Abstract
Toll-like receptor-9 (TLR9) responsive B cells have previously been associated with the onset of extensive chronic graft-versus-host disease (cGvHD). We hypothesized that the onset of cGvHD associated with a higher level of plasma-free mitochondrial DNA (mtDNA), a putative TLR9 agonist. Plasma cell-free mtDNA levels were measured in 39 adult patients post-HSCT with and without cGvHD. mtDNA was isolated from plasma and quantified by Q-PCR amplification. We correlated B cell responsiveness to CpG-DNA, a prototypical TLR9 agonist, and previously identified cGVHD biomarkers with mtDNA levels. Free plasma mtDNA were elevated in patients post-HSCT without cGvHD compared to normal non-HSCT adults. There was a significantly higher level of free plasma mtDNA associated with the onset of cGvHD (3080 ± 1586 versus 1834 ± 1435 copies/μL; p = 0.02) compared to 6 months post-HSCT controls. Free mtDNA levels post-HSCT correlated with B cell responsiveness to CpG-DNA and known cGvHD biomarkers: CXCL10 (p = 0.003), ICAM-1 (p = 0.007), CXCL9 (p = 0.03), sCD25 (p = 0.05) and sBAFF (p = 0.05), and percentage of CD21low B cells. Plasma levels of free mtDNA are increased in cGvHD and may represent an endogenous inflammatory stimulus for TLR9 expressing B cells.
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Acknowledgements
This project was funded by a Canadian Institutes of Health Operating Grant, and funding from the CIHR/Wyeth Clinical Research Chair in Transplantation (KRS). The Chronic GVHD Consortium (U54CA163438) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS). The Chronic GVHD Consortium is funded through collaboration between NCATS and the National Cancer Institute. The Canadian BMT Group Clinical Trials Network provided samples from CBMTG 0601 (funded by NIH/NCI—1R01CA108752-01A2, PI K. Schultz) and samples from CBMTG 0801 study (funded by CIHR, PI—I Walker).
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Rozmus, J., Ivison, S., Kariminia, A. et al. Higher levels of free plasma mitochondrial DNA are associated with the onset of chronic GvHD. Bone Marrow Transplant 53, 1263–1269 (2018). https://doi.org/10.1038/s41409-018-0156-y
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DOI: https://doi.org/10.1038/s41409-018-0156-y
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