HLA‐C mismatching improves outcomes following lung transplantation

HLA (HLA) are a major barrier to transplant success, as HLA‐A and ‐B molecules are principal ligands for T‐cells, and HLA‐C for Killer cell Immunoglobulin‐like Receptors (KIR), directing Natural Killer (NK) cell function. HLA‐C molecules are designated “C1” or “C2” ligands based on residues 77 and 80, which determine the NK cell responses. Here, we investigated donor/recipient HLA‐C mismatch associations with the development of chronic lung allograft dysfunction (CLAD) following lung transplantation (LTx). 310 LTx donor/recipient pairs were Next Generation Sequenced and assessed for C1 and C2 allotypes. PIRCHE scores were used to quantify HLA mismatching between donor/recipients at amino acid level and stratify recipients into low, moderate or highly mismatched groups ( n = 103–104). Associations between C ligands and freedom from CLAD was assessed with Cox regression models and survival curves. C2/C2 recipients ( n = 42) had less CLAD than those with C1/C1 ( n = 138) or C1/C2 genotypes ( n = 130) ( p < 0.05). Incidence of CLAD was lower in C2/C2 recipients receiving a mismatched C1/C1 allograft ( n = 14), compared to matched ( n = 8) or heterozygous ( n = 20) allografts. Furthermore, ~80% of these recipients (C2/C2 recipients receiving C1/C1 transplants) remained CLAD‐free for 10 years post‐LTx. Recipients with higher HLA‐C mismatching had less CLAD ( p < 0.05) an observation not explained by linkage disequilibrium with other HLA loci. Our data implicates a role for HLA‐C in CLAD development. HLA‐C mismatching was not detrimental to LTx outcome, but potentially beneficial, representing a paradigm shift in assessing donor/recipient matching. This may inform better selection of donor/recipient pairs and potentially more targeted approaches to treating CLAD.