TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection

Patricia A. Taylor, Michael J. Ehrhardt, Christopher J. Lees, Angela Panoskaltsis-Mortari, Arthur M. Krieg, Arlene H. Sharpe, William J. Murphy, Jonathan S. Serody, Hiroaki Hemmi, Shizuo Akira, Robert B Levy, Bruce R. Blazar

Research output: Contribution to journalArticle

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Abstract

Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) are synthetic ODNs with unmethylated DNA sequences that mimic viral and bacterial DNA and protect against infectious agents and tumor challenge. We show that CpG ODNs markedly accelerated graft-versushost disease (GVHD) lethality by Toll-like receptor 9 (TLR9) ligation of host antigenpresenting cells (APCs), dependent upon host IFNγ but independent of host IL-12, IL-6, or natural killer (NK) cells. Imaging studies showed significantly more green fluorescent protein-positive (GFP +) effector T cells in lymphoid and nonlymphoid organs. In engraftment studies, CpG ODNs promoted allogeneic donor bone marrow (BM) rejection independent of host IFNγ, IL-12, or IL-6. During the course of these studies, we uncovered a previously unknown and critical role of donor BM APCs in modulating the rejection response. CpG ODNs promoted BM rejection by ligation of donor BM, but not host, TLR9. CpG ODNs did not impair engraftment of TLR9 -/- BM unless wild-type myeloid (CD11b +) but not B-lineage (CD19 +) BM cells were added to the donor inoculum. The importance of donor BM APCs in modulating the strength of the host antidonor rejection response was underscored by the finding that B7-1/B7-2 -/- BM was less likely than wild-type BM to be rejected. Collectively, these data offer new insight into the mechanism of alloresponses regulating GVHD and BM

Original languageEnglish
Pages (from-to)3508-3516
Number of pages9
JournalBlood
Volume112
Issue number8
DOIs
StatePublished - Oct 15 2008

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Oligodeoxyribonucleotides
Cytosine
Guanine
Bone
Bone Marrow
Toll-Like Receptor 9
Bone Marrow Cells
Interleukin-12
Ligation
Interleukin-6
Bone Marrow Diseases
Transplants
Bacterial DNA
Grafts
Viral DNA
Green Fluorescent Proteins
Natural Killer Cells
T-cells
DNA sequences
T-Lymphocytes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Taylor, P. A., Ehrhardt, M. J., Lees, C. J., Panoskaltsis-Mortari, A., Krieg, A. M., Sharpe, A. H., ... Blazar, B. R. (2008). TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood, 112(8), 3508-3516. https://doi.org/10.1182/blood-2007-09-113670

TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. / Taylor, Patricia A.; Ehrhardt, Michael J.; Lees, Christopher J.; Panoskaltsis-Mortari, Angela; Krieg, Arthur M.; Sharpe, Arlene H.; Murphy, William J.; Serody, Jonathan S.; Hemmi, Hiroaki; Akira, Shizuo; Levy, Robert B; Blazar, Bruce R.

In: Blood, Vol. 112, No. 8, 15.10.2008, p. 3508-3516.

Research output: Contribution to journalArticle

Taylor, PA, Ehrhardt, MJ, Lees, CJ, Panoskaltsis-Mortari, A, Krieg, AM, Sharpe, AH, Murphy, WJ, Serody, JS, Hemmi, H, Akira, S, Levy, RB & Blazar, BR 2008, 'TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection', Blood, vol. 112, no. 8, pp. 3508-3516. https://doi.org/10.1182/blood-2007-09-113670
Taylor PA, Ehrhardt MJ, Lees CJ, Panoskaltsis-Mortari A, Krieg AM, Sharpe AH et al. TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. Blood. 2008 Oct 15;112(8):3508-3516. https://doi.org/10.1182/blood-2007-09-113670
Taylor, Patricia A. ; Ehrhardt, Michael J. ; Lees, Christopher J. ; Panoskaltsis-Mortari, Angela ; Krieg, Arthur M. ; Sharpe, Arlene H. ; Murphy, William J. ; Serody, Jonathan S. ; Hemmi, Hiroaki ; Akira, Shizuo ; Levy, Robert B ; Blazar, Bruce R. / TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection. In: Blood. 2008 ; Vol. 112, No. 8. pp. 3508-3516.
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AU - Taylor, Patricia A.

AU - Ehrhardt, Michael J.

AU - Lees, Christopher J.

AU - Panoskaltsis-Mortari, Angela

AU - Krieg, Arthur M.

AU - Sharpe, Arlene H.

AU - Murphy, William J.

AU - Serody, Jonathan S.

AU - Hemmi, Hiroaki

AU - Akira, Shizuo

AU - Levy, Robert B

AU - Blazar, Bruce R.

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N2 - Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) are synthetic ODNs with unmethylated DNA sequences that mimic viral and bacterial DNA and protect against infectious agents and tumor challenge. We show that CpG ODNs markedly accelerated graft-versushost disease (GVHD) lethality by Toll-like receptor 9 (TLR9) ligation of host antigenpresenting cells (APCs), dependent upon host IFNγ but independent of host IL-12, IL-6, or natural killer (NK) cells. Imaging studies showed significantly more green fluorescent protein-positive (GFP +) effector T cells in lymphoid and nonlymphoid organs. In engraftment studies, CpG ODNs promoted allogeneic donor bone marrow (BM) rejection independent of host IFNγ, IL-12, or IL-6. During the course of these studies, we uncovered a previously unknown and critical role of donor BM APCs in modulating the rejection response. CpG ODNs promoted BM rejection by ligation of donor BM, but not host, TLR9. CpG ODNs did not impair engraftment of TLR9 -/- BM unless wild-type myeloid (CD11b +) but not B-lineage (CD19 +) BM cells were added to the donor inoculum. The importance of donor BM APCs in modulating the strength of the host antidonor rejection response was underscored by the finding that B7-1/B7-2 -/- BM was less likely than wild-type BM to be rejected. Collectively, these data offer new insight into the mechanism of alloresponses regulating GVHD and BM

AB - Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) are synthetic ODNs with unmethylated DNA sequences that mimic viral and bacterial DNA and protect against infectious agents and tumor challenge. We show that CpG ODNs markedly accelerated graft-versushost disease (GVHD) lethality by Toll-like receptor 9 (TLR9) ligation of host antigenpresenting cells (APCs), dependent upon host IFNγ but independent of host IL-12, IL-6, or natural killer (NK) cells. Imaging studies showed significantly more green fluorescent protein-positive (GFP +) effector T cells in lymphoid and nonlymphoid organs. In engraftment studies, CpG ODNs promoted allogeneic donor bone marrow (BM) rejection independent of host IFNγ, IL-12, or IL-6. During the course of these studies, we uncovered a previously unknown and critical role of donor BM APCs in modulating the rejection response. CpG ODNs promoted BM rejection by ligation of donor BM, but not host, TLR9. CpG ODNs did not impair engraftment of TLR9 -/- BM unless wild-type myeloid (CD11b +) but not B-lineage (CD19 +) BM cells were added to the donor inoculum. The importance of donor BM APCs in modulating the strength of the host antidonor rejection response was underscored by the finding that B7-1/B7-2 -/- BM was less likely than wild-type BM to be rejected. Collectively, these data offer new insight into the mechanism of alloresponses regulating GVHD and BM

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