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Am J Transplant. 2017 Aug;17(8):2192-2199. doi: 10.1111/ajt.14295. Epub 2017 May 11.

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

Author information

1
Medical Service, Veterans Affairs Medical Center, San Francisco, CA.
2
Department of Medicine, University of California, San Francisco, CA.
3
Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California, San Francisco, CA.
4
Department of Surgery, University of California, San Francisco, CA.
5
Cardiovascular Research Institute, University of California, San Francisco, CA.

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

PMID:
28375571
PMCID:
PMC5519429
DOI:
10.1111/ajt.14295
[Indexed for MEDLINE]
Free PMC Article

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