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J Heart Lung Transplant. 2018 Aug;37(8):967-975. doi: 10.1016/j.healun.2018.04.009. Epub 2018 Apr 26.

Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model.

Author information

1
Genomic Research Alliance for Transplantation (GRAfT), Division of Intramural Research, National Institutes of Health, Bethesda, Maryland; Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland; Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
2
Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
3
Genomic Research Alliance for Transplantation (GRAfT), Division of Intramural Research, National Institutes of Health, Bethesda, Maryland; Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
4
Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, Maryland.
5
Revivicor, Inc., Blacksburg, Virginia.
6
Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: mmohiuddin@som.umaryland.edu.
7
Genomic Research Alliance for Transplantation (GRAfT), Division of Intramural Research, National Institutes of Health, Bethesda, Maryland; Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: Hannah.valantine@nih.gov.

Abstract

BACKGROUND:

Observational studies suggest that cell-free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury.

METHODS:

Genetically modified pig donor hearts were heterotopically transplanted into baboons (n = 7). Cell-free DNA was extracted from pre-transplant and post-transplant baboon plasma samples for shotgun sequencing. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads.

RESULTS:

The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels.

CONCLUSION:

Cross-species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02423070.

KEYWORDS:

acute humoral xenograft rejection; biomarker; cell-free DNA; cell-free DNA models; genetically engineered donors; tissue injury; xenotransplantation

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