Donor Brain Death Inhibits Tolerance Induction in Miniature Swine Recipients of Fully MHC-Disparate Pulmonary Allografts

Abstract

We have previously shown that a short course of high-dose tacrolimus induces long-term tolerance to fully mismatched lung allografts procured from healthy MHC-inbred miniature swine. Here, we investigate whether donor brain death affects tolerance induction. Four recipient swine were transplanted with fully mismatched lung grafts from donors that were rendered brain dead and mechanically ventilated for 4 h before procurement (Group 1). These recipients were compared to two control groups (Group 2: 4 h of donor ventilation without brain death [n = 5]; and Group 3: no donor brain death with <1 h of ventilation [n = 6]). All recipients were treated with a 12-day course of tacrolimus. In contrast to both groups of control animals, the swine transplanted with lung allografts from brain dead donors all rejected their grafts by postoperative day 45 and showed persistent responsiveness to donor antigen by MLR. Several additional swine underwent brain death induction and/or mechanical ventilation alone to determine the effects of these procedures on the expression of proinflammatory molecules. Significant increases in serum concentrations of IL-1, TNF-α and IL-10 were seen after brain death. Upregulation of IL-1 and IL-6 gene expression was also observed.

The effects of brain death and ischemia on tolerance induction are organ-specific

“…To demonstrate the organ-specific effects of brain death on tolerance induction, we compared the survival times of recipients co-transplanted with heart/kidney allografts from brain dead donors to recipients of brain-dead lung allografts (data published previously (3)). In this comparison, all brain-dead allografts were retrieved four hours after intracerebral injury and all allografts were transplanted across a full MHC barrier with the same 12-day course of tacrolimus.…”

“…Under general anesthesia, brain death was induced by intracranial inflation of a 30 cc Foley catheter over a period of one minute (3) which elicited a Cushing response. All donors were mechanically ventilated and similarly supported with crystalloid fluids and dopamine to maintain an adequate blood pressure for 4 or 8-hours following brain death.…”

“…We showed that a 12-day course of high-dose tacrolimus induced long-term tolerance in recipients of fully MHC-mismatched lung allografts procured from healthy, non-brain-dead donors. However, when lung allografts were procured from donors rendered brain dead and mechanically ventilated for four hours prior to organ procurement, they were all rejected within 45 days (3). These data confirm, in a preclinical model, that the deleterious effects of brain death in the donor have the potential to render an otherwise successful tolerance protocol ineffective.…”

Organ-specific differences in achieving tolerance

“…To our knowledge, the only large animal study to address this question is our earlier report in MHC inbred miniature swine showing that following traumatic brain death, proinflammatory cytokines were released systemically in the donor's serum and up-regulated in the donor's tissue. Furthermore, transplanting lung allografts procured from these brain dead donors resulted in the failure of a tolerance induction protocol that was otherwise successful when allografts were retrieved form non-brain dead donors (76). However, in contrast to lung recipients, brain death and ischemia did not prevent tolerance induction in analogously treated heart/kidney recipients (Michel S. manuscript submitted).…”

Update on lung transplantation: programmes, patients and prospects

“…There is also some evidence that the nature of injury and the duration of donor brain death, especially where PGD occurs, can suppress the development of tolerance [394] suggesting the possibility of still further improving graft harvesting and preservation methods. The improved short-and long-term outcomes seen with DCD LTx are perhaps an excellent example of this [40].…”