Abstract

Background In lung transplantation, de novo immunodominant donor-specific anti-HLA antibodies recognizing HLA-DQ antigens (dn-iDSA-DQ) are predominant and can induce chronic lung allograft dysfunction (CLAD). We previously developed a method to measure the active concentration of dn-iDSA-DQ. We aimed to determine whether this new quantitative biomarker is associated with transplantation outcomes.

Methods This retrospective multicentre cohort study included 90 lung transplant recipients (LTRs) developing dn-iDSA-DQ, evidenced through single antigen flow beads (SAFB) follow-up. We measured the active concentration of dn-iDSA-DQ at the time of their first detection (T0) for all LTRs, and within the 2 years after DSA detection, whenever possible. SAFB dn-iDSA-DQ characteristics and clinical data were retrieved up to 5 years after DSA detection.

Results We tested 184 sera with SPR (n=90 at T0, n=94 within the 2 years after DSA detection), among which 63 (34.4%) had a quantifiable concentration of the dn-iDSA-DQ (≥0.3 nM). The median SAFB mean fluorescence intensity (MFI) of the dn-iDSA-DQ with a concentration ≥0.3 nM was higher (p<0.0001), yet the correlation between SAFB MFI and active concentration was low (r=0.758, p<0.0001). In multivariate analysis, a concentration of the dn-iDSA-DQ ≥0.3 nM at T0 was independently associated with a lower 2-year CLAD-free survival (HR 2.06, p=0.02). A concentration of the dn-iDSA-DQ ≥0.3 nM within the 2 years from DSA detection was associated with a lower graft survival in univariate analysis.

Conclusions Active concentration of dn-iDSA-DQ appears as a valuable biomarker to identify pathogenic DSA at their first detection because of its association with CLAD.

Competing Interest Statement

The University of Bordeaux, the Bordeaux University Hospital, the CNRS and the INSERM have filed a patent application for measuring the active concentration of anti-HLA antibodies by SPR. J. Visentin, JL. Taupin and C. Di Primo are listed as inventors on this patent.

Clinical Trial

NCT03474536

Funding Statement

This work has benefited from grants given by Agence de la Biomedecine (AOR 2017 and 2022), Agence Nationale de la Recherche (EPIHLA, AAP 2022), Vaincre la Mucoviscidose, Association Gregory Lemarchal, La Fondation du Souffle, Societe Francophone d Histocompatibilite et Immunogenetique, and European Union Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie grant agreement 888743. The funders had no role in work design and analysis, decision to publish, or preparation of the manuscript.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of Amiens University Hospital (CPP Nord Ouest 2) gave ethical approval for this work. This study was registered on clinicaltrials.gov under the number NCT03474536.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors.

AbbreviationsACRacute cellular rejectionAMRantibody-mediated rejectionCFCAcalibration-free concentration assayCLADchronic lung allograft dysfunctiondn-iDSA-DQde novo immunodominant anti-DQ DSADSAdonor specific antibodiesHLAhuman leukocyte antigenLTRslung transplant recipientsMFImean fluorescence intensitySAFBsingle antigen flow beadsSPRsurface plasmon resonance