Background The role of the innate immune system in the development of thrombotic microangiopathy (TM) after α1,3-galactosyltransferase gene-knockout (GTKO) pig organ transplantation in primates is uncertain. Methods Twelve organs (9 hearts, 3 kidneys) from GTKO pigs were transplanted into baboons that received no immunosuppressive therapy, partial regimens, or a full regimen based on costimulation blockade. After graft failure, histological and immunohistological examinations were carried out. Results Graft survival of <1 day was prolonged to 2–12 days with partial regimens (acute humoral xenograft rejection [AHXR]) and to 5 and 8 weeks with the full regimen (TM). Clinical and/or laboratory features of consumptive coagulopathy occurred in 7 of 12 baboons. Immunohistochemistry demonstrated IgM, IgG, and complement deposition in most cases. Histopathology demonstrated neutrophil and macrophage infiltrates, intravascular fibrin deposition and platelet aggregation (TM). Grafts showed expression of primate tissue factor (TF), with increased mRNA levels, and TF was also expressed on baboon macrophages/monocytes infiltrating the graft. Conclusions Our data suggest: (i) irrespective of the presence or absence of the adaptive immune response, early or late xenograft rejection is associated with activation of the innate immune system; (ii) porcine endothelial cell activation and primate TF expression by recipient innate immune cells may both contribute to the development of TM.

Background Three costimulation-blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb. Methods All pigs were on an α1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n=4) expressed additional CD55, and those into Group B (n=3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n=2) or abatacept (Regimen 2: n=2) or anti-CD40mAb+belatacept (Regimen 3: n=2). Regimens1/2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy. Results Group A baboons survived 15–33 days, whereas Group B survived 52, 99 and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4m, areas of myofiber degeneration and scarring were seen in 2 hearts at necropsy. A T cell response was documented only in baboons receiving Regimen 2. Conclusions The combination of anti-CD40mAb+belatacept proved effective in preventing a T cell response. Expression of TBM prevented thrombocytopenia, and may possibly delay the development of TM and/or consumptive coagulopathy.

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Donor lung procurements performed by beginners with limited transplant experience included frequent technical errors with regard to adequate graft preservation, which may lead to serious complications after transplant. Sequential steps in lung procurement techniques and better understanding of organ preservation should be an integral part of a lung transplant training program.