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Toshio Hattori

Publications and source records attributed to Toshio Hattori.

At least 19 recordsLinked to original sources
PubMed2005

Properties of anti-gp41 core structure antibodies, which compete with sera of HIV-1-infected patients.

To determine the correlation between the immunoreaction against the core structure of human immunodeficiency virus type (HIV-1) transmembrane protein gp41 epitopes and the disease progression, it is essential to evaluate the anti-core structure antibody epitopes and the humoral immunity against the epitopes. For this purpose we evaluated monoclonal antibodies (mAbs) against the gp41 core structure such as mAbs 50.69, 98.6 and T26, by Western blotting (WB) and flow cytometry. WB showed mAbs 50.69 and 98.6 bound to both monomeric and oligomeric gp41, and mAb T26 exclusively bound to oligomeric gp41. We evaluated the sera from Pneumocystis pneumonia patients (PCP; n=7) and long-term survivors (LTS; n=7). Competition assay with sera and mAbs for binding to H9 cells infected with HIV-1 IIIB virus was done using flow cytometry. The results revealed that PCP sera as well as LTS sera inhibited the binding of all the three mAbs, and the PCP sera inhibited mAb T26 binding more efficiently than LTS. Therefore, PCP patients retain competing immunity to antibodies against not only the shared epitopes of the core structure (binding sites of mAbs 50.69 and 98.6) but also against oligomeric gp41 specific epitope (binding site of mAb T26).

Adolescent↗
PubMed2005

Cytokine-mediated xanthine oxidase upregulation in chronic obstructive pulmonary disease's airways.

Reactive oxygen species have been reported to be involved in the airway inflammatory process of chronic obstructive pulmonary disease (COPD). The aim of this study was to quantify the activity of xanthine oxidase (XO), which generates a potent radical superoxide anion in COPD airways. Thirteen stable COPD patients and 10 healthy subjects participated in this study. We collected the epithelial lining fluid using a newly developed microsampling technique, and quantified of cytokines responsible for the XO gene upregulation. The XO activity was significantly increased in COPD patients compared with that in healthy subjects. A significant negative correlation was found between the XO activity and the %FEV1 values. The level of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma in COPD patients was significantly higher than that in healthy subjects. Both the amount of tumor necrosis factor-alpha and interleukin-1beta were significantly correlated with the degree of XO activity. These results suggest that the XO activity is increased in COPD airways, possibly due to its gene upregulation by proinflammatory cytokines. Because the XO activity was significantly correlated with the degree of airway obstruction, these cytokine-XO production pathways may play a key role in the inflammation of COPD.

Aged↗
PubMed2005

Neutrophil survival-enhancing activity in sputum from patients with diffuse panbronchiolitis.

Diffuse panbronchiolitis (DPB) is a life-threatening airway disease in which neutrophils persistently and massively emigrating to the airways cause progressive and irreversible tissue damage. However, the pathogenesis of the airway inflammation remains unclear. The failure of non-inflammatory removal of emigrating neutrophils due to delayed apoptosis has been proposed as a mechanism by which the neutrophilic inflammation persists. Therefore, we aimed to investigate whether an activity that delays neutrophil apoptosis is present at the inflamed sites in DPB. Neutrophils isolated from normal volunteers were cultured with sputum extracts of patients with DPB, and viability and apoptosis of neutrophil was evaluated for the culture period. Neutrophils cultured with sputum extracts for 2 and 3 days showed significantly enhanced survival compared to those with medium alone. The neutrophil survival-enhancing activity in sputum extracts was heat-labile and partially, but significantly, neutralized with anti-human GM-CSF, but not with anti-human G-CSF antibody. The enhancement of neutrophil survival was associated with an inhibition of apoptosis demonstrated by cytology, TUNEL assay and DNA fragmentation analysis. These results suggest that neutrophil apoptosis is prevented by survival-enhancing factors including GM-CSF in the airways of DPB, leading to neutrophil death by necrosis that causes further recruitment and activation of neutrophils.

Adult↗
PubMed2004

Cyclic ADP-ribose, a putative Ca2+-mobilizing second messenger, operates in submucosal gland acinar cells.

Cyclic ADP-ribose (cADPR), a putative Ca(2+)-mobilizing second messenger, has been reported to operate in several mammalian cells. To investigate whether cADPR is involved in electrolyte secretion from airway glands, we used a patch-clamp technique, the measurement of microsomal Ca(2+) release, quantification of cellular cADPR, and RT-PCR for CD38 mRNA in human and feline tracheal glands. cADPR (>6 microM), infused into the cell via the patch pipette, caused ionic currents dependent on cellular Ca(2+). Infusions of lower concentrations (2-4 microM) of cADPR or inositol 1,4,5-trisphosphate (IP(3)) alone were without effect on the baseline current, but a combined application of cADPR and IP(3) mimicked the cellular response to low concentrations of acetylcholine (ACh). Microsomes derived from the isolated glands released Ca(2+) in response to both IP(3) and cADPR. cADPR released Ca(2+) from microsomes desensitized to IP(3) or those treated with heparin. The mRNA for CD38, an enzyme protein involved in cADPR metabolism, was detected in human tissues, including tracheal glands, and the cellular content of cADPR was increased with physiologically relevant concentrations of ACh. We conclude that cADPR, in concert with IP(3), operates in airway gland acinar cells to mobilize Ca(2+), resulting in Cl(-) secretion.

ADP-ribosyl Cyclase↗
PubMed2004

Thrombin activates envelope glycoproteins of HIV type 1 and enhances fusion.

To elucidate the roles of serine proteases, including thrombin, in HIV infection, we treated H9 cells infected with HIV-1 LAI virus (H9/IIIB) with four different proteases (thrombin, cathepsin G, trypsin and chymotrypsin) and observed their effects on functional epitopes on both gp120 and gp41 by using flow cytometry. Monoclonal antibodies (MAbs) against the V3 loop, V2 loop, CD4 binding site, coreceptor binding site and gp41 were used. It was found that trypsin decreased the binding of all MAbs except for one MAb against the V3 loop (IIIB-V3-21). Chymotrypsin and cathepsin G did not show any remarkable effect on the antigen expression. On the other hand, thrombin decreased the reactivities of two out of four anti-V3 MAbs and increased the exposure of functional gp120 epitopes including the coreceptor binding site and CD4 binding site. Thrombin also increased the expression of 2F5 antigen (a neutralizing epitope of gp41) but had no effect on other gp41 epitopes. The effect of trypsin or thrombin on HIV-induced cell fusion was examined through co-culturing H9/IIIB and MAGI cells. Trypsin slightly inhibited fusion. Fusion was significantly enhanced in a dose-dependent manner by thrombin, and a 280% increase at 5 U/ml (P < 0.001) was observed. In conclusion, thrombin, one of the major inflammatory molecules in blood, facilitates HIV-induced cell fusion, probably by activating gp120.

Antibodies, Monoclonal↗
PubMed2004

Quantitative assessment of protein-bound tyrosine nitration in airway secretions from patients with inflammatory airway disease.

Because reactive nitrogen species (RNS) have potent inflammatory activity, they may be involved in the inflammatory process in pulmonary diseases. We recently reported increased numbers of 3-nitrotyrosine immunopositive cells, which are evidences of RNS production, in the sputum of patients with chronic obstructive pulmonary disease (COPD) and patients with asthma compared with healthy subjects. In the present study, we attempted to quantify this protein nitration in the airways by means of high-performance liquid chromatography (HPLC) used together with an electrochemical detection system that we developed. Sputum samples were obtained from 15 stable COPD patients, 9 asthmatic patients and 7 healthy subjects by using hypertonic saline inhalation. The values for the molar ratio of protein-bound 3-nitrotyrosine/tyrosine in patients with asthma (4.31 +/- 1.13 x 10(-6), p < 0.05) and patients with COPD (3.04 +/- 0.36 x 10(-6), p < 0.01) were significantly higher than those in healthy subjects (1.37 +/- 0.19 x 10(-6)). The levels of protein-bound 3-nitrotyrosine in the airways were not significantly different in asthmatic patients and COPD patients. A significant negative correlation was found between values for protein-bound 3-nitrotyrosine/tyrosine and % FEV1 values in patients with COPD (r = -0.53, p < 0.05) but not in patients with asthma. These results suggest that our HPLC-electrochemical method is useful for quantifying RNS production in human airways. More importantly, they show that increased RNS production in the airways seems to contribute in a critical way to the pathogenesis of COPD, and that the effects of RNS in airways may differ in asthma and COPD.

Aged↗
PubMed2004

The N-terminal of the V3 loop in HIV type 1 gp120 is responsible for its conformation-dependent interaction with cell surface molecules.

The V3 loop of HIV-1 gp120 plays an important role in the interaction of the viral envelope with cellular coreceptors and/or with other cell surface molecules. To clarify this interaction we used a panel of monoclonal antibodies (MAbs) against V3 loop and synthetic looped V3 peptides V3-BH10, V3-ADA, and V3-89.6, derived from the V3 regions of the BH10 clone of IIIB (X4-tropic), ADA (R5-tropic), and 89.6 (R5X4-tropic), respectively. A linear mutant peptide, V3-BH10/CA, was also synthesized as a control. Biotinylated V3-BH10, -BH10/CA, and-ADA were also made. The binding abilities of the biotinylated and nonbiotinylated peptides to various types of cells were investigated by using flow cytometry. Subsequently, the principal region of the V3 loop involved in cell surface binding was analyzed by using MAbs against the tip (447-52D and 694-98D), N-termini (IIIB-V3-21) or C-termini (IIIB-V3-01) of the V3 loop in flow cytometry and enzyme-linked immunoabsorbent assay. We demonstrate that looped V3 peptides of both X4 and R5X4 HIV (V3-BH10 and V3-89.6) can bind to various types of cells irrespective of their CD4 and/or coreceptor expression in a conformation-dependent manner. In contrast, the V3 loop of R5 HIV (V3-ADA) can scarcely bind to the cells. Using MAbs whose epitopes cover the entire V3 loop we found that MAb IIIB-V3-21 can react with platebound but not cell-bound peptides, and the MAb blocked biotin-V3-BH10 binding suggesting that the N-terminal of the V3 loop interacts directly with cell surface molecule(s).

Amino Acid Sequence↗
PubMed2004

Long-term use of corticosteroid eye drops delays the spontaneous remission of pulmonary sarcoidosis.

Topical corticosteroid eye drops are commonly used for ocular sarcoidosis. That systemic absorption of corticosteroids by eye drops may influence the clinical course of sarcoidosis may be speculated because it has been reported that the serum concentration of corticosteroids after drop administration was dose-related. To evaluate the effects of corticosteroid eye drops on the clinical course of patients with stage I pulmonary sarcoidosis, we compared the serum levels of angiotensin converting enzyme (ACE) and bilateral hilar lymphadenopathy (BHL) on chest radiographs of group CS, which is consisted of patients who received topical therapy of betamethasone in the form of eye drops for anterior uveitis, and group CN, which is consisted of patients who did not receive any medications throughout the entire course of the disease. Although the serum ACE level was not significantly different between groups CS and CN at the time of the diagnosis of pulmonary sarcoidosis, the level of serum ACE in group CS was significantly higher than that in group CN 20 months after the topical corticosteroid treatment (24 IU/ml and 16 IU/ml, respectively). Further, the size of BHL on chest radiography in group CS was significantly larger than that in group CN 20 months after the topical treatment (82% and 37% of before control, respectively). These findings suggest the possibility that the topical corticosteroid therapy influenced the clinical course of pulmonary sarcoidosis, inducing some delay in the spontaneous remission in the longterm course.

Adrenal Cortex Hormones↗
PubMed2003

Oligodeoxynucleotides without CpG motifs work as adjuvant for the induction of Th2 differentiation in a sequence-independent manner.

The outcomes of immune responses are regulated by various parameters including how Ags are handled by APCs. In this study, we describe the intrinsic immunomodulatory characteristics of oligodeoxynucleotides (ODNs) that improve the Ag presentation by APCs. ODNs (20-mer) containing CpG motifs induced strong Th1-skewed responses. In contrast, those without CpG motifs enhanced cytokine production by effector Th cells without particular skewing toward Th1 responses or induced the differentiation of unprimed CD4(+) T cells toward Th2 cells. These functional features were prominently envisaged when ODNs were conjugated to the Ag, and were underlain by the facilitated binding of ODN-conjugated Ag to Ia(+) cells. Despite the functional differences between ODNs with CpG motifs and those without CpG motifs, both ODNs bound to Ia(+) cells with similar affinity and kinetics. Immunoenhancing activities of the ODNs were not sequence-dependent; the characteristics, including the facilitation of Ag capture, enhancement of effector Th cell responses, and induction of Th2 cells, were shared by randomly synthesized ODNs conjugated to Ag. This is the first study suggesting that ODNs, independent of the sequences, enhance immune responses through the promoted capture of ODN-conjugated Ag by APCs.

Adjuvants, Immunologic↗
PubMed2003

Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells.

Heme oxygenase 1 (HO-1) catalyzes heme breakdown, eventually releasing iron, carbon monoxide, and bilirubin IXalpha. HO-1 is induced by its substrate heme and various environmental factors, which represents a protective response against oxidative stresses. Here we show that hypoxia represses HO-1 expression in three human cell types but induces it in rat, bovine, and monkey cells, indicating the inter-species difference in the hypoxic regulation of HO-1 expression. The hypoxia-mediated repression of HO-1 expression is consistently associated with the induction of Bach1, a heme-regulated transcriptional repressor, in human cells. Bach1 is a basic leucine zipper protein, forming a heterodimer with a small Maf protein. Expression of HO-1 was also reduced in human cells when exposed to interferon-gamma or an iron chelator desferrioxamine, each of which induced Bach1 expression. In contrast, induction of HO-1 expression by CoCl(2) is associated with reduced expression of Bach1 mRNA. Thus, expression of HO-1 and Bach1 is inversely regulated. We have identified a Maf recognition element in the human HO-1 gene that is required for repression of a reporter gene by hypoxia and targeted by Bach1. Therefore, Bach1 functions as a hypoxia-inducible repressor for the HO-1 gene, thereby contributing to fine-tuning of oxygen homeostasis in human cells.

Animals↗
PubMed2003

Underdiagnosis and undertreatment of COPD in primary care settings.

OBJECTIVE: The aim of this study was to improve the detection of COPD in a primary care setting and to evaluate the subsequent management of these patients by general practitioners. METHODOLOGY: A two-step protocol was followed: patients were screened for airway obstruction and their subsequent management status reviewed. Screening spirometry was performed in 56 primary care settings (23 hospitals and 33 general practices). Inclusion criteria for screening subjects were: (i) > or =40-year-old smokers (both current and past smokers) and/or (ii) > or =40-year-old patients with respiratory symptoms of chronic cough and sputum. Patients with a previously diagnosed respiratory disease were excluded. In the second part of the study, the diagnosis and the subsequent management status of subjects with airway obstructive changes (FEV1/FVC <70%) were sought from their physician using a questionnaire 2 months after detection. RESULTS: A total of 1168 patients were screened, with 128 not analysed because of incomplete data, leaving 1040 patients. The percentages of current smokers, ex-smokers, and non-smokers among all analysed subjects were 41.7%, 29.8% and 28.5%, respectively. Airway obstructive changes (FEV1/FVC <70%) were found in 27.0% (n = 281) of all analysed subjects. Questionnaires for 194 subjects (with positive screening tests) were sent back by the participating physicians. Eighty-one per cent (n = 158) of the 194 subjects had COPD and 13.4% (n = 26) had asthma. Sixty-one per cent (n = 96) of the subjects with moderate to severe COPD according to international guidelines (FEV1 <80% predicted). However, 31.3% (n = 30) did not receive any clinical intervention (smoking cessation advice and/or drug administration). CONCLUSIONS: Screening spirometry in outpatients in a primary care setting can identify many COPD patients. However, COPD management appears to be poor in Japan.

Aged↗
PubMed2003

[Tuberculosis].

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AIDS-Related Opportunistic Infections↗
PubMed2002

Disruption of L-histidine decarboxylase reduces airway eosinophilia but not hyperresponsiveness.

Histamine has a variety of airway actions and is considered to be an important mediator in asthma. This study examined the role of endogenous histamine in allergic airway eosinophil recruitment and hyperresponsiveness using L-histidine decarboxylase gene knockout mice. Histamine levels of the airways in L-histidine decarboxylase knockout mice were largely diminished compared with wild-type mice. Inhalation challenge with ovalbumin (OVA) in OVA-sensitized wild-type mice caused eosinophil accumulation in the lung as well as airway hyperresponsiveness to methacholine 3 days after the challenge. The eosinophil recruitment was significantly reduced in the knockout mice. In the bone marrow, the proliferation of eosinophils was enhanced after OVA challenge in the wild-type mice; however, the proliferation was significantly reduced in the knockout mice. The induction of P-selectin in the lung after OVA challenge was also inhibited in the knockout mice. In contrast, airway hyperresponsiveness was not suppressed in the knockout mice. These results suggest that endogenous histamine is involved in the accumulation of eosinophils into the airways after allergic challenge, possibly acting in the bone marrow and producing P-selectin in the airways. Furthermore, allergen-induced airway hyperresponsiveness appeared to occur independently of airway eosinophilia in our present model.

Administration, Inhalation↗
PubMed2002

Activation of gp120 of human immunodeficiency virus by their V3 loop-derived peptides.

V3 loop peptides from three different human immunodeficiency virus type 1 (HIV-1) strains were synthesized. BH10, ADA, and 89.6 strains whose infections are dependent on CXCR4, CCR5, and both, respectively, were selected. Co-transfection of luciferase reporter gene and corresponding envelope genes (HXB2, ADA, and 89.6) generate pseudotype viruses (HXB2/Luc, ADA/Luc, and 89.6/Luc). The effects of each peptide on the infection of U87 cells expressing CD4 and one of the coreceptors with all pseudotype viruses were evaluated. V3 loop peptide from BH10 (V3-BH10) alone increased the HXB2/Luc infection by 93% at 10 microM. Both V3-ADA and V3-89.6 enhanced ADA/Luc infection by 38% and by 55% at 10 microM, respectively. For 89.6/Luc infection, only V3-89.6 enhanced the infections on both target cells. V3-BH10 modulated the epitopes of coreceptor binding site and V2 loop of gp120 on HIV-1 IIIB infected H9 cells, indicating that V3 loop peptide activates viral gp120 and enhances infectivity.

Antibodies, Monoclonal↗
PubMed2002

Differential effect of epidermal growth factor on serous and mucous cells in porcine airway submucosal gland.

Using a patch-clamp technique, we found that the fresh porcine submucosal gland acinar cells contained two functionally distinct cell populations, i.e. physiologically relevant concentration of acetylcholine (ACh, 30 nM) induced two distinct patterns of electric response in tracheal gland acinar cells. One was characterized by an outstanding oscillatory Cl(-)-current activity, and the other was with poor Cl(-)-current response but with a comparable K(+)-current. We examined the effect of epidermal growth factor (EGF) on the ACh-induced electric responses in these cells. EGF affected only the latter (K(+)-prominent) cell type to potentiate significantly the ACh-induced K(+)-current. An immunohistochemistry revealed that the receptor for EGF was identified preferentially on the mucous, but not serous, cells. Genistein, one of the tyrosine-kinase inhibitors, abolished the augmentation effect of EGF on the ACh-induced current. Thus, we identified the serous cell with a Cl(-)-rich current in response to ACh and the mucous cell with a K(+)-dominant response. Moreover, EGF affected the mucous cells alone to potentiate the ACh-induced electric response. EGF may contribute to the pathophysiological alterations in chronic inflammatory airways both in morphological (mucous cell hypertrophy/hyperplasia) and functional (thick viscous hypersecretion) ways.

Acetylcholine↗
PubMed2002

B cells capturing antigen conjugated with CpG oligodeoxynucleotides induce Th1 cells by elaborating IL-12.

APCs initiate T cell-mediated immune responses against foreign Ags. Dendritic cells are professional APCs that play unique roles, including Ag-nonspecific capture, priming of naive T cells, and Th1 induction, whereas B cells generally lack these functions. In this study we uncovered novel aspects of murine B cells as APCs using CpG oligodeoxynucleotides (CpG) conjugated with an Ag. B cells served as efficient APCs independently of surface Igs. This characteristic was underlaid by the CpG-mediated Ag uptake and presentation, which were functional only when CpG were covalently conjugated to Ag. The B cells cultured with CpG-conjugated Ag not only enhanced IFN-gamma formation by Th1 cells, but also induced Th1 differentiation from unprimed T cells. These effects paralleled with the increase in the expression of CD40, CD86, and class II molecules on B cells and the coordinated production of IL-12 by the cells. To our knowledge this is the first report revealing that B cells share with dendritic cells common intrinsic characteristics, such as the Ag-nonspecific capture and presentation, and the induction of Th1 differentiation from unprimed T cells.

Animals↗
PubMed2002

Delayed recovery of effector memory CD4+ T cells by highly active antiretroviral therapy in a patient with HIV-1 infection.

Effector memory T cells, which are potentially important in the protection against various pathogens, have been shown to be CCR7 negative. We report a case with HIV-1 infection in whom the change in the cell numbers of the subsets of CD4+ T cells, including CCR7 negative memory CD4 + T cells, in peripheral blood was monitored for more than one year after the initiation of highly active antiretroviral therapy. Percentage of each subsets in lymphocytes was measured by triple staining on lymphocyte fraction in flow-cytometry. The numbers of total CD4+ T cell, naive T cells, and CCR7 positive memory T cells successfully increased within half a month after the initiation of the therapy. Instead, the recovery of the cell number in CCR7 negative memory T cells delayed, and continued to increase untill 10 months after the initiation of the therapy. It suggests the possibility of delay in recovery of immune systems after the initiation of the therapy in HIV-1-infected patients, despite the prompt recovery of total CD4 + T cells.

Adult↗