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Higher levels of free plasma mitochondrial DNA are associated with the onset of chronic GvHD

Bone Marrow Transplantation volume 53, pages 1263–1269 (2018)Cite this article

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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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Author notes

  1. These authors contributed equally: Jacob Rozmus, Sabine Ivison.

Authors and Affiliations

  1. Michael Cuccione Childhood Cancer Research Program, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada

    Jacob Rozmus, Amina Kariminia, Vivian M. Leung, Susanna Sung, Peter Subrt & Kirk R. Schultz

  2. CFRI, University of British Columbia, Vancouver, BC, Canada

    Sabine Ivison

  3. Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA, USA

    Stephanie J Lee

  4. Centre Hospitalier de l’Université Laval, Quebec City, QC, Canada

    Eric Boilard

  5. Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada

    Irwin Walker & Ronan Foley

  6. Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada

    Jeff Lipton

  7. CHU de Quebec, Hopital Enfant-Jesus, Quebec City, QC, Canada

    Geneviève Gallagher

  8. Capital District Health Authority and Dalhousie University, Halifax, NB, Canada

    Stephen Couban

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  1. Jacob Rozmus
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  2. Sabine Ivison
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  3. Amina Kariminia
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  14. Kirk R. Schultz
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Correspondence to Kirk R. Schultz.

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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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