HLA Mismatching Favoring Host‐Versus‐Graft NK Cell Activity Via KIR3DL1 Is Associated With Improved Outcomes Following Lung Transplantation

Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA‐Bw4 recipients of HLA‐Bw6 grafts have enhanced host‐versus‐graft (HVG) natural killer (NK) cell activity mediated by killer cell immunoglobulin‐like receptor (KIR)3DL1 ligand. Because NK cells may promote tolerance by depleting antigen‐presenting cells, we hypothesized improved outcomes for HLA‐Bw4 recipients of HLA‐Bw6 grafts. We evaluated differences in acute cellular rejection and CLAD‐free survival across 252 KIR3DL1+ recipients from University of California, San Francisco (UCSF). For validation, we assessed survival and freedom from bronchiolitis obliterans syndrome (BOS), retransplantation, or death in 12 845 non‐KIR typed recipients from the United Network for Organ Sharing (UNOS) registry. Cox proportional hazards models were adjusted for age, gender, ethnicity, transplant type, and HLA mismatching. HVG‐capable subjects in the UCSF cohort had a decreased risk of CLAD or death (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36–0.88) and decreased early lymphocytic bronchitis. The HVG effect was not significant in subjects with genotypes predicting low KIR3DL1 expression. In the UNOS cohort, HVG‐capable subjects had a decreased risk of BOS, retransplant, or death (HR 0.95, 95% CI 0.91–0.99). Survival improved with the higher‐affinity Bw4‐80I ligand and in Bw4 homozygotes. Improved outcomes in HVG‐capable recipients are consistent with a protective NK cell role. Augmentation of NK activity could supplement current immunosuppression techniques.