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The SMARCE1 (SWI / SNF-related, matrix-associated, and actin-dependent regulator of chromatin, subfamily e, member 1) encodes BAF57 protein. Previously, we reported that BAF57 is a predictive marker of endometrial carcinoma. In this study, we investigated BAF57 expression in ovarian cancer cell lines and their sensitivities to cisplatin, doxorubicin, paclitaxel, and 5-fluorouracil. BAF57 expression was strongly correlated with sensitivities to cisplatin, doxorubicin, and 5-fluorouracil in 10 ovarian cancer cell lines. Paclitaxel sensitivity was also correlated with BAF57 expression, but without significance. In A2780 ovarian cancer cells, knockdown of BAF57 using specific siRNA increased cell cycle arrest at G(1) phase and the sensitivities to these anticancer agents. cDNA microarray analysis of A2780 cells transfected with BAF57 siRNA showed that 134 genes were positively regulated by BAF57, including ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2) encoding breast cancer resistance protein (BCRP). We confirmed that knockdown of BAF57 decreased BCRP expression in ovarian cancer cells by Western blot analysis, and that ABCG2 gene expression might be regulated transcriptionally. These results suggested that BAF57 is involved in ovarian cancer cell growth and sensitivity to anticancer agents, and that BAF57 may be a target for ovarian cancer therapy.
BAF57 expression was strongly correlated with sensitivities to cisplatin, doxorubicin, and 5-FU in 10 ovarian cancer cell lines. We found that BAF57 might be associated with cell cycle and transport of anti-cancer agents.

DOI： 10.1111/cas.12612

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WNT signaling mediates various physiological and pathological processes. We previously showed that WNT10A is a novel angio/stromagenic factor involved in such processes as tumor growth, wound healing and tissue fibrosis. In this study, we investigated the role of WNT10A in promoting the fibrosis that is central to the pathology of acute interstitial nephritis (AIN). We initially asked whether there is an association between kidney function (estimated glomerular filtration rate; eGFR) and WNT10A expression using kidney biopsies from 20 patients with AIN. Interestingly, patients with WNT10A expression had significantly lower eGFR than WNT10A-negative patients. However, changes in kidney function were not related to the level of expression of other WNT family members. Furthermore, there was positive correlation between WNT10A and alpha-SMA expression. We next investigated the involvement of WNT10A in kidney fibrosis processes using COS1 cells, a kidney fibroblast cell line. WNT10A overexpression increased the level of expression of fibronectin and peroxiredoxin 5. Furthermore, WNT10A overexpression renders cells resistant to apoptosis induced by hydrogen peroxide and high glucose. Collectively, WNT10A may induce kidney fibrosis and associate with kidney dysfunction in AIN.

DOI： 10.1371/journal.pone.0103240

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Introduction: Lysophosphatidic acid (LPA) is a hioactive lipid that binds to G protein coupled receptors (LPAI. 5). Recently, we reported that abrogation of LPA receptor 1 (LPA1) ameliorated murine collagen -induced arthritis, probably via inhibition of inflammatory cell migration, Th17 differentiation and osteoclastogenesis. In this study, we examined the importance of the LPA LPAI axis in cell proliferation, cytokine/chemokine production and lymphocyte transmigration in fibroblast -like synoviocytes (ELSs) obtained from the synovial tissues of rheumatoid arthritis (RA) patients.
Methods: FLSs were prepared from synovial tissues of RA patients. Expression of LPAI_6 was examined by quantitative real-time RT-PCR. Cell surface LPAI expression was analyzed by flow cytometry. Cell proliferation was analyzed using a cell counting kit Production of interleukin 6 (IL --6), vascular endothelial growth factor (VEGF), chemokine (C -C motif) ligand 2 (CCL2), metalloproteinase 3 (MMP 3) and chemokine (C X C motif) ligand 12 (CXCL12) was measured by enzyme linked immunosorbent assay Pseudoemperipolesis was evaluated using a coculture of RA FLSs and T or B cells. Cell motility was examined by scrape motility assay. Expression of adhesion molecules was determined by flow cytometry.
Results: The expression of LPAI mRNA and cell surface LPAI was higher in RA FLSs than in FLSs from osteoarthritis tissue. Stimulation with LPA enhanced the proliferation of RA FLSs and the production of IL 6, VEGF, CCL2 and MMP-3 by FLSs, which were suppressed by an LPN inhibitor (LA 01). Ki16425, another LPAI antagonist, also suppressed IL 6 production by LPA-stimulated RA FLSs. However, the production of CXCL12 was not altered by stimulation with LPA. LPA induced the pseudoemperipolesis of T and B cells cocultured with RA FLSs, which was suppressed by LPAI inhibition. In addition, LPA enhanced the migration of RA FLSs and expression of vascular cell adhesion molecule and intercellular adhesion molecule on RA FLSs, which were also inhibited by an LPAI antagonist.
Conclusions: Collectively, these results indicate that LPA LPAI signaling contributes to the activation of RA FLSs.

DOI： 10.1186/s13075-014-0461-9

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The aurora kinases are serine/threonine kinases that are essential for mitosis and contribute to tumorigenesis. Therefore, aurora kinases hold promise for molecularly targeted therapy. In the present study, we demonstrated that aurora B kinase (AURKB) is overexpressed in both cisplatin-and oxaliplatin-resistant cells. Downregulation of AURKB sensitized cells to both cisplatin and oxaliplatin, but not to paclitaxel, 5-FU or hydrogen peroxide. Interestingly, we found that both cisplatin-and oxaliplatin-resistant cells were hypersensitive to the AURKB specific inhibitors, AZD1152 HQPA and ZM447439, suggesting that both cisplatin-and oxaliplatin-resistant cells develop an addiction to AURKB. These data provide evidence that aurora kinase inhibitors can overcome both cisplatin and oxaliplatin resistance. Therefore, AURKB inhibitors could offer potential benefits if used after first-line platinum-based chemotherapy.

DOI： 10.2174/1871520614666140207154351

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PD-1, a negative coreceptor expressed on antigen-stimulated T cells and B cells, seems to serve as a 'rheostat' of the immune response. The molecular mechanisms of the functions of PD-1, in conjunction with the mild, chronic and strain-specific autoimmune phenotypes of PD-1-deficient mice, in contrast to the devastating fatal autoimmune disease of mice deficient in the immunomodulatory receptor CTLA-4, suggest that immunoregulation by PD-1 is rather antigen specific and is mainly cell intrinsic. Such unique properties make PD-1 a powerful target for immunological therapy, with highly effective clinical applications for cancer treatment. © 2013 Nature America, Inc.

DOI： 10.1038/ni.2762

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Objective. Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA(1-6)]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA(1) on the development of arthritis.
Methods. Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA(1) on collagen-induced arthritis (CIA) were evaluated using LPA(1)-deficient mice or LPA(1) antagonist. Migrating fluorescence-labeled CD11b+ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4+ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.
Results. LPA(1) was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA(1)-deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA(1) antagonist also ameliorated murine CIA. Abrogation of LPA(1) was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b+ macrophages from LPA(1)-deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA(1) antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA(1) deficiency or LPA(1) inhibition in vitro.
Conclusion. Collectively, these results indicate that LPA/LPA(1) signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA(1) may be a promising target molecule for RA therapy.

DOI： 10.1002/art.37991

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Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA1 on the development of arthritis.<br />
Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA1 on collagen-induced arthritis (CIA) were evaluated using LPA1 -deficient mice or LPA1 antagonist. Migrating fluorescence-labeled CD11b+ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4+ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.<br />
LPA1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA1 antagonist also ameliorated mu

DOI： 10.1002/art.37991

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CD8 T cells play a critical role in protection against viral infections. During effector differentiation, CD8 T cells dramatically change chromatin structure and cellular metabolism, but how energy production increases in response to these epigenetic changes is unknown. We found that loss of basic leucine zipper transcription factor, ATF-like (BATF) inhibited effector CD8 T-cell differentiation. At the late effector stage, BATF was induced by IL-12 and required for IL-12-mediated histone acetylation and survival of effector T cells. BATF, together with c-Jun, transcriptionally inhibited expression of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase Sirt1, resulting in increased histone acetylation of the T-bet locus and increased cellular NAD(+), which increased ATP production. In turn, high levels of T-bet expression and ATP production promoted effector differentiation and cell survival. These results suggest that BATF promotes effector CD8 T-cell differentiation by regulating both epigenetic remodeling and energy metabolism through Sirt1 expression.

DOI： 10.1073/pnas.1105133108

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Interleukin (IL)-17-producing helper T (T(H)17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases(1-3). IL-6 and transforming growth factor-beta (TGF-beta) induce TH17 development, in which the orphan nuclear receptors, ROR gamma t and ROR alpha, have an indispensable role(4-6). However, in the absence of IL-6 and TGF-beta, the ectopic expression of ROR gamma t or ROR alpha leads to only a modest IL-17 production(5,7,8). Here we identify a nuclear I kappa B family member, I kappa B zeta (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of I kappa B zeta in naive CD4(+) T cells together with ROR gamma t or ROR alpha potently induces T(H)17 development, even in the absence of IL-6 and TGF-beta. Notably, Nfkbiz(-/-) mice have a defect in T(H)17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of I kappa B zeta was clearly demonstrated by the resistance to EAE of the Rag2(-/-) mice into which Nfkbiz(-/-) CD4(+) T cells were transferred. In cooperation with ROR gamma t and RORa, I kappa B zeta enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying T(H)17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.

DOI： 10.1038/nature08922

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DOI： 10.1038/nature08922

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Rapid proliferation is one of the important features of memory CD8(+) T cells, ensuring rapid clearance of reinfection. Although several cytokines such as IL-15 and IL-7 regulate relatively slow homeostatic proliferation of memory T cells during the maintenance phase, it is unknown how memory T cells can proliferate more quickly than naive T cells upon antigen stimulation. To examine antigen-specific CD8(+) T cell proliferation in recall responses in vivo, we targeted a model antigen, ovalbumin(OVA), to DEC-205(+) dendritic cells (DCs) with a CD40 maturation stimulus. This led to the induction of functional memory CD8(+) T cells, which showed rapid proliferation and multiple cytokine production (IFN-gamma, IL-2, TNF-alpha) during the secondary challenge to DC-targeted antigen. Upon antigen-presentation, IL-18, an IFN-gamma-inducing factor, accumulated at the DC:T cell synapse. Surprisingly, IFN-gamma receptors were required to augment IL-18 production from DCs. Mice genetically deficient for IL-18 or IFN-gamma-receptor 1 also showed delayed expansion of memory CD8(+) T cells in vivo. These results indicate that a positive regulatory loop involving IFN-gamma and IL-18 signaling contributes to the accelerated memory CD8(+) T cell proliferation during a recall response to antigen presented by DCs.

DOI： 10.1371/journal.pone.0002404

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Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet beta cells. Cytotoxic CD8(+) T cells, reactive to beta cell antigens, are required for T1D development in the NOD mouse model of the disease, and CD8(+) T cells specific for beta cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic CD8(+) T cell clone A14 to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with P cell antigens leads to deletion of autoreactive CD8+ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases.

DOI： 10.1073/pnas.0802644105

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：J RHEUMATOL PUBL CO  

Objective. Programmed death-1 (PD-1) mediates a negative signal and introduces tolerance for lymphocytes. Dysfunction of the PD-1 pathway is thought to result in autoimmune diseases such as rheumatoid arthritis (RA). To investigate the role of the PD-1/PD-L system in the pathology of Sjogren's syndrome (SS), we examined the expression of PD-1 and its ligand PD-L1 in salivary lymphocytes and salivary glands from patients with SS.
Methods. Flow cytometry analysis was used to determine expression of PD-1 in SS salivary lymphocytes. Intracellular staining of interleukin 10 (IL-10) was performed after stimulation with PMA and ionomycin. Indirect immunohistochemistry was used to investigate the expression of PD-1 and PD-L1.
Results. The mean fluorescence intensity of PD-1 expression in SS salivary lymphocytes was significantly higher than that from healthy controls and patients with RA or systemic lupus erythematosus. PD-1-positive SS salivary lymphocytes expressed IL-10 intracellularly upon PMA/ionomycin stimulation. Immunohistochemical analysis showed that PD-1 was expressed on infiltrating lymphocytes in salivary gland from 52% of SS patients, and PD-L1 was expressed on ductal and acinar epithelial cells from 68% of SS patients. In vitro analysis using HSG cells revealed that PD-L1 was induced by interferon-gamma but not by tumor necrosis factor-a and IL-1 beta.
Conclusion. PD-1 is expressed on T lymphocytes and PD-L1 on epithelial cells from inflamed salivary glands of patients with SS, which suggests that dysfunction of the PD-1/PD-L1 pathway may be related to tolerance for lymphocytes, which causes SS.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Since metastasis is the major cause of death for cancer patients, there is an urgent need to develop new therapies to control hematogenous dissemination of cancer cells. Previously we and others demonstrated a novel mechanism that allows tumors to escape from the host immune response by expressing PD-L1 which can negatively regulate immune response through the interaction with PD-1, an immunoinhibitory receptor belonging to the CD28 family. In this study, we report that hematogenous spread of poorly immunogenic B16 melanoma cells to the liver was inhibited in PD-1-deficient mice. After inoculation to spleen, PD-L1 was induced on tumor cells, which did not express PD-L1 in vitro. As compared with wild-type mice, intrasplenic injection of B16 cells into PD-1-deficient mice showed enhanced induction of effector T cells in spleen, prolonged T cell proliferation and cytokine production, and augmented homing of effector T cells to tumor sites in the liver, resulting in accumulation of effector T cells in the tumor sites. PD-1 blockade by genetic manipulation or antibody treatment inhibited not only hematogenous dissemination of B16 melanoma cells to the liver on the C57BL/6 background, but also dissemination of CT26 colon cancer cells to the lung on the BALB/c background. These results suggest that PD-1 blockade may be a powerful tool for treatment of hematogenous spread of various tumor cells.

DOI： 10.1093/intimm/dxh194

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Although increased circulating tumor antigen-specific CD8(+) T cells can be achieved by vaccination or adoptive transfer, tumor progression nonetheless often occurs through resistance to effector function. To develop a model for identifying mechanisms of resistance to antigen-specific CTLs, poorly immunogenic B16-F10 melanoma was transduced to express the K-b-binding peptide SIYRYYGL as a green fluorescent protein fusion protein that should be recognized by high-affinity 2C TCR transgenic T cells. Although B16.SIY cells expressed high levels of antigen and were induced to express K-b in response to IFN-gamma, they were poorly recognized by primed 2C/RAG2(-/-) T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-gamma-treated B16-F10 cells and also on eight additional mouse tumors and seven human melanoma cell lines. Primed 2C/RAG2(-/-)/PD-1(-/-) T cells showed augmented cytokine production, proliferation, and cytolytic activity against tumor cells compared with wild-type 2C cells. This effect was reproduced with anti-PD-L1 antibody present during the effector phase but not during the priming culture. Adoptive transfer of 2C/RAG2(-/-)/PD-1(-/-) T cells in vivo caused tumor rejection under conditions in which wild-type 2C cells or CTLA-4-deficient 2C cells did not reject. Our results support interfering with PD-L1/PD-1 interactions to augment the effector function of tumor antigen-specific CD8(+) T cells in the tumor microenvironment.

DOI： 10.1158/0008-5472.CAN-03-3259

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Acute graft-vs-host disease (GVHD) is influenced by pathways that can enhance or reduce lethality by providing positive or negative signals to donor T cells. To date, the only reported pathway to inhibit GVHD is the CTLA-4:B7 pathway. Because absence of the programmed death-1 (PD-1) pathway has been implicated in a predisposition to autoimmunity and hence a lack of negative signals, the effect of PD-1 pathway blockade on GVHD was explored using several distinct approaches. In each, GVHD lethality was markedly accelerated. Coblockade of CTLA-4 and PD-1 was additive in augmenting GVHD, indicating that these pathways are not fully redundant. Although neither perforin nor Fas ligand expression was required for GVHD enhancement, donor IFN-gamma production was required for optimal GVHD acceleration in the absence of PD-1 ligation. These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-gamma production and suggest a novel therapeutic target for inhibiting GVHD lethality.

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Objective. The PD-1 receptor, whose deficiency in mice causes autoimmume diseases such as arthritis, is considered to be a negative regulator of activated T cells and to play a crucial role in peripheral tolerance. To clarify the involvement of the PD-1 system in rheumatoid arthritis (RA), we investigated PD-1 expression on synovial fluid (SF) T cells from patients with RA.
Methods. FACS analysis for PD-1 was performed on SF T cells from 44 patients with RA and 6 with osteoarthritis (OA), and also on peripheral blood (PB) T cells from 12 RA patients and 7 healthy controls. Two-color analysis of cell surface PD-1 expression and the intracellular concentration of cytokine production was used to investigate CD4+ T cells from SF of patients with RA and PB from controls.
Results. Scarcely any PD-1 expression was detected on control PB T or OA SF T cells. In contrast, PD-1+ cells made up 20.9 +/- 8.6% (mean +/- SD) of RA SF T cells. In RA SF, PD-1 was expressed more predominantly on CD4+ T cells than on CD8+ T cells. As well as, expressing CD45RO and CXCR3, CD4+ PD-1+ T cells were mostly CTLA-4 positive and CD26 negative,and were enriched in CD45RB(low) cells. Intracellular cytokine staining revealed that CD4+ PD-1+, but not CD4+ PD-1-, T cells produced interleukin 10 (IL-10), and that CD4+ PD-1+ T cells produced less IL-2 than CD4+ PD-1- T cells.
Conclusion. PD-1+ T cells in RA SF are enriched, and phenotypic analysis suggests that these cells constitute a unique anergic T cell subset in RA SF.

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Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

DOI： 10.1084/jem.20022235

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Autoreactive lymphocytes are suppressed in healthy individuals by so-called peripheral tolerance. Accumulating evidence indicates that co-receptor signaling plays a pivotal role in the regulation of autoreactive lymphocytes. The positive regulatory co-receptors CD28 and inducible co-stimulator (ICOS) transduce stimulatory cosignals, whereas the negative regulatory co-stimulators CTLA-4 and PD-1 are critical for the regulation of peripheral tolerance and autoimmunity. PD-1 deficient mice develop lupus-like glomerulonephritis and arthritis on a C57Bl/6 background and autoimmune-dilated cardiomyopathy on a BALB/c background.

DOI： 10.1016/S0952-7915(02)00398-9

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PD-1 is a member of the immunoglobulin superfamily expressed on immune cells, including T and B cells, and is involved in the delivery of inhibitory signal upon engagement of its ligands, PD-L1 and PD-L2. While the expression profile of PD-1 has been well documented, the analysis of PD-L1 and PD-L2 distributions on a protein basis has not been carried out because of the lack of available monoclonal antibodies specific for the molecules. In this study, we established two monoclonal antibodies, 1-111A and 122, specific for marine PD-L1 and PD-L2, respectively, and examined their expression profiles. Based on flow cytometric analyses, the expression of PD-L1 was detected in a variety of lymphohematopoietic cell types, including a minor proportion of T and B cells in the spleen, majority of pre-B cells and myeloid cells in bone marrow and subsets of thymocytes, while the expression of PD-L2 was not observed in the lymphohematopoietic cells at all. Notably, a significant proportion of the most immature lineage-marker-negative and c-Kit-positive bone marrow cells containing stem cells did express PD-L1. Following mitogenic stimulation, essentially all lymphocytes expressed PD-L1. Furthermore, a variety of leukemic lines also expressed PD-L1, while none of them did PD-L2. Thus, present results demonstrate the distinct expression patterns of PD-L1 and PD-L2 with the cells of lymphohematopoietic tissues exclusively expressing the former. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0165-2478(02)00142-6

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PD-1 is an immunoinhibitory receptor, which belongs structurally to the CD28 family. PD-1-deficient mice show breakdown of peripheral tolerance and manifest multiple autoimmune symptoms. We previously described expression of PD-1 on activated T and B lymphocytes and myeloid cells. However, little is known about the microanatomical distribution of PD-1 in lymphoid organs. In this study, we performed immunohistochemistry using monoclonal antibodies against human PD-1. In human tonsils, PD-1 was expressed on most of T cells and a small subset of centrocytes in the light zone of germinal centers (GCs), where clonal selection of centrocytes takes place. These results suggest that PD-1 may play an important role in GC reaction. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0165-2478(02)00088-3

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PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PID-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

DOI： 10.1073/pnas.192461099

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Programmed death I (PD-1)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4(+) T cells,At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals, In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G(0)/G(1) but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone, PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines,Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulating T cell responses.

DOI： 10.1038/85330

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PD-1 is an immuno-inhibitory receptor which belongs to the immunoglobulin superfamily and expressed on activated T, B and myeloid cells. Engagement of the PD-1 receptor with its membrane bound ligand (PD-LI) of the B7 family inhibits the proliferation of anti-CD3 stimulated T cells as well as anti-IgM stimulated B cells (Freeman et al. 2000 and our unpublished observation). Disruption of PD-1 gene in C57BL/6 mice caused typical lupus-like glomerulonephritis and destructive arthritis as they age (Nishimura et al. 1999) while in BALB/c mice caused autoantibody mediated dilated cardiomyopathy with severely impaired contraction and sudden death by congestive heart failure. Affected hearts showed diffuse deposition of IgG on the surface of cardiomyocytes. All of the affected PD-1(-/-) mice exhibited high-titered circulating IgG autoantibodies reactive to a 33-kDa protein expressed specifically on the surface of cardiomyocytes (Nishimura et al. 2001). These results indicate that PD-1 may be an important factor contributing to the prevention of autoimmune diseases.

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PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-LI) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell rcceptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(株)ライフメディコム  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：医歯薬出版  

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Language：Japanese   Publisher：医歯薬出版(株)  

免疫チェックポイント阻害剤の登場により、がん治療のパラダイムシフトが起こりつつある。PD-1やCTLA-4をはじめとする免疫チェックポイント分子は、免疫系のブレーキ役としてT細胞の活性化を抑制し、自己免疫応答や過剰な炎症反応を抑制する。がんはこの抑制機構を利用して宿主の免疫監視から逃れている。そこで、免疫系のブレーキ解除によりがんに対する免疫応答を高めるという新発想のもと開発されたのが、免疫チェックポイント阻害剤である。PD-1は1992年に京都大学の本庶研究室で発見された。動物モデルにおいて、PD-1阻害剤はCTLA-4阻害剤に比べて強い抗腫瘍効果を示し、副作用も少ないことから、完全ヒト型PD-1抗体のnivolumabが開発された。2014年にnivolumabは世界にさきがけてわが国で悪性黒色腫の治療薬として承認され、続いて非小細胞肺がんが適応となり、アメリカ、EUでも承認された。PD-1抗体はがん細胞ではなくリンパ球を標的とするので、がんが突然変異を起こしても効果が長期間持続する。また、がん抗原の特異性によらないので、さまざまな種類のがんに適応可能である。(著者抄録)

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Language：Japanese   Publisher：(株)北隆館  

PD-1抗体をはじめとする免疫チェックポイント阻害剤の登場により、がん治療のパラダイムシフトが起こりつつある。免疫チェックポイント分子PD-1は1992年に京都大学の本庶研究室で発見された。動物モデルでPD-1阻害剤は、CTLA-4阻害剤にくらべて、強い抗腫瘍効果を示し、副作用も少ないことから、完全ヒト型PD-1抗体nivolumabが開発された。2014年にnivolumabは世界に先駆けて本邦で悪性黒色腫の治療薬として承認され、続いて非小細胞肺がんが適応となり、米国、EUでも承認された。現在、世界中でさまざまながんに対する第III相臨床試験が進められている。(著者抄録)

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Language：Japanese   Publisher：東京医学社  

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Language：Japanese   Publisher：(株)東京医学社  

免疫チェックポイント阻害薬の登場でがん免疫療法は飛躍的に発展し、がんに対する治療戦略が大きく変わりつつある。世界に先駆けて本邦で販売承認されたPD-1抗体nivolumabは、メラノーマに続いて、2015年12月に切除不能な進行・再発の非小細胞肺がんにも適応となった。PD-1はT細胞上に発現して、免疫系のブレーキ役(免疫チェックポイント)として、自己免疫応答や過剰な炎症反応を抑制する。がん細胞はPD-1リガンド(PD-L1)を発現することによって、T細胞の活性化を抑制し、宿主の免疫監視から逃れる。PD-1/PD-L1抗体は、免疫系のブレーキを解除することにより、がんに対する免疫応答を増強する。PD-1/PD-L1抗体療法はがん細胞ではなくリンパ球を標的とするので、がんが突然変異を起こしても効果が長期間持続する。PD-1/PD-L1抗体療法はがん抗原の特異性によらないので、さまざまな種類のがんに適応可能である。(著者抄録)

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Language：Japanese   Publisher：(株)医学書院  

免疫システムには、免疫系を活性化するアクセルと抑制するブレーキが存在する。従来の癌免疫療法がアクセルを踏むことに重点を置いてきたのに対して、ブレーキ解除により免疫系のアクセルが入るようにしたのが免疫チェックポイント阻害剤である。免疫チェックポイント分子としては、PD-1やCTLA-4などが知られている。癌免疫療法の歴史、免疫チェックポイントについて、PD-1による免疫抑制のメカニズム、PD-1とPD-L1、PD-L2の発現の違い、CTLA-4とPD-1の作用点の違い、PD-1/PD-L1抗体による抗腫瘍効果、PD-1/PD-L1抗体による抗ウイルス効果について述べた。

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Language：Japanese  

J-GLOBAL

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Scopus

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本医師会  

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Language：Japanese   Publisher：Japan Lung Cancer Society  

In recent years, immunotherapy has emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. The concept of cancer immunotherapy dates back to the late nineteenth century, when William Coley, a young surgeon in New York, began intratumoral injections of bacterial products. It took almost a century to discover dendritic cells and their receptor sensing microorganisms. Immunotherapies can be divided into antigen-specific approaches, which induce tumor-specific T cells, or antigen non-specific approaches, which broadly activate T cells. Activating (accelerator) and inhibitory (brake) receptors on T cells regulate the balance between immune responses and immune tolerance. Although previous immunotherapies have focused on pressing the accelerator on T cells, immune checkpoint inhibitors take the brakes off the immune system and unleash anti-tumor immune responses. The success of clinical trials with novel drugs targeting immune checkpoint molecules such as PD-1 may herald a new era for cancer immunotherapy.

DOI： 10.2482/haigan.56.61

Scopus

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Language：Japanese   Publisher：(株)中外医学社  

免疫チェックポイント阻害剤の登場でがん免疫療法は飛躍的に発展し,がんに対する治療戦略そのものが大きく変わりつつある.世界に先駆けて2014年に本邦で製造販売が承認されたPD-1抗体nivolumabをはじめとする免疫チェックポイント阻害剤はこれまでのがん免疫療法に対する評価を一変させ,有望な治療法として期待されている.PD-1/PD-L1抗体による免疫療法はがん細胞ではなくリンパ球を標的とするので,がんが突然変異を起こしても効果が長期間持続する.また,がん抗原の特異性によらないのでさまざまな種類のがんに適応可能である.既に適応となったメラノーマに続いて,現在,肺がんをはじめとするさまざまながんで臨床試験が進んでいる.(著者抄録)

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Language：Japanese  

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Language：Japanese   Publisher：(一社)呼吸研究  

世界に先駆けて2014年に本邦で製造販売が承認されたPD-1抗体nivolumabはこれまでのがん免疫療法に対する評価を一変させ、有望な治療法として期待されている。PD-1は活性化T細胞に発現する免疫抑制受容体で、T細胞の増殖とエフェクター機能を抑制し、「免疫チェックポイント」として自己への不適切な免疫応答や過剰な炎症応答を抑制する。がん細胞はPD-1リガンド(PD-L1)を発現することによって、PD-1を介してT細胞の活性化を抑制し、宿主の免疫監視機構から逃れる。PD-1/PD-L1抗体はこの抑制性シグナルを阻害することで免疫応答を増強する。PD-1/PD-L1抗体による免疫療法はがん細胞ではなくリンパ球を標的とするので、がんが突然変異を起こしても効果が長期間持続する。また、がん抗原の特異性によらないのでさまざまな種類のがんに適応可能である。既に適応となったメラノーマに続いて、現在、肺がんをはじめとするさまざまながんで臨床治験が進んでいる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese  

DOI： 10.2169/naika.104.430

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Language：Japanese   Publisher：(一社)日本内科学会  

DOI： 10.2169/naika.104.430

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PubMed

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.104.430

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Language：Japanese   Publisher：(株)先端医学社  

生体の恒常性を維持するために、免疫系には自己への不適切な免疫反応や過剰な炎症反応を制御する「免疫(寛容)チェックポイント」が存在する。免疫チェックポイントの代表的な経路として、programmed cell death-1(PD-1)経路とcytotoxic T lymphocyte antigen-4(CTLA-4)経路が知られている。2014年6月にPD-1抗体製剤(ニボルマブ、商品名オプジーボ)がわが国発の新規免疫チェックポイント阻害薬として厚生労働省から新薬承認を受け、注目を集めている。そこで本稿では、免疫寛容チェックポイントにおけるPD-1/PD-L1シグナルの役割について解説し、CTLA4経路との違いについて論じたい。(著者抄録)

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

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Language：Japanese   Publisher：産業医科大学学会  

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Language：Japanese   Publisher：学研メディカル秀潤社 ; 1982-  

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Language：English   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(株)メディカルドゥ  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

Web of Science

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：FEDERATION AMER SOC EXP BIOL  

Web of Science

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：特願2014-007941  Date applied：2014.1

Announcement no：特開2014-065748  Date announced：2014.4

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：特願2014-007941  Date applied：2014.1

Announcement no：特開2014-065748  Date announced：2014.4

Patent/Registration no：特許第5885764号  Date issued：2016.2

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：特願2012-197861  Date applied：2012.9

Announcement no：特開2012-236861  Date announced：2012.12

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：特願2012-197861  Date applied：2012.9

Announcement no：特開2012-236861  Date announced：2012.12

Patent/Registration no：特許第5701266号  Date issued：2015.2

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：特願2009-203514  Date applied：2009.9

Announcement no：特開2009-286795  Date announced：2009.12

Patent/Registration no：特許第5159730号  Date issued：2012.12

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：特願2009-203514  Date applied：2009.9

Announcement no：特開2009-286795  Date announced：2009.12

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：JP2003008420  Date applied：2003.7

Announcement no：WO2004-004771  Date announced：2004.1

J-GLOBAL

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Applicant：小野薬品工業株式会社, 本庶 佑

Application no：特願2004-519238  Date applied：2003.7

Patent/Registration no：特許第4409430号  Date issued：2009.11

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