*Purpose: Induction of tolerance to heart allografts in non-human primates is possible with kidney cotransplantation and mixed chimerism-based induction therapy. However, donor brain death abrogates tolerance induction. Here, we investigated whether delaying conditioning and donor bone marrow transplantation (DBMT) eliminates the detrimental effects of donor brain death.

*Methods: Nine cynomolgus monkeys underwent combined heart/kidney transplantation from donors rendered brain-dead 4 hours prior to procurement. We compared two groups: group A (n=6) received DBMT on the day of solid organ transplant while group B (n=3) were maintained on triple immunosuppression for 4 months before undergoing DBMT. At time of DBMT, all recipients underwent conditioning with total body irradiation, thymic irradiation, ATG, anti-CD40L mAb and 28 days of CyA, after which all immunosuppression was stopped.

*Results: In group A, three simultaneous recipients rejected their allografts on days 127, 131 and 383, respectively, two died of PTLD and infection, and the remaining one underwent elective euthanasia on day 400 without signs of rejection. In group B, one recipient developed no detectable donor chimerism and rejected its allografts on day 135 and one was euthanized without signs of rejection due to sepsis. A third animal is still ongoing without histological signs of cellular or humoral allograft rejection on day 467 after DBMT and has been challenged with allonephrectomy on day 442 after DBMT.

*Conclusions: Donor brain death negatively impacts tolerance induction after mixed chimerism conditioning leading to a higher incidence of allograft rejection. Delaying recipient DBMT may mitigate the detrimental effects of donor brain death and its associated pro-inflammatory side-effects, thus increasing the chance of long-term tolerance compared to simultaneous solid organ and bone marrow transplantation.

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