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

Jacob Rozmus; Sabine Ivison; Amina Kariminia; Vivian M. Leung; Susanna Sung; Peter Subrt; Stephanie J. Lee; Eric Boilard; Irwin Walker; Ronan Foley; Jeff Lipton; Geneviève Gallagher; Stephen Couban; Kirk R. Schultz

doi:10.1038/s41409-018-0156-y

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

Jacob Rozmus, Sabine Ivison, Amina Kariminia, Vivian M. Leung, Susanna Sung, Peter Subrt, Stephanie J. Lee, Eric Boilard, Irwin Walker, Ronan Foley, Jeff Lipton, Geneviève Gallagher, Stephen Couban, Kirk R. Schultz

Medicine

Medicine

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14 Citations (Scopus)

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 CD21^low B cells. Plasma levels of free mtDNA are increased in cGvHD and may represent an endogenous inflammatory stimulus for TLR9 expressing B cells.

Original language	English
Pages (from-to)	1263-1269
Number of pages	7
Journal	Bone Marrow Transplantation
Volume	53
Issue number	10
DOIs	https://doi.org/10.1038/s41409-018-0156-y
Publication status	Published - Oct 1 2018

Bibliographical note

Funding Information:
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).

Funding Information:
Samples in this study were collected as a part of the Canadian Institutes of Health Research (CIHR) funded Vancouver International cGvHD biomarker study or from the Fred Hutchinson Cancer Research Center [6]. Sixteen onset samples were collected within 30 days of onset of cGvHD diagnosis. Thirty-one control samples, obtained from 23 patients with no GvHD, were collected at 3 (n = 10), 6 (n = 15), and 12 (n = 6) months post-HSCT with 4 patients having samples drawn at all three time-points. Platelet depleted plasma and peripheral blood mononuclear cells were isolated and stored at −80 °C within 24 h of patient collection. Samples were accompanied by clinical data including transplant characteristics, history of acute GvHD-and NIH-based diagnosis criteria. Patient characteristics are shown in Table 1. This study was approved by all local institutional review boards and informed consent was obtained from subjects in accordance with the Helsinki Declaration.

Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.

ASJC Scopus Subject Areas

Hematology
Transplantation

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Cite this

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title = "Higher levels of free plasma mitochondrial DNA are associated with the onset of chronic GvHD",

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.",

author = "Jacob Rozmus and Sabine Ivison and Amina Kariminia and Leung, {Vivian M.} and Susanna Sung and Peter Subrt and Lee, {Stephanie J.} and Eric Boilard and Irwin Walker and Ronan Foley and Jeff Lipton and Genevi{\`e}ve Gallagher and Stephen Couban and Schultz, {Kirk R.}",

note = "Funding Information: 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). Funding Information: Samples in this study were collected as a part of the Canadian Institutes of Health Research (CIHR) funded Vancouver International cGvHD biomarker study or from the Fred Hutchinson Cancer Research Center [6]. Sixteen onset samples were collected within 30 days of onset of cGvHD diagnosis. Thirty-one control samples, obtained from 23 patients with no GvHD, were collected at 3 (n = 10), 6 (n = 15), and 12 (n = 6) months post-HSCT with 4 patients having samples drawn at all three time-points. Platelet depleted plasma and peripheral blood mononuclear cells were isolated and stored at −80 °C within 24 h of patient collection. Samples were accompanied by clinical data including transplant characteristics, history of acute GvHD-and NIH-based diagnosis criteria. Patient characteristics are shown in Table 1. This study was approved by all local institutional review boards and informed consent was obtained from subjects in accordance with the Helsinki Declaration. Publisher Copyright: {\textcopyright} 2018, Macmillan Publishers Limited, part of Springer Nature.",

year = "2018",

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doi = "10.1038/s41409-018-0156-y",

language = "English",

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T1 - Higher levels of free plasma mitochondrial DNA are associated with the onset of chronic GvHD

AU - Rozmus, Jacob

AU - Ivison, Sabine

AU - Kariminia, Amina

AU - Leung, Vivian M.

AU - Sung, Susanna

AU - Subrt, Peter

AU - Lee, Stephanie J.

AU - Boilard, Eric

AU - Walker, Irwin

AU - Foley, Ronan

AU - Lipton, Jeff

AU - Gallagher, Geneviève

AU - Couban, Stephen

AU - Schultz, Kirk R.

N1 - Funding Information: 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). Funding Information: Samples in this study were collected as a part of the Canadian Institutes of Health Research (CIHR) funded Vancouver International cGvHD biomarker study or from the Fred Hutchinson Cancer Research Center [6]. Sixteen onset samples were collected within 30 days of onset of cGvHD diagnosis. Thirty-one control samples, obtained from 23 patients with no GvHD, were collected at 3 (n = 10), 6 (n = 15), and 12 (n = 6) months post-HSCT with 4 patients having samples drawn at all three time-points. Platelet depleted plasma and peripheral blood mononuclear cells were isolated and stored at −80 °C within 24 h of patient collection. Samples were accompanied by clinical data including transplant characteristics, history of acute GvHD-and NIH-based diagnosis criteria. Patient characteristics are shown in Table 1. This study was approved by all local institutional review boards and informed consent was obtained from subjects in accordance with the Helsinki Declaration. Publisher Copyright: © 2018, Macmillan Publishers Limited, part of Springer Nature.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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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Higher levels of free plasma mitochondrial DNA are associated with the onset of chronic GvHD

Abstract

Bibliographical note

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