The donor lung as Trojan Horse*: flushing after preservation radically reduces immune burden
Flushing the donor lung after preservation prior to transplantation removes harmful “passenger”* leukocytes and inflammatory cytokines involved in primary graft dysfunction (PGD).
A recent porcine study from Manchester(2) found that a post-preservation flush with 500 ml STEEN SolutionTM after cold preservation removed at least a billion harmful “passenger” leukocytes and inflammatory cytokines implicated in the etiology of ischemia-reperfusion injury and PGD. The vast majority of these donor leukocytes were T-cells and the most abundant cytokine was IL-18.
*Of course , this problem with “passenger” donor leukocytes concealed within the donor Trojan horse lung and thereby bypassing the body´s natural immunodefense barrier, is not new – as we reported in INSIGHTS in June 2017.
EVLP filter traps passenger leukocytes
Earlier studies(3) from the same group in Manchester have shown that a substantial part of these donor-derived passenger leukocytes is removed by the leukocyte filter built into XVIVO’s XPSTM and other ex-vivo lung perfusion (EVLP) circuits. But this protection only applies, of course, to lungs subjected to EVLP, which are primarily sub-standard or marginal lungs.
For standard lungs not subjected to EVLP, the new intriguing findings from Manchester on the effects of post-preservation flushing with STEEN SolutionTM seem to offer a simple, rational option for all preserved lungs, whatever their quality, to further minimize the risks of post-transplant ischemia-reperfusion injury and associated primary graft failure.
Many studies, although not all, also indicate that passenger leukocytes probably drive acute rejection and may also be involved in the development of subsequent chronic rejection(3, 3A, 3B, 3C, 3D).
Cytokine absorbent devices
Although the leukocyte filter incorporated into the EVLP circuits removes a substantial portion of harmful passenger leukocytes, most of the inflammatory cytokines pass through the filter and re-circulate in the perfusate.
To address this issue, studies from Zurich have focused on inclusion of a cytokine-absorbent device (Cytosorb) placed in the EVLP circuit. Previous work on this device from the same center(4), showed that continuous perfusate filtration through Cytosorb sorbent beads is effective and safe during prolonged EVLP. Cytokine removal decreased the development of pulmonary edema and electrolyte imbalance through the suppression of anaerobic glycolysis and neutrophil activation in this setting.
More recently, a deeper investigation by the same Zurich group(5), in the same extremely prolonged (24 hours) ischemic injury model, reports marked depletion of a broad spectrum of inflammatory cytokines from the EVLP perfusate. The authors were also able to correlate cytokine reductions with improved EVLP physiology and biochemistry during the six-hour perfusion period and with improved immediate post-transplant graft function and a less intense inflammatory response to reperfusion.
Although several commentaries generated after publication of this latest Zurich study were generally quite positive, some authors noted that the current Cytosorb device is non-discriminatory, absorbing both pro- and anti-inflammatory cytokines and also reducing perfusate levels of antibiotics and steroids.
The lung as immune garbage collector
Apart from the high concentrations of residual leukocytes normally present in the donor lung, it´s worth noting that during the last few hours of the donor´s life, the lung has functioned as the body´s principle filter for all manner of circulating thromboembolic and necrotic cell debris, microaggregates of activated adhesive leukocytes, platelets and fibrin. And although standard quality lungs may present a lower immune burden risk than sub-standard or marginal lungs, all donor lungs, whatever their quality, pose an inherent risk of ischemia-reperfusion injury, ARDS and other complications directly related to the Trojan horse nature of their origin.
Fortunately, the presence of dextran in PERFADEX® and STEEN SolutionTM suppresses further activation and adhesion of leukocytes and platelets to the microcirculatory endothelium(6, 7) thereby aiding the flush removal of these unwelcome guests.
XVIVO Insights PB-2021-02-04
3a. Maria Lucia L Madariaga, et al: Recipient-matching of Passenger Leukocytes Prolongs Survival of Donor Lung Allografts in Miniature Swine. Transplantation. 2015 Jul;99(7):1372-8. doi: 10.1097/TP.0000000000000676. Full text at; – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494890/ (link to Abstract)
3b. Kate Colette Tatham, et al: Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury Thorax . 2018 Apr;73(4):350-360. doi: 10.1136/ Full text at; – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870457/ (link to Abstract)
3c. Pietra BA, et al: CD4 T cell‐mediated cardiac Acute Rejection requires donor but not host MHC class II. J Clin Invest 2000; 106: 1003–1010.
3d. R I Lechler, et al: Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J Exp Med . 1982 Jan 1;155(1):31-41. doi: 10.1084/jem.155.1.31. PMID: 7033437 PMCID: DOI: 10.1084/jem.155.1.31