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

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-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.

journal_name

Blood

journal_title

Blood

authors

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

doi

10.1182/blood-2007-09-113670

subject

Has Abstract

pub_date

2008-10-15 00:00:00

pages

3508-16

issue

8

eissn

0006-4971

issn

1528-0020

pii

blood-2007-09-113670

journal_volume

112

pub_type

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