Class‐II Molecular Mismatch as an Independent Risk Factor of Chronic Allograft Lung Dysfunction Development in Lung Transplantation

Chronic allograft dysfunction (CLAD) is the main cause of graft loss after lung transplantation (LTR). Within the immunological factors involved in CLAD development, the antibody-mediated rejection (ABMR) has the most impact. However, ABMR diagnosis is difficult due to the limited sensitivity of histopathological, immunhistochemical, and immunological criteria currently used. Growing evidence is demonstrating the impact of molecular mismatch in ABMR; here, we ought to assess the potential role of molecular mismatch in CLAD development. A total of 457 LTR were recruited for the study, with HLA type from donors and recipients to assess molecular mismatch, and with a minimum follow-up of 180 days. The combination of molecular mismatch in class-II (HLA-EMMA and HLA-Matchmaker algorithms) with EMMA DR score >12 and antibody verified eplet mismatch in DRB1345 (AbV DRB1345) > 3 predicts CLAD development independently of ex-smoker, prolonged period of hospitalization (>33 days), acute cellular rejection (ACR), and ABMR. The HR of the prediction model for molecular mismatch in class-II was 1.52 (1.01-2.56, p=0.045). This observation could point to a potential role of poor molecular mismatch in class-II to fill the gap of underdiagnosis of ABMR, previous to CLAD development. Prospective studies should be addressed to confirm the utility of molecular mismatch in the identification of patients at risk of CLAD development.