title: 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.
authors.affiliation: Medical Service, Veterans Affairs Medical Center, San Francisco, CA.|Department of Medicine, University of California, San Francisco, CA.
authors.forename: J R
authors.identifier: http://orcid.org/0000-0003-1422-8367
authors.initials: JR
authors.lastname: Greenland
authors.affiliation: Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, CA.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Medicine, University of California, San Francisco, CA.
authors.forename: D
authors.initials: D
authors.lastname: Calabrese
authors.affiliation: Department of Medicine, University of California, San Francisco, CA.
authors.forename: T
authors.initials: T
authors.lastname: Chong
authors.affiliation: Department of Medicine, University of California, San Francisco, CA.
authors.forename: J P
authors.initials: JP
authors.lastname: Singer
authors.affiliation: Department of Surgery, University of California, San Francisco, CA.
authors.forename: J
authors.initials: J
authors.lastname: Kukreja
authors.affiliation: Department of Medicine, University of California, San Francisco, CA.
authors.forename: S R
authors.initials: SR
authors.lastname: Hays
authors.affiliation: Department of Medicine, University of California, San Francisco, CA.|Department of Surgery, University of California, San Francisco, CA.
authors.forename: J A
authors.initials: JA
authors.lastname: Golden
authors.affiliation: Medical Service, Veterans Affairs Medical Center, San Francisco, CA.|Department of Medicine, University of California, San Francisco, CA.|Cardiovascular Research Institute, University of California, San Francisco, CA.
authors.forename: G H
authors.initials: GH
authors.lastname: Caughey
authors.affiliation: Department of Medicine, University of California, San Francisco, CA.
authors.forename: J M
authors.initials: JM
authors.lastname: Venstrom
authors.affiliation: Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, CA.
authors.forename: R
authors.initials: R
authors.lastname: Rajalingam
mesh_terms: D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D006085:Graft Survival / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D006648:Histocompatibility / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D054341:Receptors, KIR3DL1 / Q000276:immunology / Q000378:metabolism*; D066027:Transplant Recipients; D014184:Transplantation, Homologous
chemical_list: D015235:HLA-B Antigens; C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1
keywords: immunobiology; lung (allograft) function/dysfunction; lung transplantation/pulmonology; major histocompatibility complex (MHC); natural killer (NK) cells/NK receptors; translational research/science