Brugière Olivier, Dreyfuss Dora, Guilet Ronan, Rong Sophie, Hirschi Sandrine, Renaud-Picard Benjamin, Reynaud-Gaubert Martine, Coiffard Benjamin, Bunel Vincent, Messika Jonathan, Demant Xavier, Le Pavec Jérôme, Dauriat Gaelle, Saint Raymond Christel, Falque Loic, Mornex Jean-Francois, Tissot Adrien, Lair David, Le Borgne Krams Aurelie, Bousseau Veronique, Magnan Antoine, Picard Clément, Roux Antoine, Glorion Matthieu, Carmagnat Maryvonick, Gazeau Florence, Aubertin Kelly, Carosella Edgardo, Vallée Alexandre, Landais Cecile, Rouas-Freiss Nathalie, LeMaoult Joel
Service de Pneumologie et Transplantation Pulmonaire, Hôpital Foch, Suresnes, France.
CEA, DRF-Institut de Biologie Francois Jacob, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.
Transplantation. 2025 Apr 1;109(4):736-745. doi: 10.1097/TP.0000000000005175. Epub 2024 Sep 19.
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.
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.
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]).
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.
循环细胞外囊泡（EVs）作为预测实体器官移植疾病预后的非侵入性生物标志物已显示出有前景的结果。由于肺移植（LTx）后移植物细胞原位表达耐受性分子HLA - G与移植接受相关，我们推测血浆中与EV结合的HLA - G（HLA - G EV）水平可预测慢性肺移植功能障碍（CLAD）的发生。
我们分析了来自肺移植队列的78例LTx受者，他们在LTx后的第一年内均处于稳定（STA）状态。在3年时，41例患者仍处于STA状态，37例发生了CLAD（闭塞性细支气管炎综合征，BOS，[n = 32]或限制性移植综合征[n = 5]）。在78例患者的第6个月（M6）和第12个月（M12）测量了HLA - G EV血浆水平。根据早期HLA - G EV血浆水平评估LTx后3年时CLAD的发生情况和移植物失败情况。
在随后发生BOS的患者中，（1）M12时的HLA - G EV水平显著低于STA患者（P = 0.013），（2）也显著低于其在M6时的先前水平（P = 0.04）。在M12时血浆HLA - G EV水平高的患者中，观察到3年时CLAD和BOS的发生率较低，移植物存活率较高（高HLA - G EV与低HLA - G EV患者[临界值21.3 ng/mL]：无CLAD，P = 0.002；无BOS，P < 0.001；移植物存活，P = 0.04，[对数秩检验]）。此外，在多变量分析中，M12时低HLA - G EV水平与3年后CLAD、BOS和移植物失败的后续风险独立相关（分别为P = 0.015、P = 0.036和P = 0.026 [Cox模型]）。
这项探索性研究表明，与EV结合的HLA - G血浆水平作为液体活检在预测CLAD/BOS发病和随后的移植物失败方面具有潜力。
