Xenotransplantate vom Schwein – ist das Ende des Organmangels in Sicht?

Zusammenfassung

Unter „Xenotransplantation“ wird die Übertragung von funktionsfähigen Zellen, Geweben oder Organen zwischen verschiedenen Spezies verstanden, insbesondere von Schweinen auf den Menschen. In den meisten Industrieländern klafft eine große Lücke zwischen der Anzahl geeigneter Spenderorgane und der Anzahl benötigter Transplantate. Weltweit können nur etwa 10% des Organbedarfs durch Spenden gedeckt werden. Eine erfolgreiche Xenotransplantation könnte diesen Mangel mildern oder sogar weitgehend vermeiden. Das Schwein wird aus verschiedenen Erwägungen heraus als am besten geeignete Spenderspezies angesehen. Bei einer Übertragung porziner Organe auf Primaten treten verschiedene immunologisch bedingte Abstoßungsreaktionen auf, die das übertragene Organ innerhalb kurzer Zeit zerstören können, wie die HAR (hyperakute Abstoßung), die AVR (akute vaskuläre Abstoßung) und die spätere zelluläre Abstoßung. Diese Abstoßungsreaktionen müssen durch genetische Modifikationen im Schwein und eine geeignete immunsuppressive Behandlung des Empfängers kontrolliert werden. Dazu müssen Tiere mit mehrfachen genetischen Veränderungen produziert und im Hinblick auf ihre Eignung für eine erfolgreiche Xenotransplantation geprüft werden. Inzwischen können die HAR und auch die AVR durch Knockouts von antigenen Oberflächenepitopen (z. B. αGal [Galaktose-α1,3-Galaktose]) und transgene Expression humaner Gene mit antiinflammatorischer, antiapoptotischer oder antikoagulativer Wirkung zuverlässig kontrolliert werden. Nach orthotopen Transplantationen in nicht humane Primaten konnten inzwischen mit Schweineherzen Überlebensraten von bis zu 264 Tagen und mit porzinen Nieren von 435 Tagen erzielt werden. Eine Übertragung pathogener Erreger auf den Empfänger kann bei Einhaltung einschlägiger Hygienemaßnahmen ausgeschlossen werden. PERV (porzine endogene Retroviren) können durch RNA-(Ribonukleinsäure-)Interferenz oder Gen-Knockout ausgeschaltet werden. Sie stellen damit kein Übertragungsrisiko für den Empfänger mehr dar. Anfang 2022 wurde in Baltimore (USA) ein Schweineherz mit 10 genetischen Modifikationen auf einen Patienten mit schwerem Herzleiden übertragen, mit dem der Empfänger 2 Monate offenbar ohne größere Probleme lebte. Es wird erwartet, dass Xenotransplantate vom Schwein in absehbarer Zeit zur klinischen Anwendungsreife kommen werden. Dazu werden klinische Versuche zur systematischen Erfassung aller Auswirkungen solcher Transplantate auf den Patienten sowie geeignete rechtliche und finanzielle Rahmenbedingungen benötigt.

Abstract

Xenotransplantation entails the transplantation of functional cells, tissue, or whole organs between different species, in particular from animals, such as the domestic pig, to human patients. In most industrialized countries there is a growing gap between the number of suitable donor organs and the number of needed transplants. Globally, only ≈10% of the organs in need can be met by donation. A successful xenotransplantation could potentially overcome this ever growing shortage of suitable organs. The domestic pig has been identified as the best suited donor species due to a number of specific advantages. When transplanting porcine organs into primates, several immunological rejection responses are induced that would destroy the xenograft within minutes or few hours, incl. the hyperacute rejection response (HAR), the acute vascular rejection (AVR), and later the cellular rejection. The primary goal is to control the HAR and the AVR by genetic modification of the donor pigs and an appropriate immune suppressive treatment of the recipient. This requires production of multi-transgenic pigs and extensive testing of their suitability for successful xenotransplantation. Intensive research around the globe has demonstrated that both, the HAR and AVR, can be reliably controlled via knockouts of specific antigenic surface epitopes (f.ex. galactose-α1,3 galactose [α1,3 Gal]) and simultaneous transgenic expression of human genes with anti-inflammatory, anti-apoptotic and anti-coagulative function. Following orthotopic porcine organ transplantation into non-human primates, maximum survival rates of 264 days (heart) and 435 days (kidney) could be achieved. The potential risk of transmission of pathogens by the xenograft to the recipient can be eliminated by applying strict hygienic measures. Porcine endogenous retroviruses (PERV) can be eliminated by specific breeding programs, RNA-interference, or gene knockout, so that they do not present a risk for disease transmission. In january 2022, it was reported that the first ever pig heart from a donor pig with 10 genetic modifications had been transplanted into a human patient with severe heart disease; the patient lived for 2 months without major problems. Thus, it is expected that porcine xenografts will be used in a clinical setting within a foreseeable period of time. This requires clinical trials to systematically analyse the effects of such xenotransplants on the patient and will also need a suitable legal and financial framework.

Schlüsselwörter

Organmangel - genetisch veränderte Schweine - spezifische Abstoßungsreaktionen - porcine endogene Retroviren - Xenotransplantation - nicht humane Primaten

Key words

organ shortage - genetically modified pigs - specific immune rejection responses - porcine endogenous retroviruses - PERV - xenotransplantation - non-human primates

Publikationsverlauf

Artikel online veröffentlicht:
16. November 2022

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