816 Different immunosuppressive regimens in preclinical, discordant xenogeneic, heterotopic thoracic pig-to-baboon heart transplantations
Wednesday November 18, 2015 from 15:30 to 17:00
Room 109

Tanja A. J. Mayr, Germany


Department of Anaesthesiology

Walter-Brendel-Centre - LMU Munich


Different immunosuppressive regimens in preclinical, discordant xenogeneic, heterotopic thoracic pig-to-baboon heart transplantations

Tanja Mayr1,3, Sonja Guethoff1,3, Bruno Reichart3, Stefan Buchholz1, Fabian Werner1,3, Martin Langenmayer4, Eckhard Wolf5, Nikolai Klymiuk5, David Ayares6, Christopher McGregor7, Claus Belka8, John Lambris9, Keith Reimann10, Christian Hagl1, Paolo Brenner1,3, Jan-Michael Abicht2,3.

1Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany; 2Department of Anaesthesiology, Ludwig-Maximilians University, Munich, Germany; 3Walter-Brendel-Centre, Ludwig-Maximilians University, Munich, Germany; 4Department of Veterinary Pathology, Ludwig-Maximilians University, Munich, Germany; 5Department of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians University, Munich, Germany; 6Revivicor Inc., Blacksburg, VA, United States; 7Department of Cardiothoracic Surgery, University College, London, United Kingdom; 8Department of Radiation Oncology, Ludwig-Maximilians University, Munich, Germany; 9Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States; 10MassBiologics, University of Massachusetts Medical School, Boston, MA, United States

Background: Preclinical discordant heterotopic thoracic cardiac xenotransplantation (XTx) combines a working heart model with the advantage of the recipient`s native heart as a backup in case of graft failure.

Methods: 23 captive-bred baboons were used as recipients of heterotopically transplanted hearts (technique Barnard, Losman) of juvenile genetically-modified pigs (genotype: GGTA1-knock out / hCD46 ± hTM or ± HLA-E). Basic immunosuppression (IS) included antiCD20mAb, bortezomib, anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, methylprednisolone, and immunoadsorption before and after XTx. There were 3 groups:  A (n=10) basic IS therapy only; B (n=11) long (1) respectively short (2) myeloablative pre-treatment and postoperative thoracic and abdominal lymphoid irradiation (TLI); and C (n=2) costimulation blockade with CD40mAb (clone 2C10R4).

Results:  Group A: four animals died during the early postoperative course, two within 24 hours. Excluding these early failures, the mean graft survival time for the remaining six animals was 22 ± 5.7 days. All pathologic findings correlated with the preclinical diagnoses of delayed humoral rejection.

Group B: in the subgroup 1, 3 of 4 animals did not come off the operation table due to friable (vascular) tissue, remaining baboon developed septic features on POD 14; 7 of 7 baboons of subgroup 2 were  weaned from extracorporeal circulation and extubated. Two animals succumbed to non-IS related causes: central pontine myelinolysis, acute peritonitis; omitting the two experiments, mean graft survival time was 20.2 ± 8.4 d. Pathohistological signs of humoral rejection were significantly less when compared to these of group A.

Group C: both baboons had to be sacrificed with good graft functions on POD 13 (pulmonary oedema) and POD 35 (bacterial sepsis). Only the first xenograft showed mild humoral rejection grades, while that of POD 35 had a nearly normal myocardium.

Conclusions: Preclinical heterotopic thoracic cardiac XTx is possible. The immediate postoperative results were excellent, but in the longer-term run limited by our IS regimens of groups A and B; the big donor organs within the narrow baboon`s chests were also detrimental (will not be a problem in a future clinical setting). In accordance to the implementation of the new European Directive on animal welfare we had to stop our experiments. After major changes, including new operative facilities, we will now continue with orthotopic procedures and CD40mAb as in group C.

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