Abstract Rationale Chronic lung allograft dysfunction (CLAD) is the most common cause of death in patients following lung transplantation, affecting half of all transplant recipients by 5 years. While risk factors for severe CLAD have been identified, there are to date no clear predictive biomarkers of CLAD. The objective of this project is to identify patterns of cytokine secretion, including the serine protease granzyme K (GZMK) and TGF-beta family member GDF15, in patients who have undergone lung transplant, and to determine whether they are predictive of acute and/or chronic rejection. Understanding of plasma and BAL predictors of CLAD will allow for better management of transplant patients and potential identification of targetable mechanisms of chronic rejection. Methods Plasma samples and BAL supernatant were obtained from a biobank of specimens collected from lung transplant patients at time of surveillance bronchoscopy. ACR status, BAL culture results, and CMV/EBV titers at sample collection were obtained from chart review. Cytokine levels in plasma and BAL were measured using ELISA for GZMK/GDF15 and a multiplexed flow cytometric bead array for 13 inflammation-associated cytokines. Plasma samples were clustered using UMAP. Results A total of 86 plasma and 56 BAL samples from a total of 57 patients were analyzed, with 42 patients with paired plasma and BAL and 33 patients with plasma and/or BAL from time points with and without ACR. Plasma cytokine signatures formed roughly 4 clusters, based primarily on CCL2 and GDF15/GZMK expression. There was no association between plasma GZMK and GDF15 levels; CMV viremia was associated with increases in all inflammatory markers. Plasma cytokine signature, GZMK, and GDF15 levels did not significantly correlate with acute cellular rejection (ACR). Consistent with prior work, elevations in IL-6, IL-8, and IL-18 were seen in BAL samples with positive cultures. Conclusions Plasma cytokine signatures from post-lung transplant patients form discrete phenotypes based on expression of inflammatory cytokines including GDF15 and GZMK. There was no correlation between plasma and BAL cytokine levels, implying tissue specificity of cytokine signatures. Future work will aim to correlate these signatures with the development of CLAD and investigate expression patterns of other secreted factors. This abstract is funded by: NIH T32HL007563-37, NIH R01HL167901-03
Lieberman et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: