TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection.
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-versus-host disease (GVHD) lethality by Toll-like receptor 9 (TLR9) ligation of host antigen-presenting cells (APCs), dependent upon host IFNgamma 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 IFNgamma, 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 rejection.
Taylor
Patricia A
PA
Cancer Center and the Department of Pediatrics, Division of BMT, University of Minnesota, Minneapolis, USA.
Ehrhardt
Michael J
MJ
Lees
Christopher J
CJ
Panoskaltsis-Mortari
Angela
A
Krieg
Arthur M
AM
Sharpe
Arlene H
AH
Murphy
William J
WJ
Serody
Jonathan S
JS
Hemmi
Hiroaki
H
Akira
Shizuo
S
Levy
Robert B
RB
Blazar
Bruce R
BR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology*; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D006086:Graft vs Host Disease; D007107:Immune System; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051193:Toll-Like Receptors / Q000819:agonists*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D015850:Interleukin-6; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma