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

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.