Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update

Vasco, Maria; Benincasa, Giuditta; Fiorito, Carmela; Faenza, Mario; Rosa, Paride De; Maiello, Ciro; Santangelo, Michele; Vennarecci, Giovanni; Napoli, Claudio

doi:10.1016/j.trre.2021.100609

Cited by 23 publications

(16 citation statements)

References 64 publications

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“…Furthermore, our assay does not require any donor or recipient genotyping and has the potential to be developed as a rapid and targeted assay using, for example, digital droplet PCR, as opposed to other assays which may require whole genome or extensive DNA sequencing 35 . In addition, as suggested in the recent review by Vasco et al, interrogation of DNA methylation after solid organ transplantation may provide insight into cellular processes that cannot be assessed by DNA sequence variants alone 36 . Following future studies and validation, there is hope that a methylation‐based assay could complement or reduce the need for invasive tissue biopsies.…”

Section: Discussionmentioning

confidence: 99%

Identification of cell‐free DNA methylation patterns unique to the human left ventricle as a potential indicator of acute cellular rejection

Pattar

Aleinati

Iqbal

et al. 2021

Clinical Transplantation

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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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Section: Discussionmentioning

confidence: 99%

Identification of cell‐free DNA methylation patterns unique to the human left ventricle as a potential indicator of acute cellular rejection

Pattar

Aleinati

Iqbal

et al. 2021

Clinical Transplantation

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“…Although the specific mechanism of Treg in promoting human organ transplantation tolerance in terms is unclear, Treg level has an obvious correlation with allograft survival rate ( 59 ), and cardiac transplantation related study has found that the local and total Treg and iTreg level is negatively related to the incidence of allograft rejection present ( 60 ), prompting that Treg may play a positive role in graft tolerance. In addition, some studies have found that FOXP3 gene hypomethylation may be used as a marker of the percentage of infiltrated Treg in the graft to predict the incidence of rejection events after the suppression of solid organs ( 61 ).…”

Section: Relationship Between Th17 Treg and Ktmentioning

confidence: 99%

The immunomodulation role of Th17 and Treg in renal transplantation

Huang

Liu

et al. 2023

Front. Immunol.

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Kidney transplantation (KT) is an ultimate treatment of end-stage chronic kidney disease, which can meet a lot of complications induced by immune system. With under-controlled immunosuppression, the patient will obtain a good prognosis. Otherwise, allograft disfunction will cause severe organ failure and even immune collapse. Acute or chronic allograft dysfunction after KT is related to Th17, Treg, and Th17/Treg to a certain extent. Elevated Th17 levels may lead to acute rejection or chronic allograft dysfunction. Treg mainly plays a protective role on allografts by regulating immune response. The imbalance of the two may further aggravate the balance of immune response and damage the allograft. Controlling Th17 level, improving Treg function and level, and adjusting Th17/Treg ratio may have positive effects on longer allograft survival and better prognosis of receptors.

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“…Moreover, histones play an important role in the adaptive immune response after kidney translation. Histone modifications contribute to the control of expression of major histocompatibility complex (MHC) I and II [22]. Serum concentrations of histone H3, as marker of circulating cell-free nucleosomes, were shown to be significantly higher in patient with acute rejection [23].…”

Section: Introductionmentioning

confidence: 99%

Extracellular histone release by renal cells after warm and cold ischemic kidney injury: Studies in an ex-vivo porcine kidney perfusion model

et al. 2023

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Extracellular histones are cytotoxic molecules involved in experimental acute kidney injury. In patients receiving a renal transplant from donors after circulatory death, who suffer from additional warm ischemia, worse graft outcome is associated with higher machine perfusate extracellular histone H3 concentrations. We now investigated temperature-dependent extracellular histone release in an ex vivo porcine renal perfusion model, and subsequently studied histone release in the absence and presence of non-anticoagulant heparin. Seven pairs of ischemically damaged porcine kidneys were machine perfused at 4°C (cold ischemia) or 28°C (warm ischemia). Perfusate histone H3 concentration was higher after warm as compared to cold ischemia (median (IQR) = 0.48 (0.20–0.83) μg/mL vs. 0.02 (0.00–0.06) μg/mL; p = .045, respectively). Employing immune-electron microscopy (EM), histone containing cytoplasmic protrusions of tubular and endothelial cells were found after warm ischemic injury. Furthermore, abundant histone localization was detected in debris surrounding severely damaged glomerular cells, in a “buck shot” pattern. In vitro, histones were cytotoxic to endothelial and kidney epithelial cells in a temperature-dependent manner. In a separate ex vivo experiment, addition of heparin did not change the total histone H3 levels observed in the perfusate but revealed a continuous increase in the level of a lower molecular weight histone H3 variant. Our findings show that ischemically damaged kidneys release more extracellular histones in warm ischemia, which by EM was due to histone release by renal cells. Blocking of histone-mediated damage during transplantation may be beneficial in prevention of renal injury.

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Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update

Cited by 23 publications

References 64 publications

Identification of cell‐free DNA methylation patterns unique to the human left ventricle as a potential indicator of acute cellular rejection

Identification of cell‐free DNA methylation patterns unique to the human left ventricle as a potential indicator of acute cellular rejection

The immunomodulation role of Th17 and Treg in renal transplantation

Extracellular histone release by renal cells after warm and cold ischemic kidney injury: Studies in an ex-vivo porcine kidney perfusion model

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