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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
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.