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

Abstract

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.

Keywords: immunobiology; lung (allograft) function/dysfunction; lung transplantation/pulmonology; major histocompatibility complex (MHC); natural killer (NK) cells/NK receptors; translational research/science.

Figure 1. Proposed mechanism for NK cell mediated protection from rejection

(A) NK cell licensing can occur following stimulation of recipient KIR3DL1 inhibitory receptors by recipient HLA antigens bearing the Bw4 epitope. (B) Bw4-licensed NK cells will kill cells that do not express HLA-Bw4, such as the depicted Bw6/Bw6 donor APC. Thus, host-versus-graft depletion of donor APC would be expected to result in improved graft survival for KIR3DL1+Bw4+ recipients who receive Bw6/Bw6 organs.

Figure 2. KIR3DL1 frequency in NK cells from post-lung transplant BAL fluid

(A) KIR3DL1 expression was determined by flow cytometry in BAL fluid NK cells that express KIR2D and/or KIR3D for 49 BAL samples from 35 lung transplant recipients. (B) Subjects were stratified by recipient genotype, with “Low” indicating at least one low-expressing KIR3DL1 allele, or (C) by donor and recipient Bw4 typing. Lines indicate mean and standard error estimates from general estimating equation-adjusted generalized linear models. “○” indicates low genotype, while “●” indicates normal expression. KIR3DL1 expression of the total KIR+ NK cell population was less frequent in the low KIR3DL1 genotype by 13.5% (95% CI 1.9–25.0%, P = 0.02). Donor / recipient Bw4 status was not associated with KIR3DL1 expression.

Figure 3. CLAD-free survival and acute cellular rejection stratified by potential KIR3DL1-mediated host-versus graft NK cell activity in the UCSF cohort

(A) CLAD-free survival in KIR3DL1+ Bw4+ recipients of Bw6+ lung allografts was compared with the remainder of the cohort using Kaplan-Meier analysis. Bw4+ recipients of Bw6+ lung allografts had improved CLAD-free survival by log-rank test (P = 0.01). The number of subjects at risk in each stratum is shown at 2-year intervals. (B) Average scores for perivascular (A-score, 946 biopsies on 233 subjects), bronchiolar (B-score, 937 biopsies on 233 subjects), and bronchial (E-score, 834 biopsies on 227 subjects) lymphocytic inflammation were quantified on large and small airway biopsies acquired within the first 6 months following transplant for 240 lung transplant recipients are shown stratified by Bw4+ recipients and Bw6+ donor status. Mean +/− 95% confidence intervals are shown, and differences between groups were determined by Student’s t-test.

Figure 4. Long-term outcomes by potential KIR3DL1-mediated host-versus graft NK cell activity in the UNOS cohort

Freedom from BOS, death, or retransplantation (A) and overall survival (B) is shown for Bw4+ recipients of Bw6+ lung allografts compared other combinations was by Kaplan-Meier analysis. Bw4+ recipients of Bw6+ lung allografts had improved freedom from BOS, death, or retransplantation by log-rank test (A, P = 0.005) and improved overall survival (B, P = 0.005). The number of subjects at risk in each stratum is shown at 2-year intervals.