TY - JOUR
T1 - Cytosine-Phosphorothionate-Guanine Oligodeoxynucleotides Exacerbates Hemophagocytosis by Inducing Tumor Necrosis Factor-Alpha Production in Mice after Bone Marrow Transplantation
AU - Liu, Jiajia
AU - Guo, Yong Mei
AU - Onai, Nobuyuki
AU - Ohyagi, Hideaki
AU - Hirokawa, Makoto
AU - Takahashi, Naoto
AU - Tagawa, Hiroyuki
AU - Ubukawa, Kumi
AU - Kobayashi, Isuzu
AU - Tezuka, Hiroyuki
AU - Minamiya, Yoshihiro
AU - Ohteki, Toshiaki
AU - Sawada, Kenichi
N1 - Funding Information:
Financial disclosure: This study was supported in part by a grant-in-aid (23591412), funds from the “Global Center of Excellence Program (G-COE)” of the Ministry of Education, Science, Technology, Sports, and Culture of Japan, a research grant from the Idiopathic Disorders of Hematopoietic Organs Research Committee of the Ministry of Health, Labour and Welfare of Japan, SENSHIN Medical Research Foundation and the Joint Usage/Research Program of the Medical Research Institute, Tokyo Medical and Dental University (K.S.); and a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan (T.O.). The authors are grateful to Hiromi Kataho and Etsuko Kobayashi (Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine) for their valuable technical assistance.
Publisher Copyright:
© 2016 American Society for Blood and Marrow Transplantation.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-α inhibitors. However, the mechanisms of how HPS occurs and how a TNF-α inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-γ but not TNF-α, and it was suppressed by blockade of IFN-γ but not TNF-α. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-α, IL-6, and IFN-γ. Blocking of TNF-α, but not IL-6 or IFN-γ, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF-α-driven HPS in BMT mice and is effectively treated through TNF-α inhibition.
AB - Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-α inhibitors. However, the mechanisms of how HPS occurs and how a TNF-α inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-γ but not TNF-α, and it was suppressed by blockade of IFN-γ but not TNF-α. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-α, IL-6, and IFN-γ. Blocking of TNF-α, but not IL-6 or IFN-γ, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF-α-driven HPS in BMT mice and is effectively treated through TNF-α inhibition.
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U2 - 10.1016/j.bbmt.2015.12.018
DO - 10.1016/j.bbmt.2015.12.018
M3 - Article
C2 - 26740374
AN - SCOPUS:84960472167
VL - 22
SP - 627
EP - 636
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
SN - 1083-8791
IS - 4
ER -