Evidence of indirect allorecognition of HLA /non-HLA antigens expressed by bronchial epithelial cells from lung transplant recipients

Survival after lung transplantation (LTx) remains limited by the occurrence of bronchiolitis obliterans (BO), thought to be a form of chronic rejection. In BO, an indirect allorecognition of both HLA and non-HLA antigens (Ags) expressed by bronchial epithelial cells (BEC) is highly suspected as a crucial trigger for BECs damages, although levels of proof remain weak. We here investigated the indirect allorecognition of Ags expressed by BEC in an original ex-vivo model established from samples of LTx recipients (LTxR). To reproduce the immune crosstalk that may occur in patients, 3 distinct cell types originated from the same LTxR were used: allogenic BECs (graft cells) in primary cultures, monocyte derived dendritic cells (DCs) and peripheral T cells. Mixed lymphocyte reactions were performed between T cells (responding cells) and DCs (stimulating cells) that had been or not previously loaded with Ags such as alloBECs lysates (n=10) or tetanus toxoid (TT) (n=6) as Ag positive control. Four healthy individuals were used as controls with TT-loaded DCs. In LTxR, T-cell proliferation was increased by 49% [16-87%] when DCs loaded with alloBEC lysates were used. TT-loaded DCs increased T-cell proliferation by 51% [9-97]% in controls, but only by 4% [0-76%] in LTxR. These measures were highly variable in both patients and controls. This ex-vivo model allowed us to demonstrate that LTxR display a specific T-cell response against alloBECs Ags through indirect allorecognition mechanism. Further objectives are the ability of this model to early predict BO in LTxR and to gain insight into the respective role of HLA and non-HLA Ags from BECs in alloreactivity.