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Life-supporting orthotopic cardiac xenotransplantations (OHXTx) in a pig-to-baboon model with GalT-KO/hCD46/hTM transgenic donor pigs were performed with a compatible, non-toxic immunosuppression (IS) based on CD40mAb co-stimulation blockade in group G1 and in a group G2 with a new pasylated, non-thrombogenic CD40L-Ab. Chemical procedure of PASylation prolongs plasma half-life by 170-fold to several days. Primary aims were to realize a constant preclinical long-term survival in a life-supporting cardiac xenotransplantation model and to prevent perioperative cardiac xenograft dysfunction (PCXD) as a kind of cardiac low output.OHXTx according to the technique of Lower and Shumway were performed in 11 baboons with transgenic pig hearts. The new IS consisted of a recombinant mouse-rhesus chimeric CD40 (clone 2C10R4) antibody in G1 (n=7) or a PASylated Fab-CD40L antibody (XL-protein/Wacker-Chemie) in G2 (n=4) combined with ATG, rituximab, MMF (no tacrolimus or cyclosporine!) and steroids.Survival in G1 with CD40mAb were 3, 1, 30, 1, 1** and 27 day(s) with 2 cases of PCXD. Using CD40L-Ab in G2 PCXD was observed in 1 case and the recipients survived 1, 18 and 40 days. Ischemic time of the hearts ranged from 112-128 min. Primary cause of death mostly were renal and hepatic failure, one died of a neurological deficit**, another after hematothorax, but no hyperacute or delayed xenograft rejection occurred. After several weeks a pig donor organ (over)growth was found. All long-term surviving baboons were in good general conditions until to the last days. Mean survival in G1 (CD40Ab) was 10.5+/-4.90 days and in G2 (Fab-CD40L) 19.7+/-7.84 days and without PCXD and brain damage** 20+/-6.55 days in G1 and 29+/-7.78 days in G2. In a preliminary modified subgroup (unpublished data und matter of a patent) one baboon with CD40L-Ab survived 50 days and another baboon (B67 with CD40Ab) reached and was successfully terminated at the endpoint of study on day 90 with no signs of rejection of the xenograft.Co-stimulation blockade with CD40L antibody tended to prolong survival time after orthotopic cardiac xenotransplantation, but with so far incomplete groups statistically not significant. In total survival in this important life-supporting orthotopic model was significantly prolonged with a less toxic IS and better quality of life. This is an important milestone and progress on the way to a long-term survival of 2 -3 months, which is necessary for first clinical cardiac xenotransplantations. This aim was now first time worldwide reached with our last 90-days surviving baboon B67 in the last subgroup and must be replicated another 5 times before starting a clinical study.