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 (LT).
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 (41%) patients developed CLAD; 170 (49%) died. Multivariable analysis revealed donor SNP +3142 (GG+CG versus CC) was associated with increased mortality (HR 1.78 [1.12–2.84], p=0.015). In contrast, five donor SNPs -201(CC), -716(TT), SNP -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 of patients who later developed CLAD.
Specific donor SNPs are associated with mortality risk after LT, 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 LT outcome.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Lazarte has nothing to disclose.
Conflict of interest: Dr. Ma has nothing to disclose.
Conflict of interest: Dr. Martinu has nothing to disclose.
Conflict of interest: Dr. Levy has nothing to disclose.
Conflict of interest: Dr. Klement has nothing to disclose.
Conflict of interest: Dr. White has nothing to disclose.
Conflict of interest: Dr. Pelling has nothing to disclose.
Conflict of interest: Dr. Guan has nothing to disclose.
Conflict of interest: Dr. Azad has nothing to disclose.
Conflict of interest: Dr. Tikkanen has nothing to disclose.
Conflict of interest: Dr. Rao reports personal fees from Medtronic, personal fees from Abbott, outside the submitted work.
Conflict of interest: Dr. Tomlinson has nothing to disclose.
Conflict of interest: Dr. Delgado has nothing to disclose.
Conflict of interest: Dr. Keshavjee reports other from Perfusix Canada, other from XOR Labs, outside the submitted work; .Dr. Keshavjee reports other from Perfusix Canada, other from XOR Labs, outside the submitted work.
Conflict of interest: Dr. Juvet has nothing to disclose.
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