Donor Brain Death Affects Tolerance Induction in Nonhuman Primates

Background: Induction of durable allograft acceptance in combined heart/kidney transplantation in nonhuman primates is possible by applying a mixed chimerism-based conditioning protocol. However, the impact of donor brain death on tolerance induction is unclear. To gain insight on these clinically relevant donor characteristics, we investigated whether donor brain death impacts allograft acceptance in combined heart/kidney transplantation.

Methods: Six cynomolgus monkey underwent combined heart/kidney transplantation using organs from donors rendered brain death 4 hours prior to organ procurement. As a control group, six animals underwent the same protocol using non-brain-dead donors. Recipients underwent nonmyeloablative conditioning that including total body irradiation, thymic irradiation, horse anti-thymocyte globulin, anti-CD154 mAb, CyA, and donor bone marrow transplantation (DBMT). All drugs were stopped 29 days after DBMT.

Results: Brain dead donor animals showed significantly elevated levels of IL-6, IL-10, as well as IL-1 receptor antagonist as compared with non-brain-dead animals. In the control cohort using non-brain-dead donors, all but one recipient developed long-term allograft acceptance. In the experimental group, two animals rejected their allografts due to severe cellular rejection by days 127 and 131, respectively. A third animal showed signs of antibody mediated as well as cellular rejection 24 weeks after transplantation and the allo-heart finally stopped beating on day 383 after transplantation. Two animals were euthanized without signs of rejection on days 30 and 114 after transplantation due to sepsis and PTLD, respectively. One animal underwent elective euthanization on day 400 after transplantation without signs of rejection. Animals receiving organs from brain dead donors developed earlier and higher levels of donor-specific antibodies as compared to control animals. Donor brain death had no impact on donor chimerism but animals receiving organs from brain dead donors showed elevated levels of proinflammatory cytokines for a prolonged period after transplantation.

Conclusion: Donor brain death negatively impacts tolerance induction in a mixed chimerism model, leading to higher incidence of humoral as well as cellular rejection. Further investigations are currently assessing whether a period of ex vivo perfusion would quench the intra-graft inflammatory state and enable tolerance induction of organs from brain dead donors.