Molecular criteria for pulmonary antibody-mediated rejection are associated with an increased risk of allograft failure

Michael B Keller¹, David Newman², Muhtadi Alnababteh³, Ann Bon⁴, Lucia Ponor⁵, Pali Shah⁶, Joby Mathew⁶, Hyesik Kong⁴, Temesgen Andargie⁴, Woojin Park⁴, Ananth Charya⁷, Helen Luikart⁸, Tyler Intrieri⁸, Shambhu Aryal⁹, Steven D Nathan⁹, Jonathan B Orens⁶, Kiran K Khush¹⁰, Moon Jang⁴, Sean Agbor-Enoh¹¹

Affiliations

¹ Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland.
² College of Nursing, Florida Atlantic University, Boca Raton, Florida.
³ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.
⁴ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland.
⁵ Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Division of Hospital Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland.
⁶ Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland.
⁷ Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
⁸ Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California; Department of Pathology, Stanford University School of Medicine, Palo Alto, California.
⁹ Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Pulmonary Division, Inova Fairfax Hospital, Falls Church, Virginia.
¹⁰ Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California.
¹¹ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland. Electronic address: sean.agbor-enoh@nih.gov.

PMID: 40120999
PMCID: PMC12353349 (available on 2026-03-20)
DOI: 10.1016/j.healun.2025.03.015

Observational Study

Molecular criteria for pulmonary antibody-mediated rejection are associated with an increased risk of allograft failure

Michael B Keller et al. J Heart Lung Transplant. 2025 Oct.

. 2025 Oct;44(10):1535-1542.

doi: 10.1016/j.healun.2025.03.015. Epub 2025 Mar 20.

Authors

Affiliations

¹ Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland.
² College of Nursing, Florida Atlantic University, Boca Raton, Florida.
³ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.
⁴ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland.
⁵ Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Division of Hospital Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland.
⁶ Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland.
⁷ Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
⁸ Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California; Department of Pathology, Stanford University School of Medicine, Palo Alto, California.
⁹ Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Pulmonary Division, Inova Fairfax Hospital, Falls Church, Virginia.
¹⁰ Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California.
¹¹ Laborarory of Applied Precision Omics (APO) National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland. Electronic address: sean.agbor-enoh@nih.gov.

PMID: 40120999
PMCID: PMC12353349 (available on 2026-03-20)
DOI: 10.1016/j.healun.2025.03.015

Abstract

Background: Current International Society for Heart and Lung Transplantation (ISHLT) criteria for pulmonary antibody-mediated rejection (AMR) is predicated on a constellation of clinical, laboratory and histopathological parameters, including the presence of donor-specific antibodies (DSA). However, molecular evidence of allograft injury is not considered. The aim of this study was to investigate if allograft injury on the molecular level, as measured by donor-derived cell-free DNA (dd-cfDNA), identifies DSA positive patients experiencing a form of AMR associated with increased risk of chronic lung allograft dysfunction (CLAD) or death.

Methods: This multicenter, observational analysis included adult lung transplant recipients from 2 prospective cohort studies. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. Molecular AMR was defined as the presence of DSA and dd-cfDNA level >1% occurring >30 days post-transplant. Clinical AMR was defined using ISHLT criteria. Time-dependent multivariable Cox regression models were used to determine the association of Clinical AMR or Molecular AMR with the composite outcome of CLAD or death.

Results: The final analysis included 209 subjects. Sixty-one subjects met criteria for molecular AMR. Molecular AMR captured 42/46 (91%) of patients who experienced Clinical AMR. Molecular AMR was associated with an increased risk of CLAD or death (HR 2.00, 95% CI: 1.18-3.38, p = 0.010). The results remained consistent analyzing Molecular AMR subjects without concomitant ISHLT Clinical AMR, acute rejection, or infection (HR 2.45, 95% CI: 1.01-5.94, p = 0.047).

Conclusions: Molecular AMR identifies a population of lung transplant recipients potentially experiencing antibody-mediated rejection not captured by current ISHLT criteria.

Keywords: Acute Rejection; Antibody Mediated Rejection; Donor Specific Antibodies; Lung Transplantation; Molecular Allograft Injury.

PubMed Disclaimer

References

1. Charya AV, Ponor IL, Cochrane A, Levine D, Philogene M, Fu Y-P, Jang MK, Kong H, Shah P, Bon AM, Krishnan A, Mathew J, Luikart H, Khush KK, Berry G, Marboe C, Iacono A, Orens JB, Nathan SD, Agbor-Enoh S. Clinical features and allograft failure rates of pulmonary antibody-mediated rejection categories. The Journal of Heart and Lung Transplantation 2023; 42: 226–235. - PubMed
1. Levine DJ, Glanville AR, Aboyoun C, Belperio J, Benden C, Berry GJ, Hachem R, Hayes D Jr., Neil D, Reinsmoen NL, Snyder LD, Sweet S, Tyan D, Verleden G, Westall G, Yusen RD, Zamora M, Zeevi A. Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2016; 35: 397–406. - PubMed
1. Jang MK, Tunc I, Berry GJ, Marboe C, Kong H, Keller MB, Shah PD, Timofte I, Brown AW, Ponor IL, Mutebi C, Philogene MC, Yu K, Iacono A, Orens JB, Nathan SD, Agbor-Enoh S. Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study. J Heart Lung Transplant 2021; 40: 822–830. - PMC - PubMed
1. Keller M, Sun J, Mutebi C, Shah P, Levine D, Aryal S, Iacono A, Timofte I, Mathew J, Varghese A, Giner C, Agbor-Enoh S. Donor-derived cell-free DNA as a composite marker of acute lung allograft dysfunction in clinical care. J Heart Lung Transplant 2022; 41: 458–466. - PubMed
1. De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Bernstein D, Weisshaar D, Quake SR, Khush KK. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med 2014; 6: 241ra277. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Molecular criteria for pulmonary antibody-mediated rejection are associated with an increased risk of allograft failure

Affiliations

Molecular criteria for pulmonary antibody-mediated rejection are associated with an increased risk of allograft failure

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous