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Stand der Technik und Durchbruch bei der kardialen Xenotransplantation

Schweineherzen als alternative Lösung des Spenderorganmangels

State of the art and breakthrough in orthotopic cardiac xenotransplantation (Nature paper 12/2018 (1))

Porcine hearts as alternative solution to lack of donor organs

  • Stand der Wissenschaft
  • Published:
Zeitschrift für Herz-,Thorax- und Gefäßchirurgie Aims and scope

Zusammenfassung

Ziel

Um terminal herzkranken Patienten, die häufig aufgrund des Spendermangels nicht die erforderliche Herztransplantation erhalten, eine mögliche Alternative zu bieten, gelang nach 25 Jahren Forschung der Münchner Arbeitsgruppe um Prof. Paolo Brenner und Prof. Bruno Reichart, gemäß einer Nature-Publikation, im erforderlichen präklinischen Modell, der sog. orthotopen Xenotransplantation von Schwein auf Pavian, der entscheidende Durchbruch.

Methoden

Dabei konnte ein konstantes, reproduzierbares Langzeitüberleben von multitransgenen (GalKO/CD46/hTM‑)Schweineherzen mit einer neuen Immunsuppression beim Empfänger auf der Basis einer CD40-Antikörper-Kostimulationsblockade erzielt werden. Zusätzlich wurde die initiale Xenotransplantatfunktion durch die Verwendung einer neuen, nichtischämischen, sauerstoffhaltigen Kaltperfusionstechnik deutlich verbessert, und dadurch wurde das Problem der „perioperativen kardialen Xenotransplantatdysfunktion“ (PCXD), eines häufigen, frühen Xenotransplantatversagens, gelöst. Schließlich wurde noch die Problematik der schnell wachsenden, jungen Schweineherzen mit einer Wachstumskontrolle durch antihypertensive und antiproliferative Medikamente (mit unter anderem einem mTOR-Inhibitor) erfolgreich angegangen.

Ergebnisse und Diskussion

Insgesamt wurde ein einzigartiges Langzeitüberleben von 90 Tagen (n = 4) und in 2 Fällen 182 sowie 195 Tagen mit gezieltem Versuchsabbruch erreicht, ohne Nachweis einer hyperakuten oder verzögerten Abstoßung. Die Arbeit stellt gemäß den Empfehlungen der ISHLT, nämlich ein Überleben von 90 Tagen im orthotopen Primatenmodell von 60 % der Tiere zu erreichen, die Grundlage für einen Einsatz von Schweineherzen und die Voraussetzung für eine erste klinische Phase-I-Studie in den nächsten 2–5 Jahren am Patienten dar.

Abstract

AIM

According to the ISHLT advisory board guidelines for xenotransplantation (XT) a 90-day survival of a minimal 60 % (6 of 10 baboons) in a life-supporting orthotopic pig-to-baboon model (oXHTx) is recommended as a prerequisite to begin a clinical cardiac XT program.

The Munich xenotransplantation research team around Prof. Paolo Brenner and Prof. Bruno Reichart reproduced a previous excellent survival of 945 days in a non-life-supporting abdominal model now in a life-supporting orthotopic model with the same CD40mAb costimulation blockade immunosuppression (IS).

Methods

In the Munich team oXHTx in baboons with GalKO/hCD46/hTM transgenic (tg) pig hearts was performed using a basic IS consisting of ATG, rituximab, MMF, cortisone and CD40mAb. To avoid early perioperative cardiac xenograft dysfunction (PCXD) as a kind of early cardiac low output, we replaced the crystalloid cardioplegia with a non-ischemic 8 ℃ cold perfusion solution with oxygenated erythrocytes. To prevent pig xenograft overgrowth and hypertrophy, antihypertensive drugs and an anti-proliferative mTOR inhibitor (temsirolimus) were used.

Results

In comparison to crystalloid cardioplegia, now with non-ischemic cold perfusion no PCXD was found. With successful treatment of xenograft (over)growth and hypertrophy, 6 recipient baboons were long-term surviving (4 were actively terminated after 90 days according to the guidelines of the government). Two further experiments could be prolonged up to 182 and 195 days. All baboons lived under excellent physical conditions with no hyperacute or delayed xenograft rejection.

Discussion

Within the last 3 years after 25 years of experimental research in oXHT now we achieved a major progress and the essential milestone and breakthrough by realizing a constantly reproducible long-term survival of 3–6 months. Now the prerequisite according to the ISHLT for beginning a clinical phase I study are fulfilled and paves the way to clinical cardiac XT in the next 2–5 years.

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  1. Herzchirurgische Klinik und Poliklinik am Klinikum Großhadern, Ludwig-Maximilians-Universität München, Marchioninistraße 15, 81377, München, Deutschland

    Paolo Brenner

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Der vorliegende Beitrag ist eine Zusammenfassung der Originalarbeit der Autoren: Längin M, Mayr T, Reichart B (2018) Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 564 (7736): 430–433.

Der Inhalt dieser Arbeit wurde 2020 mit dem Ernst-Derra-Preis der Deutschen Gesellschaft für Thorax‑, Herz- und Gefäßchirurgie ausgezeichnet.

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Brenner, P. Stand der Technik und Durchbruch bei der kardialen Xenotransplantation. Z Herz- Thorax- Gefäßchir 36, 334–354 (2022). https://doi.org/10.1007/s00398-022-00534-6

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