tubular y necrosis (Fig. 4b).…”

Section: A B C Dunclassified

“…Esto indica que en nuestro experimento se mantiene indemne la respuesta inmune inmediata. A nivel inmunohistoquímico existe un depósito extenso de IgG e IgM xenogénicas en el endotelio del riñón del cerdo, así como de complemento, implicados en el rechazo hiperagudo 25 . Existe depósito perivascular de linfocitos, células T y macrófagos, pero noinfiltrado intersticial.…”

Section: A B C Dunclassified

Rechazo celular agudo en modelo ex vivo de xenotrasplante renal cerdo-hombre

Vega

Alonso

Barrón

et al. 2004

Actas Urológicas Españolas

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RESUMEN RECHAZO CELULAR AGUDO EN MODELO EX VIVO DE XENOTRASPLANTE RENAL CERDO-HOMBRE OBJETIVOS:Desarrollo de un modelo ex vivo de perfusión de riñones de cerdo con sangre humana, intentando reproducir el xenotrasplante renal cerdo-hombre, para el estudio de las manifestaciones que se producen una vez evitado el rechazo hiperagudo.MÉTODO: Perfusión de los riñones de cerdo durante 3 horas con sangre de cerdo (grupo 1; n=5), sangre humana (grupo 2; n=5), sangre humana decomplementada por calor (grupo 3; n=5), sangre humana deplaquetada por centrifugación (grupo 4; n=5), sangre humana inmuonadsobida con proteína A estafilocócica (grupo 5; n=5). Las piezas se estudian por microscopía óptica e inmunohistoquímica RESULTADOS: Rechazo hiperagudo con hemorragia difusa, trombosis y lesiones glomerulares en el grupo con sangre humana sin manipular. Ausencia de rechazo hiperagudo en el resto de los grupos: decomplementada, deplaquetada e inmunoadsorbida, con presencia de rechazo celular agudo con diferentes grados de infiltración intersticial de células mononucleares, en especial en el grupo con sangre inmunoadsorbida.CONCLUSIONES: El modelo que permite valorar de forma aislada elementos de la respuesta inmune xenogé-nica cerdo-hombre. La depleción de complemento, plaquetas y xenoanticuerpos protege a los riñones de cerdo del rechazo hiperagudo, observando por primera vez la presencia de rechazo celular agudo en 3 horas, manifestación que suele precisar para su aparición varios días.PALABRAS CLAVE: Xenotrasplante. Rechazo hiperagudo. Rechazo celular agudo. ABSTRACT CELLULAR ACUTE REJECTION PIG TO HUMAN IN AN EX VIVO RENAL TRANSPLANT MODELOBJECTIVE: Ex vivo perfusion model of pig-to-human kidney xenotransplantation to evaluate human antiporcine xenograft rejection once hyperacute rejection (HAR) is avoided.METHODS: Pig kidneys were perfused for 3 hours with pig blood (group 1; n=5), human blood (group 2; n=5), complement heat innactivated human blood (group 3; n=5), platelet-depleted human blood (group 4; n=5); and xenoreactive natural antibodies (XNA)-depleted human blood (group 5; n=5). Tissue samples were studied with immunoperoxidase techniques.RESULTS: Pig kidneys perfused with human blood, group 2, showed HAR with interstitial haemorrhage, vascular thrombi and glomerular injury. Pig kidneys perfused with manipulated human blood (groups 3 to 5) had no histologic evidence of HAR, but showed signs of acute cellular rejection with different degrees of interstitial infiltrate of mononuclear cells, specially in the XNA-depleted group. CONCLUSIONS: The model may be valuable in the isolated evaluation of the elements involved in the pig-tohuman xenorejection. The depletion of complement, platelets and XNA protected porcine kidneys form HAR in our study and allowed the development of an acute cellular rejection, a very unusual fact in this short time, 3 hours.

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“…The ¢rst step in the pathogenesis of hyperacute rejection is the binding to graft endothelium of xenoreactive natural antibodies, so named because they recognize the cells of foreign species and because they are present in the circulation without a known history of exposure to the corresponding antigen (Boyden 1964;Platt et al 1990). The natural antibodies in humans which bind to pig cells are predominantly directed against Gala1,3Gal, a saccharide expressed on the cells of lower mammals but not on the cells of humans, apes and Old World monkeys (Galili et al 1988).…”

Section: The Immune Response To Xenograftsmentioning

confidence: 99%

Xenotransplantation and tolerance

Samstein

Platt

2001

Phil. Trans. R. Soc. Lond. B

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The application of xenotransplantation faces daunting immunological hurdles, some of which might be overcome with the induction of tolerance. Porcine organs transplanted into primates are subject to several types of rejection responses. Hyperacute rejection mediated by naturally occurring xenoreactive antibodies and complement can be overcome without tolerance. Acute vascular rejection and cellular rejection, however, may present important opportunities for immunological tolerance, and humoral rejection might be approached by various mechanisms including (i) clonal deletion, (ii) anergy, (iii) immune deviation, (iv) induction of immunoregulatory or suppressor cells, or (v) veto cells. B-cell tolerance, useful for preventing humoral rejection, might be approached through clonal anergy. It remains to be determined, however, whether tolerance induction is required for xenotransplantation and by which means the various mechanisms of tolerance can be applied in the setting of xenotransplantation. Regardless, the study of tolerance will surely expand understanding of the physiology and pathophysiology of the immune system.

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Immunopathology of Hyperacute Xenograft Rejection in a Swine-to-Primate Model

Cited by 425 publications

References 0 publications

Aberrations in hemostasis and coagulation in untreated discordant hepatic xenotransplantation: Studies in the dog-to-pig model

Aberrations in hemostasis and coagulation in untreated discordant hepatic xenotransplantation: Studies in the dog-to-pig model

Rechazo celular agudo en modelo ex vivo de xenotrasplante renal cerdo-hombre

Xenotransplantation and tolerance

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