Thorac Cardiovasc Surg 2016; 64 - OP257
DOI: 10.1055/s-0036-1571687

Costimulation Blockade with CD40mAb in (Life-Supporting) Heterotopic and Orthotopic Cardiac Xenotransplantation of GalT-KO/hCD46/hTM Transgenic Pig Hearts in a Pig-to-Baboon Model

P. Brenner 1, T. Mayr 2, S. Guethoff 1, S. Buchholz 1, T. Pöttinger 1, I. Lutzmann 2, F. Werner 2, A. Bauer 3, N. Klymiuk 4, E. Wolf 4, K. Reimann 5, M. Mohiuddin 6, W. Hermanns 7, D. Ayares 8, C. McGregor 9, J. Lambris 10, C. Hagl 1, B. Reichart 2, J.-M. Abicht 3
  • 1Clinic of Grosshadern, Ludwig-Maximilians-University of Munich, Dept. of Cardiac Surgery, Munich, Germany
  • 2Walter-Brendel-Centre, LMU Munich, Munich, Germany
  • 3Clinic of Grosshadern, Ludwig-Maximilians-University of Munich, Dept. of Anesthesiology, Munich, Germany
  • 4Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-University of Munich, Munich, Germany
  • 5MassBiologics, University of Massachusetts Medical School, Boston, United States
  • 6Cardiothoracic Surgery Research Laboratory, NHLBI; NIH, Bethesda, United States
  • 7Clinic of Grosshadern, Ludwig-Maximilians-University of Munich, Dept. of Veterinary Pathology, Munich, Germany
  • 8Revivicor Inc., Blackburg, United States
  • 9University College London, Dept. of Cardiothoracic Surgery, London, United Kingdom
  • 10University of Pennsylvania, Pathology and Laboratory Medicine, Philadelphia, United States

Aim: To verify and reproduce the excellent > 2 years long-term survival of the heterotopic, nonlife-supporting abdominal heart xenotransplantation (AHHXTx) model of Mohiuddin's group with a recombinant mouse-rhesus chimeric CD40 antibody (clone 2C10R4) this costimulation blockade was used in the life-supporting thoracic heterotopic (THHXTx) and orthotopic (OHXTx) heart transplant models.

Methods: Barnard and Losmaǹs piggy back technique of the HHXTx was done in 2 baboons, orthotopic OHXTx (Lower and Shumway technique) in four. Therefore a specially designed heart-lung machine was utilized with small tubings and a crystalloid filling volume of 190 ml; Bretschneider solution served for heart preservation (ischemic times 183 ± 17 minute, 122 ± 8 minute respectively). Donor organs were used from triple genetically-modified pigs (GalT-KO/hCD46/hTM). CD20mAb (Rituximab) was administered on days -7, 0, 7, 14, CD40mAb on days -1, 0, 3,7,10, 14, 19, then weekly, ATG on days -2, -1; basic immunosuppression consisted of mycophenolate mofetil ± tacrolimus and steroids. It was started the C3-complement inhibitor Compstatin on day -1 and was then continuously given at a dose of 5.7mg/kg.

Results: In total all recipients were weaned from cardiopulmonary bypass, extubated were five. Survival after THHXTx was 13 and 35d and after OHXTx 3, 29 and twice 1 day (s). Primary causes of death were: pulmonary edema, mediastinitis respectively renal failure, vagal syncope, arrhythmias/heart failure (in the last 2). There was no hyperacute rejection observed in any case and delayed humoral xenograft rejection once (pulmonary edema on POD13). Summarizing both long-term survivors were in good general condition till almost the end of the observation period.

Conclusion: Thus in this preclinical setting, THHXTx was helpful in the immediate p.o. handling, since the recipient̀s heart was able to support a temporarily weak donor organ function (due the extended ischemic time). In the longer-term, the doubling of the cardiac weights impedes the lung function due to the special baboon chest anatomy (an observation which fortunately will not apply to a clinical situation). Further improvements of the heart-lung machine run and CD40 mAb will make preclinical OHXTx a long-term reality in view to a clinical application.