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Articles by H Yamada
Total Records ( 4 ) for H Yamada
  Y Kamiryo , M Eto , H Yamada , T Yajima , M Harano , A Takeuchi , K Tatsugami , M Hamaguchi , S Naito and Y. Yoshikai
 

Nonmyeloablative allogeneic stem cell transplantation (SCT) has been used for various malignancies, although detailed mechanisms of antitumor effects remain unclear. We showed that a nonmyeloablative allogeneic SCT regimen, which consists of mixed chimerism induced by an injection of donor spleen and bone marrow cells followed by cyclophosphamide treatment and a donor lymphocyte infusion (DLI), exerted antitumor effects on established murine bladder tumor, MBT-2. An expansion of donor CD4 T cells accompanied by transient but vigorous IFN- production was detected shortly after DLI. In vivo neutralization of IFN- or depletion of CD4 T cells from DLI abolished the antitumor effects, indicating an indispensable role of donor CD4 T cells producing IFN-. Donor as well as host CD8 T cells accumulated in the tumor region with time. Importantly, depletion of CD8 T cells from DLI did not reverse the suppression of tumor growth, indicating that CD4 T cells play a more essential role in mediating early antitumor effects. Furthermore, tumor-specific response of host CD8 T cells was suggested. These results not only provide the first evidence of nonmyeloablative allogeneic SCT for the treatment of bladder tumor but also elucidate detailed mechanisms of antitumor effects provoked by DLI. [Cancer Res 2009;69(12):5151–8]

  M Goto , K Shinmura , H Igarashi , M Kobayashi , H Konno , H Yamada , M Iwaizumi , S Kageyama , T Tsuneyoshi , S Tsugane and H. Sugimura
 

A base excision repair enzyme, NTH1, has activity that is capable of removing oxidized pyrimidines, such as thymine glycol (Tg), from DNA. To clarify whether the NTH1 gene is involved in gastric carcinogenesis, we first examined the NTH1 expression level in eight gastric cancer cell lines, and the results showed that NTH1 expression was downregulated in all of them, including cell line AGS. Next, a comparison of excisional repair activity against Tg by empty vector-transfected AGS clones and FLAG-NTH1-expressing AGS clones showed that a low NTH1 expression level led to low capacity to repair the damaged base in the gastric epithelial cells. Reduced messenger RNA expression of NTH1 was also detected in 36% (18/50) of primary gastric cancers. Moreover, immunohistochemical analysis revealed that NTH1 was predominantly localized in the cytoplasm in 24% (12/50) of the primary gastric cancers in contrast to the nuclear localization in non-cancerous tissue, suggesting impaired excisional repair ability for nuclear DNA. No associations between clinicopathological factors and NTH1 expression level or localization pattern were detected in the gastric cancers. Next, we found two novel genetic polymorphisms, i.e. c.-163C>G and c.-241_-221del, in the NTH1 promoter region, and a luciferase assay showed that both were associated with reduced promoter activity. However, there were no associations between the polymorphisms and risk of gastric cancer in a gastric cancer case–control study. These findings suggested that downregulation of NTH1 expression and abnormal localization of NTH1 may be involved in the pathogenesis of a subset of gastric cancers.

  E Ishikawa , T Ishikawa , Y. S Morita , K Toyonaga , H Yamada , O Takeuchi , T Kinoshita , S Akira , Y Yoshikai and S. Yamasaki
 

Tuberculosis remains a fatal disease caused by Mycobacterium tuberculosis, which contains various unique components that affect the host immune system. Trehalose-6,6'-dimycolate (TDM; also called cord factor) is a mycobacterial cell wall glycolipid that is the most studied immunostimulatory component of M. tuberculosis. Despite five decades of research on TDM, its host receptor has not been clearly identified. Here, we demonstrate that macrophage inducible C-type lectin (Mincle) is an essential receptor for TDM. Heat-killed mycobacteria activated Mincle-expressing cells, but the activity was lost upon delipidation of the bacteria; analysis of the lipid extracts identified TDM as a Mincle ligand. TDM activated macrophages to produce inflammatory cytokines and nitric oxide, which are completely suppressed in Mincle-deficient macrophages. In vivo TDM administration induced a robust elevation of inflammatory cytokines in sera and characteristic lung inflammation, such as granuloma formation. However, no TDM-induced lung granuloma was formed in Mincle-deficient mice. Whole mycobacteria were able to activate macrophages even in MyD88-deficient background, but the activation was significantly diminished in Mincle/MyD88 double-deficient macrophages. These results demonstrate that Mincle is an essential receptor for the mycobacterial glycolipid, TDM.

  K Gotoh , Y Tanaka , A Nishikimi , R Nakamura , H Yamada , N Maeda , T Ishikawa , K Hoshino , T Uruno , Q Cao , S Higashi , Y Kawaguchi , M Enjoji , R Takayanagi , T Kaisho , Y Yoshikai and Y. Fukui
 

Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IB kinase (IKK) –dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK- activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN- induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK- and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN- induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2–Rac signaling pathway acts in parallel with TLR engagement to control IKK- activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN–related autoimmune diseases.

 
 
 
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