TY - JOUR
T1 - TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection
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.
PY - 2008/10/15
Y1 - 2008/10/15
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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U2 - 10.1182/blood-2007-09-113670
DO - 10.1182/blood-2007-09-113670
M3 - Article
C2 - 18614760
AN - SCOPUS:54049153247
SN - 0006-4971
VL - 112
SP - 3508
EP - 3516
JO - Blood
JF - Blood
IS - 8
ER -