Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury

McCurry, Kenneth R.; Kooyman, David L.; Alvarado, Cristobal G.; Cotterell, Adrian; Martin, Michael; Logan, John S.; Platt, Jeffrey L.

doi:10.1038/nm0595-423

Cited by 510 publications

(270 citation statements)

References 19 publications

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“…Success in controlling hyperacute rejection (HAR) in pig-to-primate solid organ transplantations was achieved by using donor pigs transgenic for human complement regulatory proteins like DAF and/or CD59 (1). Recently, 'knockout' pigs for the major xenoantigen Gala1-3Gal have also been presented (2,3), but data on transplantation experiments with such organs are not yet available.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Laumonier¹,

Mohaçsi²,

Matozan³

et al. 2004

American Journal of Transplantation

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We showed recently that low molecular weight dextran sulfate (DXS) acts as an endothelial cell (EC) protectant and prevents human complement-and NK cellmediated cytotoxicity towards porcine cells in vitro. We therefore hypothesized that DXS, combined with cyclosporine A (CyA), could prevent acute vascular rejection (AVR) in the hamster-to-rat cardiac xenotransplantation model. Untreated, CyA-only, and DXS-only treated rats rejected their grafts within 4-5 days. Of the hearts grafted into rats receiving DXS in combination with CyA, 28% survived more than 30 days. Deposition of anti-hamster antibodies and complement was detected in long-term surviving grafts. Combined with the expression of hemoxygenase 1 (HO-1) on graft EC, these results indicate that accommodation had occurred. Complement activity was normal in rat sera after DXS injection, and while systemic inhibition of the coagulation cascade was observed 1 h after DXS injection, it was absent after 24 h. Moreover, using a fluorescein-labeled DXS (DXS-Fluo) injected 1 day after surgery, we observed a specific binding of DXS-Fluo to the xenograft endothelium. In conclusion, we show here that DXS + + CyA induces long-term xenograft survival and we provide evidence that DXS might act as a local EC protectant also in vivo.

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Section: Introductionmentioning

confidence: 99%

Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Laumonier¹,

Mohaçsi²,

Matozan³

et al. 2004

American Journal of Transplantation

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“…Il a donc été envisagé de contrôler le rejet hyperaigu en utilisant des animaux transgéniques pour ces molécules régu-latrices. Des porcs transgéniques pour le DAF [21] et/ou le CD59 [22] humains ont été produits et utilisés avec succès dans des modèles de greffe cardiaque [23], rénale [24] ou hépatique [7]. Néanmoins, en l'absence de tout traitement, la prolongation obtenue ne dépasse pas quelques jours, les organes étant rejetés par un mécanisme appelé rejet vasculaire aigu (AVR) ou rejet retardé.…”

Section: Quelle Approche Pour Quel Type De Rejet?unclassified

“…En effet, loin d'être seulement un organe vital, l'organe humain greffé provient du don volontaire d'un humain à un autre humain, et est à ce titre précieusement investi. Réduit à une matière vivante animale, il simplifiera certainement les Transgénique pour une MRCh Sans traitement < une semaine Rein [27] Transgénique pour une MRCh IS classique Quelques heures à 3 mois Coeur [50,51], rein [27] Transgénique pour une MRCh IS novatrice 3 jours à 4 mois et demi Coeur [52,11] Transgénique pour une MRCh IS + « thymus-rein » Jusqu'à un mois Rein [40] Transgénique pour une MRCh Sans traitement < une semaine Coeur [23], rein [53] Gal KO IS classique 1 mois (n = 1) Rein [54] Gal KO IS classique+ « thymus-rein » Environ 2 mois et demi (n = 1) Rein [32] Tableau I. Survies de xénogreffes porc/primate en fonction des manipulations effectuées sur le donneur et/ou le receveur. MRCh: molécule régulatrice du complément humain (CD55, CD59, CD46); IS: immunosuppression.…”

Section: Acceptabilité Psychosociale De La Xénotransplantationunclassified

Les xénogreffes finiront-elles par être acceptées ?

Séveno

Fellous²,

Ashton‐Chess

et al. 2005

Med Sci (Paris)

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“…18 In an effort to prevent clinical hyperacute xenograft rejection, investigators have transfected human complement regulatory proteins into pigs. [19][20][21] This results only in temporary delay of xenograft destruction. 22,23 The reason is that the other mechanisms of innate immunity (shown in Table 1) promptly cause inexorable rejection.…”

Section: The Transplant Analogymentioning

confidence: 99%

Will Xenotransplantation Ever Be Feasible?

Starzl¹

1998

Journal of the American College of Surgeons

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In several recent conferences, the principal questions have been whether Xenotransplantation technology should be encouraged and, if so, how it should be regulated. Because the prospect of successful transplantation of animal organs into humans is still remote, the rush to achieve consensus about clinical application 1,2 would be inexplicable were it not for two ostensibly unrelated issues. The first is the small but undeniable theoretical hazard of causing new human infections with the intermingling of tissues from different species. The second, advanced by animal-rights advocates, concerns the spiritual and ethical relationship of humans to animals. CLOSELY RELATED SPECIESThe rhetoric of these discussions has been heightened by the fact that all clinical organ xenotransplantations attempted since 1963 have failed, including >25 involving subhuman primate donors (19 reported or unreported chimpanzees, 10 baboons, and 1 [or 2] Rhesus monkeys). This experience began with Reemtsma and associates, 3 who proved in 1963 that kidneys from at least two subhuman primate donor species (Rhesus and chimpanzee) would not be rejected hyperacutely by humans. In fact, one of his chimpanzee xenografts functioned for 9 months. However, Reemtsma was the first to recognize that the humanoid qualities and threatened extinction of the chimpanzee would prevent its widespread use as a donor.Later in 1963, a team at the University of Colorado/Minnesota showed that baboon kidneys also would escape hyperacute rejection. In contrast to the chimpanzee, baboons flourished, and still do, in southern and central Africa. The six baboon renal xenografts of 1963 supported dialysis-free life for 6-60 days before undergoing fierce cellular rejection. 4 In addition, all of the baboon kidneys had occlusive endotheliolitis that was severe enough to cause regional parenchymal infarcts and islands of gangrene. We concluded by early 1964 that this humoral component of xenograft rejection could not be controlled with cell-directed immune suppression (azathioprine and prednisone at the time). A moratorium was selfimposed on further attempts. This hiatus lasted for 28 years, until investigations by Murase and colleagues 5 with the hamsterto-rat model appeared to justify a further trial. In this strain combination, in which the immune barrier resembles that between the baboon and human, 6 the combination of T-cell-specific immune suppression with tacrolimus plus B-cell-directed cyclophosphamide permitted the unprecedented routine survival of heart and liver xenografts for >100 days.In June 1992 and January 1993, two baboon-to-human orthotopic liver transplantations were performed in patients with chronic end-stage organ failure caused by hepatitis B virus infection.

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Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury

Cited by 510 publications

References 19 publications

Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Endothelial Cell Protection by Dextran Sulfate: A Novel Strategy to Prevent Acute Vascular Rejection in Xenotransplantation

Les xénogreffes finiront-elles par être acceptées ?

Will Xenotransplantation Ever Be Feasible?

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