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Biomedical subjects

D Mizuno

Publications and source records attributed to D Mizuno.

At least 73 records · Page 4Linked to original sources
PubMed1986

Endogenous production of TNF in mice long after BCG sensitization.

The effect of tuberculin-antigen protein (PPD: purified protein derivatives) on the priming of tumor necrosis factor (TNF) a long time after sensitization with bacillus Calmette-Guérin (BCG) was investigated in mice. Mice were infected intravenously (i.v.) with 4 X 10(7) colony-forming units (CFU) of BCG per mouse, and the TNF activity triggered by 15 micrograms lipopolysaccharide (LPS) was assayed with time using L-929 cells. The activity was maximal 4 weeks after sensitization and decreased to the control level after 10 weeks. The i.v. injection of 10 micrograms of PPD per mouse enhanced the TNF production triggered by LPS in mice even 10-20 weeks after sensitization. This enhancement was unexpectedly quite transient, being maximal 3 h after PPD treatment. The activity was comparable to that in mice 4 weeks after sensitization of BCG (without PPD). The enhancing effect of PPD was observed in the dose range of 0.1-10 micrograms/mouse, and 10 micrograms of PPD significantly enhanced the TNF activity triggered by even 0.6 microgram LPS. These findings indicate that priming of sensitized animals with some antigens followed by triggering with LPS induces a significant endogenous production of TNF even a long time after antigen sensitization. The possible application of these findings for inducing endogenous production of TNF in human patients by use of tuberculin allergy is discussed.

Animals↗
PubMed1986

Induction by heterologous fibrinogen of release of TNF-like cytotoxic factor from murine macrophages.

In an attempt to find nontoxic triggering agents to release cytotoxin from primed macrophages of mice, the abilities of eight plasma components to induce release of cytotoxin from J-774.1, a murine macrophage-like cell line, were examined. Heterologous, but not homologous, fibrinogen and fibrin were found to enhance the release of cytotoxin. The fibrinogen and fibrin did not contain any lipopolysaccharide (LPS) as tested with polymyxin B. Thus, heterologous fibrinogen and fibrin could be useful as nontoxic triggering agents.

Animals↗
PubMed1986

Induction of a cytotoxin from murine macrophages by an animal lectin.

Vertebrate lectin purified from loach eggs stimulated release of cytotoxin from BCG-or glucan (TAK)-elicited peritoneal macrophages and a murine macrophage cell line (J774.1), but not from resident peritoneal cells. The cytotoxin released from J774.1 cells on stimulation with loach egg lectin was a heat-labile protein with a molecular weight of about 55K.

Animals↗
PubMed1986

Endogenous production of TNF in mice with immune complex as a primer.

C3H/He mice were immunized i.v. with sheep red blood cells (SRBC), and then the effect of i.v. challenge with SRBC on the priming of endogenous production of tumor necrosis factor (TNF) was investigated. Mice were immunized i.v. with 10(8) SRBC/mouse, and their serum TNF activity, triggered by 3 micrograms lipopolysaccharide (LPS) per mouse, was assayed by an in vitro cytotoxicity test using L-929 cells. Anti-SRBC antibodies were induced maximally in 2 weeks, but the acquired immunity did not affect TNF triggering. However, 9-10 weeks after the primary challenge, when there was still a relatively high antibody titer in the serum, i.v. rechallenge with 10(8) SRBC/mouse transiently enhanced the TNF activity triggered by LPS to about 10 times that in normal control mice. This priming effect of SRBC challenge was antigen specific, because challenge with horse red blood cells (HRBC) had no effect. SRBC opsonized with anti-treated with anti-SRBC antiserum or sonicated SRBC had no effect. These findings suggest two ways of facilitating the triggering of endogenous TNF production: booster challenge of immunized animals with the corresponding antigens makes them ready for TNF triggering, and direct injection of immune complexes, even into normal animals, makes them ready for triggering of TNF. The possible application of these findings for inducing endogenous TNF production in human cancer patients by use of immune complexes is discussed.

Animals↗
PubMed1985

Purification of antineoplastic factor from eggs of a sea hare.

An antineoplastic factor inducing tumor lysis was purified to apparent homogeneity from the supernatant of a homogenate of eggs of the sea hare Aplysia kurodai. On gel filtration, the purified substance gave a single band of material of 250 kDa containing 3 different subunits and this band coincided with cytolytic activity. The purified factor was half-maximally active at 10-60 ng protein/ml and lysed all tumor cells tested, but not normal cells.

Animals↗
PubMed1985

Purification of rabbit tumor necrosis factor.

Rabbit tumor necrosis factor (TNF) was purified and shown by SDS-PAGE to be a single protein of 18 kDa. TNF in 355 ml rabbit serum was precipitated with ammonium sulfate, and purified by repeated DEAE-Sephadex and Sephacryl S-200 chromatographies, and the final fractionation on Blue-Sepharose 6B. By this procedure its yield was 22% and its specific activity was 2.4 X 10(7) U/mg protein. The sequence of the N-terminal 20 amino acids was determined.

Amino Acid Sequence↗
PubMed1985

Induction of macrophage growth by the lipid moiety of lipoprotein and its augmentation by denaturation of the lipoproteins.

Lipoprotein (d less than 1.21) isolated from mouse tumor ascitic fluid or mouse-serum induced growth of peritoneal macrophages in vitro. Lipoprotein fractions that stimulated macrophage growth were the chylomicron, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL), whereas the high-density lipoprotein (HDL) fraction did not. Lipids extracted from total lipoprotein also showed significant macrophage-growth-stimulating activity and lost this activity when hydrolyzed. The macrophage-growth-stimulating activity of the lipoprotein (d less than 1.21) was increased about ten times by heat treatment of the lipoprotein (100 degrees C, 30 min). The HDL fraction that had no activity in the native form also showed activity after heat treatment. Lipoprotein-depleted ascitic fluid and simple proteins such as bovine serum albumin (BSA) had no activity even after heat treatment. These results show that the lipid moiety of lipoproteins caused proliferation of macrophages and that denatured lipoproteins were more effective than native ones.

Animals↗
PubMed1985

Hydrogen peroxide as a tumoricidal mediator of murine polymorphonuclear leukocytes induced by a linear beta-1,3-D-glucan and some other immunomodulators.

Polymorphonuclear leukocytes (PMN) of mice can destroy tumor cells effectively in vitro in the presence of antitumor polysaccharide, linear beta-1, 3-D-glucan from Alcaligenes faecalis var. myxogenes IFO 13140 (TAK), and some other immunomodulators. In the present study, we investigated the mechanism of the tumoricidal activity of PMN induced by these immunomodulators and especially TAK. The TAK-induced PMN cytotoxicity was concluded to involve hydrogen peroxide from the following results: (a) the cytotoxicity depended on glucose consumption; (b) it was almost completely inhibited by catalase but not affected by superoxide dismutase; (c) it was not reduced by cyanide or azide, which are inhibitors of myeloperoxidase; (d) it was not affected by scavengers of singlet oxygen or hydroxyl radical; (e) release of hydrogen peroxide from PMN was observed by the addition of TAK; (f) MM46 target cells were lysed directly by hydrogen peroxide in the absence of myeloperoxidase; (g) the supernatant of PMN in the presence of TAK, tested as a stable cytotoxic factor, did not have cytotoxic activity, and protease inhibitors had no effect on this cytotoxicity. These results suggest that hydrogen peroxide is a direct cytotoxic mediator in TAK-induced PMN cytotoxicity. Next, the mechanism of PMN cytotoxicities induced by other immunomodulators was also examined and was compared with that induced by TAK. The results suggest that hydrogen peroxide is also important for these cytotoxicities whereas, unlike the results with TAK, the H2O2:halide:myeloperoxidase system may partly participate in the cytotoxicities with some immunomodulators.

Adjuvants, Immunologic↗
PubMed1985

Induction of tumoricidal activity of polymorphonuclear leukocytes by a linear beta-1,3-D-glucan and other immunomodulators in murine cells.

The cytotoxic activity of polymorphonuclear leukocytes (PMN) against tumor cells induced in vitro by antitumor immunomodulators was examined by a 51Cr release cytotoxicity assay. Among 28 immunomodulators and other agents thus far tested, only beta-1,3-glucan from Alcaligenes faecalis var. myxogenes IFO 13140, Bacillus Calmette-Guérin, Propionibacterium acnes, zymosan A, and Nocardia cell wall skeleton were found to cause induction. The cytotoxic activity of PMN with the beta-1,3-glucan was very high, almost 100% cytolysis being observed at an effector:target ratio as low as 3. The other four potent immunomodulators had effects very similar to that of the beta-1,3-glucan. All five tumor cell lines tested, MM46, MM48, MH134, EL-4, and YAC-1, were lysed, whereas normal spleen and thymus cells and PMN were not. Of four types of effector cells tested, PMN and casein-induced macrophages were effective, whereas resident macrophages and J774 cells were not effective. The cytotoxic activity of PMN was greater than that of induced macrophages, although both were induced by casein. From results on the polysaccharides tested, a linear beta-1,3-glucan structure and a minimum number average degree of polymerization of 125 of the beta-1,3-glucan seemed to be required for induction of cytotoxicity of PMN. The cytotoxic features of PMN and possible chemical structures of antitumor polysaccharides for induction of cytotoxicity are discussed.

Adjuvants, Immunologic↗
PubMed1985

Complete regression of Lewis lung carcinoma by cyclophosphamide in combination with immunomodulators.

Several types of combination therapy, including OK432, cyclophosphamide (CY), and/or lentinan plus bacterial lipopolysaccharide (LPS), reported to have strong antitumor activity against some tumors, were only slightly effective on Lewis lung carcinoma (LC) in C57BL/6 mice. Combination therapy by intralesional injection of OK432 followed by intraperitoneal administration of CY, lentinan and LPS caused almost complete regression of intradermal solid-type LC. Maximal antitumor activity was observed when lentinan and LPS were administered later than CY. Mice in which LC had regressed due to this combination therapy showed an antitumor delayed hypersensitivity reaction (measured by the footpad test), but they were not resistant to rechallenge with LC. These results provide a new model for combination therapy against weakly immunogenic tumors.

Animals↗
PubMed1985

Combination antitumor therapy with rabbit tumor necrosis factor and chemo- and immuno-therapeutic agents against murine tumors.

The antitumor activity of partially purified rabbit tumor necrosis factor (TNF) in combination with lentinan or chemotherapeutic agents was tested. Partially purified TNF was obtained from TNF-containing rabbit sera by salt precipitation and ion-exchange chromatography. Its specific activity, determined in vitro as its cytotoxic activity against L929 cells in the presence of actinomycin D, was 10(5) U/mg protein or about 30-fold that of the crude rabbit sera. The growths of MH134 hepatoma in C3H/He mice and Lewis lung carcinoma in C57BL/6 mice were partially inhibited by intratumoral administration of a suboptimal dose of the TNF preparation. Additional treatment with lentinan, actinomycin D, mitomycin C or adriamycin significantly increased the antitumor activity. In particular, combination therapy with TNF and lentinan was very effective against MH134 hepatoma without having detectable side-effects, showing that lentinan expanded the therapeutical potential of TNF. These results are discussed in relation to our previous results on combination antitumor therapy.

Animals↗
PubMed1985

Drug-dependent cellular cytotoxicity mediated by polymorphonuclear leukocytes.

Several anticancer drugs were tested for induction of cytolysis mediated by polymorphonuclear leukocytes (PMNs). Among them, actinomycin D and vincristine sulfate induced tumor lysis mediated by PMNs (drug-dependent cellular cytotoxicity). The cell-free supernatant of PMNs incubated with actinomycin D in vitro could lyse various murine tumor cells, although normal spleen cells and sheep red blood cells were not lysed. The cytolytic activity of the supernatant was resistant to treatment with superoxide dismutase, catalase, trypsin inhibitor or arginine. However, the cytolytic activity was labile to heat treatment at 56 degrees (30 min) or trypsin treatment, suggesting a protein nature. These results suggest that PMNs can lyse tumor cells in the presence of certain anticancer drugs and that a factor(s) from PMNs may participate in the killing of tumor cells.

Animals↗
PubMed1985

Induction of macrophage growth by lipoprotein.

Cell-free tumorous ascitic fluid stimulated growth of variously induced mouse peritoneal macrophages and resident macrophages in vitro. This induction of macrophage growth by the tumorous ascitic fluid was confirmed by autoradiography. The macrophage growth-stimulating activity was stable on heating at 100 degrees C, in contrast to that of macrophage growth factor (colony stimulating factor) previously reported. This heat-stable macrophage growth-stimulating activity was recovered in the lipoprotein fraction of tumorous ascitic fluid. The lipoprotein from heat-treated normal mouse serum also induced growth of macrophages. These results indicate that lipoprotein can induce macrophage proliferation, at least in vitro.

Animals↗
PubMed1984

Macrophage-mediated tumor lysis induced by loach egg lectin.

Vertebrate lectin purified from loach egg was tested for induction of tumor lysis mediated by macrophages. Loach egg lectin lysed tumor cells but not normal spleen cells in cooperation with BCG- or glucan (TAK)-elicited peritoneal macrophages of mice. Corynebacterium parvum-, OK432-, glycogen-, lipopolysaccharide-elicited or resident macrophages were not effective. Neither loach egg lectin nor BCG nor glucan macrophages alone had a cytolytic action on tumor cells. Thus, the vertebrate lectin from loach egg is a mediator in macrophage-mediated tumor lysis, inducing binding of macrophages to target cells. This lectin-dependent macrophage-mediated cytolysis (LDMC) was inhibited by galactose, N-acetylgalactosamine, fucose, or rhamnose. These results suggest that tumor cells can be recognized via glycoconjugates on cell membrane in addition to tumor-associated antigen and that some animal lectins participate in macrophage-mediated tumor lysis.

Animals↗