Donor and Recipient Cytokine Profiles Predict Acute Rejection and Graft-Related Survival After Heart Transplantation

Abstract

<h3>Purpose</h3> Heart transplant results have improved but primary graft dysfunction (PGD) and acute rejection remain obstacles for long-term survival. Donor and recipient inflammation may be involved in immune activation of the transplant, resulting in adverse consequences. Here, we investigated donor and recipient plasma and intragraft cytokine profiles and searched for predictive markers for unfavourable outcomes. <h3>Methods</h3> Perioperative donor and recipient plasma samples and myocardial biopsies of 84 heart transplants were analyzed. Plasma and intragraft cytokine levels were determined by multiplexed and next-generation sequencing platforms. The development of PGD, acute rejection, and graft-related survival up to 1 year after transplantation, were examined. Maximally selected rank statistics was used to determine the cytokine cut-off values for prediction of rejection or graft-related survival. <h3>Results</h3> Severe PGD was associated with early mortality and an increase in intragraft and plasma proinflammatory cytokines. Cytokine network analysis identified interleukins -6, -8, -10, and -18 as key players during reperfusion injury. Low donor plasma levels of IL-1Ra, MIF, MIP1a, and eotaxin increased the risk of ≥G2R rejection in the first year. High recipient preoperative and postoperative levels of various proinflammatory cytokines were linked with an increased risk of graft-related 1-year mortality. <h3>Conclusion</h3> Severe PGD was associated with a proinflammatory cytokine profile in the recipients. A high immunological risk score based on donor plasma cytokines predicted acute rejection, while recipient cytokine-based risk scores predicted graft-related 1-year mortality. Our results suggest that these predictive markers could potentially be used to tailor recipient immunosuppression and to improve organ allocation.