A Multi-Center Study of BAL CXCR3 Chemokines during Allograft Injury after Lung Transplantation
PURPOSE: The occurrence of acute allograft injuries remains one of the most important factors responsible for the development of early chronic lung allograft dysfunction. We and others have previously demonstrated a consistent association between acute lung injury (ALI), acute perivascular rejection (AR) and lymphocytic bronchiolitis (LB) and the subsequent development of CLAD. However, the pathogenesis of these allograft injuries remains poorly understood. CXCL9, CXCL10, and CXCL11 are CXC chemokines induced by interferon-γ and act as potent chemoattractants of mononuclear cells (e.g., activated T-cells and NK cells). We hypothesized that episodes of ALI, AR and LB would be associated with increased activity of these CXCR3 chemokines, as measured in the BAL at the time of the injury. METHODS: The study cohort consisted of the first 200 lung transplant recipients enrolled in Clinical Trials in Organ Transplantation-20 (NCT02631720), a prospective multi-center observational study collecting serial clinical data and biologic samples from 5 North American transplant centers. Recipients received a median (Q1,Q3) of 5 (3, 6) bronchoscopies during the first-year post-transplant. Transbronchial biopsies (TBBXs) with no histopathologic evidence of allograft injury were classified as "healthy". BALF CXCL9, CXCL10 and CXCL11 mean fluorescence intensities (MFIs) were measured using luminex bead assays. To evaluate differences in CXCR3 chemokine levels between allograft injuries and healthy biopsies, multivariable linear mixed effects models were constructed taking into account repeated measurements from recipients. RESULTS: There were 844 TBBXs with 249(30%) episodes of allograft injury observed. There were 173(20%) episodes of AR, 30(4%) episodes of LB and 42(5%) episodes of ALI. Biopsies with AR, LB or ALI were associated with significant elevations in all three chemokines compared with healthy biopsies (p<0.01). For CXCL9 and CXCL10, ALI had the highest MFIs, followed by AR and LB. For CXCL11, AR had the highest MFIs followed by ALI and LB. CONCLUSION: We demonstrate for the first time in a multicenter study, CXCR3 chemokine elevations during episodes of acute allograft injury. These findings support the association of CXCR3 chemokines during episodes of AR, LB and ALI, and may potentially offer novel therapeutic targets to prevent and treat these deleterious events.
Shino, MY; Elashoff, RM; Li, N; Todd, JL; Neely, ML; Kopetskie, H; Sever, M; Kirchner, J; Frankel, CW; Snyder, LD; Pavlisko, EN; Martinu, T; Singer, LG; Tsuang, W; Budev, M; Shah, PD; Williams, N; Robien, M; Reynolds, JM; Palmer, SM; Weigt, SS; Belperio, JA
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