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. 2024 Sep 19:37:13010.
doi: 10.3389/ti.2024.13010. eCollection 2024.

High-Risk HLA-DQ Mismatches Are Associated With Adverse Outcomes After Lung Transplantation

Lisa Kleid #  1 , Julia Walter #  2   3   4 , Patrick Moehnle  1 , Christian Wichmann  1 , Julia Kovács  2   3 , Andreas Humpe  1 , Christian Schneider  2   3 , Sebastian Michel  3   5 , Nikolaus Kneidinger  3   4   6 , Michael Irlbeck  7 , Jan Fertmann  2   3 , Andrea Dick #  1 , Teresa Kauke #  2   3   8
Affiliations

High-Risk HLA-DQ Mismatches Are Associated With Adverse Outcomes After Lung Transplantation

Lisa Kleid et al. Transpl Int. .

Abstract

Human leukocyte antigen (HLA) mismatches (MM) between donor and recipient lead to eplet MM (epMM) in lung transplantation (LTX), which can induce the development of de-novo donor-specific HLA-antibodies (dnDSA), particularly HLA-DQ-dnDSA. Aim of our study was to identify risk factors for HLA-DQ-dnDSA development. We included all patients undergoing LTX between 2012 and 2020. All recipients/donors were typed for HLA 11-loci. Development of dnDSA was monitored 1-year post-LTX. EpMM were calculated using HLAMatchmaker. Differences in proportions and means were compared using Chi2-test and Students' t-test. We used Kaplan-Meier curves with LogRank test and multivariate Cox regression to compare acute cellular rejection (ACR), chronic lung allograft dysfunction (CLAD) and survival. Out of 183 patients, 22.9% patients developed HLA-DQ-dnDSA. HLA-DQ-homozygous patients were more likely to develop HLA-DQ-dnDSA than HLA-DQ-heterozygous patients (p = 0.03). Patients homozygous for HLA-DQ1 appeared to have a higher risk of developing HLA-DQ-dnDSA if they received a donor with HLA-DQB1*03:01. Several DQ-eplets were significantly associated with HLA-DQ-dnDSA development. In the multivariate analysis HLA-DQ-dnDSA was significantly associated with ACR (p = 0.03) and CLAD (p = 0.01). HLA-DQ-homozygosity, several high-risk DQ combinations and high-risk epMM result in a higher risk for HLA-DQ-dnDSA development which negatively impact clinical outcomes. Implementation in clinical practice could improve immunological compatibility and graft outcomes.

Keywords: HLA-DQ antibody; de novo donor specific antibody; eplet matching; lung transplantation; risk-stratification.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Kaplan-Meier curves stratified by different risk-factors. Notes: Kaplan-Meier curves of time until first detection of HLA-DQ-dnDSA, stratified by being homozygous or heterozygous for HLA-DQ (A), by having the high-risk allele combination (homozygous HLA-DQ1 patients, recipients transplanted with HLA-DQ3/DQ1 typed donors) or any other allele combination (B) and stratified by the presence of one or more high-risk eplets (C). Patients and donors who were homozygous either for HLA-DQ5 and/or -DQ6 were combined as HLA-DQ1 homozygous, patients homozygous for either HLA-DQ7, -DQ8 and/or DQ9 were termed as HLA-DQ3 homozygous. The following eplets are determined as high-risk eplets 55PP, 55PPD, 66ER, 182N, 70RT, 45EV, 167H, 66IL, 61FT, 84QL. P-values from LogRank test. HLA, human leucocyte antigen; HLA-DQ-dnDSA, de-novo donor-specific antibodies against HLA-DQ locus.
FIGURE 2
FIGURE 2
Kaplan Meier curves stratified by HLA-DQ-dnDSA. Notes: Kaplan-Meier curves of time until ACR, time until CLAD and time until death, stratified by development of HLA-DQ-dnDSA. P-values from LogRank test. ACR, acute cellular rejection; CLAD, chronic allograft dysfunction; HLA-DQ-dnDSA, de-novo donor-specific antibodies against HLA-DQ locus. Notes: Kaplan-Meier curves of time until ACR (A), time until CLAD (B) and time until death (C), stratified by development of HLA-DQ-dnDSA.
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