Abstract
Human leukocyte antigen (HLA)-G is a non-classical HLA that inhibits immune responses. Its expression is modified by single nucleotide polymorphisms (SNPs), which are associated with transplant outcomes. Our aim was to investigate the association of donor and recipient HLA-G SNPs with chronic lung allograft dysfunction (CLAD) and mortality after lung transplantation.
In this single-centre study, we examined 11 HLA-G SNPs in 345 consecutive recipients and 297 donors of a first bilateral lung transplant. A multivariable Cox proportional hazards model assessed associations of SNPs with death and CLAD. Transbronchial biopsies (TBBx) and bronchoalveolar lavage (BAL) samples were examined using quantitative PCR, ELISA and immunofluorescence.
Over a median of 4.75 years, 142 patients (41%) developed CLAD; 170 (49%) died. Multivariable analysis revealed donor SNP +3142 (GG+CG versus CC) was associated with increased mortality (hazard ratio 1.78, 95% CI 1.12–2.84; p=0.015). In contrast, five donor SNPs, -201(CC), -716(TT), -56(CC), G*01:03(AA) and 14 bp INDEL, conferred reduced mortality risk. Specific donor–recipient SNP pairings reduced CLAD risk. Predominantly epithelial HLA-G expression was observed on TBBx without rejection. Soluble HLA-G was present in higher concentrations in the BAL samples of patients who later developed CLAD.
Specific donor SNPs were associated with mortality risk after lung transplantation, while certain donor–recipient SNP pairings modulated CLAD risk. TBBx demonstrated predominantly epithelial, and therefore presumably donor-derived, HLA-G expression in keeping with these observations. This study is the first to demonstrate an effect of donor HLA-G SNPs on lung transplantation outcome.
Abstract
This largest-ever study on HLA-G SNPs and their relationship to transplant outcomes recognises the role of lung donor HLA-G SNPs on allograft HLA-G expression and outcomes post lung transplantation, a factor previously ignored http://bit.ly/2VZURhm
Footnotes
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Author contributions: J. Lazarte conceived of the project, collected data, performed ELISA, analysed data and wrote the manuscript. S. Azad collected data. J. Ma and G. Tomlinson assisted with project design and performed statistical analyses. M. White, Z. Guan and J. Pelling performed immunofluorescence and quantitative PCR experiments and analysed data. T. Martinu, W. Klement and J. Tikkanen performed analysis of CLAD data. L. Levy performed analysis of PCR and ELISA data with reference to CLAD. V. Rao, D. Delgado and S. Keshavjee conceived of the project and contributed to study design. T. Martinu contributed to study design and overall data analysis. S.C. Juvet conceived of the project, collected and analysed PCR, ELISA and CLAD data, supervised data collection, and wrote the manuscript.
Conflict of interest: J. Lazarte has nothing to disclose.
Conflict of interest: J. Ma has nothing to disclose.
Conflict of interest: T. Martinu has nothing to disclose.
Conflict of interest: L. Levy has nothing to disclose.
Conflict of interest: W. Klement has nothing to disclose.
Conflict of interest: M. White has nothing to disclose.
Conflict of interest: J. Pelling has nothing to disclose.
Conflict of interest: Z. Guan has nothing to disclose.
Conflict of interest: S. Azad has nothing to disclose.
Conflict of interest: J. Tikkanen has nothing to disclose.
Conflict of interest: V. Rao reports personal fees for advisory board work from Medtronic and personal fees for consultancy from Abbott, outside the submitted work.
Conflict of interest: G. Tomlinson has nothing to disclose.
Conflict of interest: D. Delgado has nothing to disclose.
Conflict of interest: S. Keshavjee is a founder of Perfusix Canada, a non-profit company that provides ex vivo lung perfusion services to the University Health Network (Perfusix played no role in the conduct of this study); and is a founder of XOR Labs, Toronto, a company currently developing a medical device for ex vivo lung perfusion (not used in this study).
Conflict of interest: S.C. Juvet has nothing to disclose.
Support statement: J. Lazarte was supported by an International Society for Heart and Lung Transplantation (ISHLT) travel award. The work was supported by institutional start-up funds (to S.C. Juvet) and by Canadian Institutes for Health Research Project Bridge Grant (to S.C. Juvet and T. Martinu). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 7, 2018.
- Accepted May 12, 2019.
- Copyright ©ERS 2019
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