Immune-mediated injury of a transplanted organ can lead to allograft dysfunction and even patient death. Acute cellular rejection typically occurs within the first months post-transplantation but patients are at life-time risk, particularly if there is medication non-compliance or reduction of immunosuppression due to complications. Therefore, safe and accurate monitoring of the donated organ for signs of rejection is essential for long-term survival of the transplanted organ and recipient. The current gold standard for rejection surveillance is through tissue biopsy and histology, which is costly, invasive, and subjective. Thus, efforts to develop non-invasive methods for the detection of rejection post-transplantation are a priority in the field. The first FDA-approved noninvasive assay, AlloMap, was developed in 2006 and monitored the peripheral expression of 11 genes associated with immune system activation. More recently, there has been a shift towards interrogating the status of the transplanted organ directly. Fragments of genomic DNA are released into the blood during cellular apoptosis and levels of cell-free DNA (cfDNA) have been shown to be elevated in the presence of organ injury, including after transplantation. Since the genomic characteristics of DNA are maintained in cfDNA (eg, sequence variants), this circulating molecule represents a promising organ-specific biomarker for allograft injury. DNA sequence variants have been used to distinguish donor and recipient cfDNA with or without a priori donor genotyping in a variety of solid organs post-transplant. Current research has established the groundwork and future multicenter trials will determine if this novel molecular diagnostic tool represents a viable alternative to tissue biopsy. Other nucleic acid molecules released from the transplanted organ (eg, microRNAs) are presently less well developed in comparison to cfDNA but may also represent potential novel biomarkers. This review summarizes current literature and evaluates the promises and pitfalls of circulating nucleic acids as biomarkers for allograft injury post-transplant.
Increased levels of donor‐derived cell‐free DNA (dd‐cfDNA) in recipient plasma have been associated with rejection after transplantation. DNA sequence differences have been used to distinguish between donor and recipient, but epigenetic differences could also potentially identify dd‐cfDNA. This pilot study aimed to identify ventricle‐specific differentially methylated regions of DNA (DMRs) that could be detected in cfDNA. We identified 24 ventricle‐specific DMRs and chose two for further study, one on chromosome 9 and one on chromosome 12. The specificity of both DMRs for the left ventricle was confirmed using genomic DNA from multiple human tissues. Serial matched samples of myocardium (n = 33) and plasma (n = 24) were collected from stable adult heart transplant recipients undergoing routine endomyocardial biopsy for rejection surveillance. Plasma DMR levels increased with biopsy‐proven rejection grade for individual patients. Mean cellular apoptosis in biopsy samples increased significantly with rejection severity (2.4%, 4.4% and 10.0% for ACR 0R, 1R, and 2R, respectively) but did not show a consistent relationship with DMR levels. We identified multiple DNA methylation patterns unique to the human ventricle and conclude that epigenetic differences in cfDNA populations represent a promising alternative strategy for the non‐invasive detection of rejection.
Increased levels of donor-derived cell-free DNA (dd-cfDNA) in recipient plasma have been associated with rejection after transplantation. DNA sequence differences have been used to distinguish between donor and recipient but epigenetic differences could also potentially identify dd-cfDNA. This pilot study aimed to identify ventricle-specific differentially methylated regions of DNA (DMRs) that could be detected in cfDNA. We identified 24 ventricle-specific DMRs and chose two for further study, one on chromosome 9 and one on chromosome 12. The specificity of both DMRs for the left ventricle was confirmed using genomic DNA from multiple human tissues. Serial matched samples of myocardium (n=33) and plasma (n=24) were collected from stable adult heart transplant recipients undergoing routine endomyocardial biopsy for rejection surveillance. Plasma DMR levels increased with biopsy-proven rejection grade for individual patients. Mean cellular apoptosis in biopsy samples increased significantly with rejection severity (2.4%, 4.4% and 10.0% for ACR 0R, 1R and 2R, respectively) but did not show a consistent relationship with DMR levels. We identified multiple DNA methylation patterns unique to the human ventricle and conclude that epigenetic differences in cfDNA populations represent a promising alternative strategy for the non-invasive detection of rejection.
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