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

56 Scopus citations

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

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Taylor, P. A., Ehrhardt, M. J., Lees, C. J., Panoskaltsis-Mortari, A., Krieg, A. M., Sharpe, A. H., Murphy, W. J., Serody, J. S., Hemmi, H., Akira, S., Levy, R. B., & 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