Donor and recipient human leukocyte antigen-G polymorphisms modulate the risk of adverse immunologic events following lung transplantation.

The long-term benefits of lung transplantation (LTx) are limited by pathogenic alloimmune responses that drive injury, inflammation, and chronic dysfunction. Human leukocyte antigen-G (HLA-G) plays a key role in the modulation of these pathways. This study assesses the impact of the HLA-G genotype on immunologic risk and survival following LTx. This retrospective cohort study included 289 bilateral LTx. Recipient and donor HLA-G genotypes were analyzed to identify associations with de novo donor-specific antibodies, acute rejection, chronic lung allograft dysfunction, and allograft survival. We further assessed these associations, both individually and in paired analysis, based on a grouped haplotype classification of HLA-G expression. Donor HLA-G single nucleotide polymorphisms were associated with allograft injury, the onset of chronic lung allograft dysfunction following injury, and allograft survival. Recipient HLA-G single nucleotide polymorphisms were associated with allograft injury, cellular rejection, and donor-specific antibody formation. "Low HLA-G expression" donor haplotypes were associated with impaired allograft survival, as were "low HLA-G expression" donor-recipient haplotype pairs. This study provides compelling evidence for the role of HLA-G in modulating immunologic risk after LTx. Our results highlight the importance of both donor and recipient HLA-G genotypes on the overall risk profile and underscore the lasting influence of donor genotype on lung transplant outcomes.