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Biomedical subjects

K Nomoto

Publications and source records attributed to K Nomoto.

At least 271 records · Page 15Linked to original sources
PubMed1995

Superoxide dismutase (SOD) activity with Fe-chlorin e6-Na and suppression of malignant tumor growth in rats.

Derivatives of porphyrin, specifically Fe-chlorin e6-Na (FeCNa), mimic superoxide dismutase (SOD). This SOD activity was determined by decrease in electron spin resonance (ESR) signals and increase in hydrogen peroxide (H2O2) as the intermediate of O2-. by the coloration using 4-aminoantipyrin. Chlorin e6-Na used for cancer photodynamic therapy (PDT)(1) does not show SOD mimicking activity. The specific activity of FeCNa, comparing with bovine RBC-SOD, was 1/7.5 as determined by ESR analysis. The iron element of Fe-chlorin e6-Na, being tightly encased in the molecule, did not participate in the Fenton reaction. The SOD mimetic activity of FeCNa was stable against physico-chemical treatment such as pH shock, heat and digestion by pronase. For cancer bearing rats with oxidative stress (OS), immediate relief of OS was possible by a single intraperitoneal injection of FeCNa and relief continued for 24 hours. The subsequent administration of FeCNa suppressed cancer growth in vivo.

Animals↗
PubMed1995

Autogenous production of hydroxyl radicals from thiopental.

It is generally believed that barbiturates can protect neural tissues from the damage induced by cerebral hypoxia. One of the mechanisms for protecting neurons is through the inhibition of lipid peroxidation (LPO). We therefore examined LPO in rat brain, liver and kidney by measuring the accumulation of thiobarbituric acid-reactive substances (TBAR) after thiopental administration under 21% O2. We also designed an in vitro study to gain insight into free radical generation leading to the formation of LPO from thiopental by electron spin resonance (ESR). An accumulation of TBAR in the rat liver was observed after the administration of a large dose of thiopental (70 mg/kg intraperitoneally). However, no change in LPO in the brain and kidney was observed. In the in vitro study, thiopental could scavenge superoxide (O2-.) radicals, while it spontaneously generated hydroxyl radicals (.OH) in solution. We conclude that thiopental can scavenge O2-., while producing .OH, subsequently resulting in membrane lipid peroxidation under physiologic O2 conditions. This formation of .OH may damage cell membrane lipids.

Animals↗
PubMed1995

Induction of apoptosis of T cells by infecting mice with murine cytomegalovirus.

Cytomegalovirus (CMV) is associated with several lymphocyte dysfunctions, but the precise mechanisms of the dysfunctions are still unclear. To elucidate the mechanisms, a cell cycle-DNA content analysis was performed on splenic T cells of murine CMV (MCMV)-infected BALB/c mice. T cells from mice infected with 3 x 10(3) PFU of MCMV contained a higher percentage of hypodiploid nuclei after 12 or 24 h of culture than those from naive mice. T cells from infected mice also contained a larger amount of fragmented DNA. Taken together, these results suggested that infection with MCMV induced the apoptotic cell death of T cells. This induction of apoptosis accounted for the dysfunction of lymphocytes, at least partially. Flow cytometric analysis showed that T cells as well as B cells from MCMV-infected mice expressed an augmented level of Fas antigen, an apoptosis-associated cell surface molecule, which might be the cause of the apoptosis of cells. T cells from MCMV-infected C57BL/6-lpr/lpr mice with mutations at the lpr/fas locus, however, also showed a substantial level of apoptosis, which was reproducibly lower than that seen in C57BL/6 mice. Therefore, it was suggested that the Fas-mediated pathway contributed to but was not sufficient for the induction of apoptosis and that mechanisms other than the Fas-associated pathway were also involved in the induction of apoptosis.

Animals↗
PubMed1995

Characterization of mitogenic substances in the hot water extracts of bupleuri radix.

Bupleuri Radix is a commonly used medicinal plant in Kampo medicine, and its hot water extracts show mitogenic activity to murine lymphocytes. In this paper the mitogenic substances in the hot water extracts of Bupleuri Radix (Bup-HWE) were fractionated and characterized physicochemically and immunologically. Most of these substances were recovered from mol. wt of more than 200 kDA fraction (fr. C-13). Separation of fr. C-13 by phenol-water fractionation method gave water soluble and phenol soluble mitogenic substances. These substances showed the activity even in C3H/HeJ mice, and polymyxin B or lysozyme treatment did not abrogate the activity, suggesting that the active substances are not related to bacterial lipopolysaccharide. Treatment of the mitogenic substances recovered from the phenol layer with NaCLO2, a polyphenol degrading chemical, significantly reduced the activity, but pronase and pectinase treatments were not effective. The mitogenic substances in the water layer were active even after NaCLO2 treatment. These findings suggested that the mitogenic substances of Bup-HWE are large molecular weight polyphenolic compounds and polysaccharide. The mitogenic substances are suggested to be B cell mitogens.

Adjuvants, Immunologic↗
PubMed1995

A polysaccharide fraction of shosaiko-to active in augmentation of natural killer activity by oral administration.

Shosaiko-to (Xiao-chai-hu-tang, SHO), which is a Kampo medicine prepared by decocting a prescription of 7 kinds of medical plants, has been used mainly to treat chronic hepatitis in Japan. Previously, we reported that an oral administration of SHO augmented natural killer (NK) activity in the peripheral blood. To characterize its active substance, SHO was fractionated. The high molecular weight fraction showed the ability to augment NK activity by oral administration, but the low molecular weight fraction did not. Furthermore, we obtained an active acidic polysaccharide from the high molecular weight fraction. This polysaccharide fraction, with a molecular weight of approximately 1.2 x 10(5), is probably responsible for the effect of the original Shosaiko-to. It contained no protein. The sugar moiety was composed of rhamnose, arabinose, mannose, galactose, glucose and galacturonic acid in molar ratios of 1:17:3:21:100:87.

Administration, Oral↗
PubMed1995

Influence on HMG-COA reductase inhibitors on plaque-forming cell (PFC) response in mice.

Effects of pravastatin and simvastatin on the humoral immune response were studied using Cunningham's method of the IgM plaque-forming cell (PFC) assay system in mice. The vehicle (0.5% CMC), pravastatin (1 mg/body : about 50 mg/kg) or simvastatin (0.5 mg/body : about 25 mg/kg) were given orally for 14 days in experiment Exp-I and Exp-II. The vehicle, pravastatin (0.5 mg/body : about 25 mg/kg) or simvastatin (0.25 mg/body : about 12.5 mg/kg) were given orally 29 times for 32 days in Exp-III. There were no significant differences in the mean numbers of PFCs per 10(6) splenocytes between the pravastatin groups and the vehicle groups. In the simvastatin groups, however, there were significant reductions of the numbers of PFCs in Exp-I, Exp-II and Exp-III, as compared with the vehicle group. Based on these results, it was considered that suppressive effect on IgM antibody production was induced by simvastatin, whereas such a suppression was not observed with pravastatin.

Animals↗
PubMed1995

Concomitant immunity against tumor development is enhanced by the oral administration of a kampo medicine, Hochu-ekki-to (TJ-41: Bu-Zhong-Yi-Qi-Tang).

The oral administration of a kampo herbal medicine, Hochu-ekki-to (TJ-41: Bu-Zhong-Yi-Qi-Tang) using a water-supplying bottle resulted in a slight but significant inhibition of Meth A growth. The oral administration of TJ-41 with gastric gavage significantly enhanced the specific antitumor activity against Meth A at rechallenge on day 9. In a tumor-neutralizing assay, the tumor draining LN cells of the TJ-41 administered mice showed an antitumor activity against Meth A. In a cytolytic assay, the anti-Meth A specific cytolytic T lymphocyte activity was not detected in the spleen cells of the Meth A bearing and TJ-41 administered mice. The oral administration of TJ-41 enhanced the natural killer (NK) activity of the spleen cells in naive mice but could not improve the decreased NK activity of spleen cells from the tumor bearing mice. In a cytostatic assay, the peritoneal exudate cells from the Meth A bearing and TJ-41 administered mice showed a significantly higher amount of cytostatic activity against Meth A than that from either Meth A bearing or TJ-41 administered mice. These results indicate that the oral administration of TJ-41 into the tumor bearing mice may thus be able to enhance concomitant antitumor immunity through the augmentation of the cytostatic activity.

Adjuvants, Immunologic↗
PubMed1995

The induction of renal autoantigen-specific T cells by a local Listeria monocytogenes infection.

In order to examine the possibility that a local chronic infection can induce organ-specific autoimmune disease, we inoculated unilateral kidneys with viable Listeria monocytogenes (intrarenal infection). The delayed footpad reaction against syngeneic kidney homogenate (KH) became positive from 1 week after initiating the intrarenal infection. A proliferative response of the spleen T cells from the infected mice was also observed against KH from 1 week after initiating the intrarenal infection, but no such response was seen against liver homogenate (LH). In contrast, an intravenous Listeria infection did not induce a delayed footpad reaction or proliferative response against KH, suggesting that these autoimmune responses were not caused by molecular mimicry between renal antigens and Listeria antigens. Furthermore, the ability to transfer the autoimmune response of spleen T cells from intrarenally infected mice was examined. The transferred mice showed a positive delayed footpad reaction against KH and an interstitial infiltration of mononuclear cells in their kidneys. These results demonstrate that the intrarenal Listeria infection induced renal autoantigen-specific T cells, which subsequently induced an autoimmune interstitial nephritis (AIN). The autoreactive T cells were all induced without immunization by autoantigens mixed with complete Freund's adjuvant. Based on these findings, we propose that a local bacterial infection may induce an autoimmune response against autoantigens in the infected organ and subsequently trigger organ-specific autoimmune disease.

Animals↗
PubMed1995

Prevention of anti-T-cell receptor alpha beta monoclonal antibody-induced side-effects by treatment with cyclosporin A without interference of monoclonal antibody-induced immunosuppression in mice.

Anti-T-cell receptor (TCR)alpha beta monoclonal antibody (mAb; H57-597) injection in mice caused cytokine (tumour necrosis factor and interferon-gamma) release and clinical side-effects such as piloerection and body weight loss similar to anti-CD3 mAb (145-2C11) injection. Treatment with cyclosporin A (CsA) for 3 days, from day -2 to day 0, prior to anti-TCR alpha beta mAb injection almost completely abolished the mAb-induced cytokine release, and completely inhibited the mAb-induced body weight loss. Furthermore, treatment with CsA from day -2 to day 0 did not inhibit the mAb-induced in vivo immunosuppressive effects, i.e. prolongation of skin allograft and T-cell depletion in the periphery. These results indicate that CsA treatment prior to mAb treatment could effectively inhibit the mAb-induced side-effects without interference of the mAb-induced in vivo immunosuppression. From these results, we propose that CsA treatment prior to injection of anti-TCR alpha beta mAb may be recommended to reduce mAb-induced side-effects.

Animals↗
PubMed1995

Early-appearing tumour-infiltrating natural killer cells play a crucial role in the generation of anti-tumour T lymphocytes.

Natural killer (NK) cells that infiltrated into the primary tumour site at an early stage of tumour development, were examined for their participation in the generation of anti-tumour cytotoxic T lymphocytes (CTL). NK cells, which were detected by anti-NK1.1 monoclonal antibody (mAb), increased in the peritoneal exudate cells (PEC) on days 3 and 7 after an intraperitoneal (i.p.) inoculation of syngeneic B16 melanoma cells. These tumour-infiltrating NK cells showed a high level of cytotoxic activity against NK-sensitive YAC-1 cells and an increased expression of interferon-gamma (IFN-gamma) mRNA and interleukin-2 (IL-2) mRNA. The in vivo depletion of NK cells with anti-NK1.1 mAb, prior to i.p. inoculation of B16 melanoma cells, resulted in an increased number of tumour cells in the PEC compared to NK cell non-depleted mice. Interestingly, the differences in tumour cell number between both groups were more prominent on days 7 and 14 than on day 3, which strongly suggested that early-infiltrating NK cells have a large influence on the subsequent anti-tumour response. The in vivo depletion of NK cells prior to immunization with melanoma cells abrogated the capacity of the spleen cells to generate CD8+ tumour-specific CTL after in vitro restimulation. This inability of generating anti-tumour CTL was partially restored by additional i.p. injections of recombinant IL-2 and/or IFN-gamma simultaneously with the immunization of melanoma cells. The in vitro depletion of NK cells prior to the in vitro restimulation with melanoma cells partially impaired the anti-tumour CTL generation from the spleen cells of the immunized mice. Lastly, the in vivo depletion of NK cells prior to immunization with melanoma cells abolished the protective immunity against melanoma cells at the rechallenge. Overall, these results indicate that early-appearing tumour-infiltrating NK cells not only participate in the anti-tumour early defence by themselves, but also play a crucial role in the generation of anti-tumour CTL.

Animals↗
PubMed1995

Prolongation of kidney graft survival by cyclophosphamide-induced tolerance in rats.

In this study, we have extended a cyclophosphamide (CP)-induced tolerance system to kidney transplantation in rats to examine whether or not we can overcome fully allogeneic (major histocompatibility complex plus minor histocompatibility) antigen barriers in organ transplantation. In the recipient Lewis (LEW, RT1(1)) rats that were primed intravenously with 4 x 10(8) spleen cells plus 2 x 10(8) bone marrow cells from Brown-Norway (BN, RT1n) rats and treated intraperitoneally with 100 mg./kg. of cyclophosphamide (CP) 2 days later, the survival of kidney allografts, but not skin allografts, from BN was prolonged as compared with that in the untreated LEW rats. Some of the kidney allografts survived for more than 100 days without further immunosuppressants. The tolerant state induced was tolerogen specific, and the suppression of tissue damage of the grafted kidney in such tolerant rats was also confirmed by the histopathological findings of the grafted kidney. These results indicate that considerable levels of tolerance can be induced, at least in organ transplantation, across fully allogeneic antigen barriers in rats by a CP-induced tolerance system. We believe that the present study is the first step in applying our CP-induced tolerance system using skin grafting in the murine model to clinical organ transplantation.

Animals↗
PubMed1995

Infection of Mycobacterium bovis bacillus Calmette-Guérin in antibody-mediated gamma delta T-cell-depleted mice.

To evaluate the hypothesis that gamma delta T cells participate in protective immunity against mycobacterial infection, we depleted gamma delta T cells from mice by administration of anti-T-cell receptor (TCR)gamma delta monoclonal antibody (mAb) and analysed protection against Mycobacterium bovis bacillus Calmette-Guérin (BCG). The gamma delta T-cell-depleted mice did not show any exaggerated bacterial multiplication compared with control mice. In contrast, alpha beta T-cell-depleted mice, which were administrated anti-TCR alpha beta mAb before BCG infection, showed a depressed protective immunity. These results suggest that gamma delta T cells are not essential for coping with a primary BCG infection.

Animals↗
PubMed1995

Anti-T cell receptor antibody treatment of mice with lupus-like graft versus host disease: suppression of glomerulonephritis without reduction in anti-DNA antibody levels.

OBJECTIVE: To evaluate the therapeutic efficacy of anti-alpha beta T cell receptor (TCR) monoclonal antibody (Mab) on lupus-like graft versus host disease (GVHD). An attempt was also made to deduce the role of T cells in the progression of lupus nephritis. METHODS: [C57BL/6 x DBA/2]F1 mice inoculated with 5 x 10(7) DBA/2 spleen cells developed a variety of immunostimulatory symptoms, including the hyperproduction of anti-dsDNA antibodies and severe glomerulonephritis. Anti-alpha beta TCR Mab was injected intraperitoneally at a dose of 400 micrograms either on Day 2 or Day 21, followed 5 days later by another administration of 200 micrograms. RESULTS: Short term treatment with anti-alpha beta TCR Mab starting 2 days after cell transfer markedly reduced the serum anti-dsDNA antibody (IgG) titers and virtually abolished the induction of glomerulonephritis. Anti-alpha beta TCR treatment begun on Day 21 was also found effective in preventing the development of glomerulonephritis. In this case, however, the serum anti-dsDNA IgG titers were not significantly reduced compared with untreated GVHD controls. Immunohistochemical staining of the kidney with antimouse IgG + IgM detected no antibody deposition in the glomerulus either in the mice given delayed anti-alpha beta TCR treatment or in the mice treated prophylactically with anti-alpha beta TCR Mab, despite the high titers of serum anti-dsDNA IgG observed in the former group. In contrast, massive antibody deposition was regularly detectable in the glomerulus of the untreated GVHD controls. CONCLUSION: Our report demonstrates the therapeutic potential of anti-alpha beta TCR Mab for lupus-like disease, while suggesting that some help from cellular immunity is likely required for the hyperproduced autoantibodies to become deposited in the glomerulus in this model.

Animals↗
PubMed1994

Inhibition of the T-cell receptor-mediated signal transduction by microinjection of anti-Lck monoclonal antibody into T-cells.

Engagement of T-cell receptor (TcR)/CD3 complexes on T-cells rapidly provokes tyrosine phosphorylation of cellular proteins, which is thought to be an essential step to the following events of T-cell activation. p56lck, a member of src-related, non-receptor type protein tyrosine kinases, is expressed predominantly in lymphocytes. Accumulating data suggest that p56lck is one of the kinases responsible for TcR-mediated protein tyrosine phosphorylation. To investigate the role of p56lck in TcR-signaling in detail, we injected anti-Lck monoclonal antibody (mAb), MOL171 or MOL294, both specifically suppress Lck kinase activity in vitro, into Jurkat T-cells by the erythrocyte-ghost procedure in order to block the activity of p56lck. In Jurkat cells injected with anti-Lck mAb, intracellular Ca2+ mobilization induced by TcR-stimulation was markedly reduced in comparison with control mouse IgG-injected samples. This block of Ca2+ influx seems to be specific for TcR-signaling because anti-Lck mAb-injection did not cause significant suppression of phytohaemagglutinin-induced Ca2+ increase. Furthermore, injection of anti-Lck mAb inhibited TcR-mediated protein tyrosine phosphorylation of 100 kDa protein and phospholipase C gamma 1. These results confirm that p56lck is an indispensable element of TcR-signaling and p100 and phospholipase C gamma 1 are strongly presumed to be candidates for substrates for p56lck.

Antibodies, Monoclonal↗
PubMed1994

Amelioration of acute graft-versus-host disease and re-establishment of tolerance by short-term treatment with an anti-TCR antibody.

We investigated whether tolerance can be re-established in mice with graft-vs-host disease (GVHD) by using a short-term, T cell-depleting treatment with an anti-TCR-alpha beta mAb. GVHD was induced in 950-rad-irradiated AKR mice (H-2k, Mls-1a) by injecting 5 x 10(6) T cell-depleted bone marrow cells together with either 10(7) or 2 x 10(6) lymph node (LN) cells from BALB/c mice (H-2d, and Mls-1b). AKR mice that received 10(7) LN cells exhibited a severe form of acute GVHD, in which all mice died by day 60. In this severe form of GVHD, treatment with anti-TCR-alpha beta mAb completely ameliorated the induction of GVHD when initiated on day 0 (a total of 800 micrograms/mouse administered on days 0,5, and 10). When the same protocol was begun on day 10, it had no therapeutic effect. However, this delayed treatment with anti-TCR-alpha beta mAb was very effective in reversing a less severe form of GVHD that was induced by the injection of 2 x 10(6) donor LN cells. Recipient mice given prophylactic anti-TCR-alpha beta treatment achieved host-specific tolerance in association with clonal deletion of host Mls-1a-reactive V beta 6+ T cells. In contrast, spleen cells from recipient mice that recovered from the mild form of GVHD as a result of the delayed anti-TCR-alpha beta treatment contained a considerable proportion of the V beta 6+ T cells, despite the healthy appearance of these mice. A MLR assay revealed that the spleen cells from these mice responded well to Mls-1a Ag but not to H-2k Ag, in contrast with the apparent responses of spleen cells from untreated GVHD controls to both Ags. In addition, cells from the anti-TCR-alpha beta-treated mice exhibited a specific reduction in cytotoxicity against AKR blasts. Collectively, these data indicate that a short-term treatment of mice having GVHD with an anti-TCR-alpha beta mAb, starting even after disease onset, can re-establish host-specific tolerance, at least to the host-histo-compatibility Ag.

Acute Disease↗