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High Throughput Sequential ELISA for Validation of Biomarkers of Acute Graft-Versus-Host Disease
Published on: October 31, 2012
Chronic graft-versus-host disease detected by tissue-specific cell-free DNA methylation biomarkers
Batia Avni1, Daniel Neiman2, Elior Shaked2
1Bone Marrow Transplantation and Cancer Immunotherapy Department, Hadassah University Medical Center and Faculty of Medicine, the Hebrew University, Jerusalem, Israel.
Insights
Circulating cell-free DNA (cfDNA) with tissue-specific markers can detect chronic graft-versus-host disease (cGVHD) after stem cell transplants. This method reveals hidden tissue damage even in asymptomatic patients, improving cGVHD diagnosis.
Area of Science:
- Genomics
- Transplantation Medicine
- Molecular Diagnostics
Background:
- Accurate detection of graft-versus-host disease (GVHD) is critical for patients undergoing hematopoietic stem cell transplantation (HCT).
- Current diagnostic methods face challenges in identifying early or subclinical tissue damage.
- Circulating cell-free DNA (cfDNA) offers a potential non-invasive biomarker for tissue turnover.
Purpose of the Study:
- To evaluate the utility of cfDNA and tissue-specific methylation markers for detecting tissue turnover.
- To assess the diagnostic performance of cfDNA markers in identifying chronic GVHD (cGVHD) in HCT recipients.
- To explore cfDNA's potential in detecting subclinical pathology.
Main Methods:
- Development of a cocktail of tissue-specific DNA methylation markers.
- Quantification of cfDNA from liver, skin, lungs, colon, and immune cells in 101 HCT patients.
- Establishment of an integrative model combining cfDNA concentration, specific cell cfDNA, and liver enzymes.
Main Results:
- Elevated cfDNA concentrations and tissue-specific markers correlated with active cGVHD clinical scores.
- Abnormally high tissue-specific markers were observed in asymptomatic patients, indicating hidden tissue turnover.
- An integrative model achieved 86% specificity and 89% precision (AUC 0.8) for GVHD identification.
Conclusions:
- cfDNA markers effectively detect cGVHD and underlying tissue dynamics in allogeneic stem cell transplant recipients.
- This approach provides novel insights into subclinical tissue damage.
- cfDNA analysis represents a promising tool for improved GVHD monitoring and management.
Background:
Accurate detection of graft-versus-host disease (GVHD) is a major challenge in the management of patients undergoing hematopoietic stem cell transplantation (HCT). Here, we demonstrated the use of circulating cell-free DNA (cfDNA) for detection of tissue turnover and chronic GVHD (cGVHD) in specific organs.
Methods:
We established a cocktail of tissue-specific DNA methylation markers and used it to determine the concentration of cfDNA molecules derived from the liver, skin, lungs, colon, and specific immune cells in 101 patients undergoing HCT.
Results:
Patients with active cGVHD showed elevated concentrations of cfDNA, as well as tissue-specific methylation markers that agreed with clinical scores. Strikingly, transplanted patients with no clinical symptoms had abnormally high levels of tissue-specific markers, suggesting hidden tissue turnover even in the absence of evident clinical pathology. An integrative model taking into account total cfDNA concentration, monocyte/macrophage cfDNA levels and alanine transaminase was able to correctly identify GVHD with a specificity of 86% and precision of 89% (AUC of 0.8).
Conclusion:
cfDNA markers can be used for the detection of cGVHD, opening a window into underlying tissue dynamics in patients that receive allogeneic stem cell transplants.
Funding:
This work was supported by grants from the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation and the Helmsley Charitable Trust (to YD).
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