Circulating Vesicular-bound HLA-G as Noninvasive Predictive Biomarker of CLAD After Lung Transplantation

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BACKGROUND: Circulating extracellular vesicles (EVs) have shown promising results as noninvasive biomarkers for predicting disease outcomes in solid organ transplantation. Because in situ graft cell expression of the tolerogenic molecule HLA-G is associated with acceptance after lung transplantation (LTx), we hypothesized that plasma EV-bound HLA-G (HLA-G EV ) levels could predict chronic lung allograft dysfunction (CLAD) development. METHODS: We analyzed 78 LTx recipients from the Cohort-for-Lung-Transplantation cohort, all in a stable (STA) state within the first year post-LTx. At 3 y, 41 patients remained STA, and 37 had CLAD (bronchiolitis obliterans syndrome, BOS, [n = 32] or restrictive allograft syndrome [n = 5]). HLA-G EV plasma levels were measured at month 6 (M6) and M12 in 78 patients. CLAD occurrence and graft failure at 3 y post-LTx were assessed according to early HLA-G EV plasma levels. RESULTS: In patients with subsequent BOS, (1) HLA-G EV levels at M12 were significantly lower than those in STA patients ( P = 0.013) and (2) also significantly lower than their previous levels at M6 ( P = 0.04).A lower incidence of CLAD and BOS and higher graft survival at 3 y were observed in patients with high HLA-G EV plasma levels at M12 (high versus low HLA-G EVs patients [cutoff 21.3 ng/mL]: freedom from CLAD, P = 0.002; freedom from BOS, P < 0.001; and graft survival, P = 0.04, [log-rank]). Furthermore, in multivariate analyses, low HLA-G EV levels at M12 were independently associated with a subsequent risk of CLAD, BOS, and graft failure at 3 y ( P = 0.015, P = 0.036, and P = 0.026, respectively [Cox models]). CONCLUSIONS: This exploratory study suggests the potential of EV-bound HLA-G plasma levels as a liquid biopsy in predicting CLAD/BOS onset and subsequent graft failure.

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