Chiaki Ishihara

Stimulation of cytokine production in mice using deacetylated chitin

The effect of 70% deacetylated chitin (DAC-70) on the production of cytokines in mice was examined. DAC-70 stimulated the production of colony-stimulating factor and interferon at 6 to 12 h and 24 h after intraperitoneal injection, respectively. Interleukin 1 and colony-stimulating activity were induced in the supernatants of thioglycolate-induced macrophages stimulated with DAC-70 in vitro. However, DAC-70 did not stimulate the production by spleen cells of interleukin 2, interferon, colony-stimulating or macrophage-activating factor or of interferon by macrophages in vitro. DAC-70 showed no effect on the production of tumour necrosis factor in vivo.

Stimulation of non-specific host resistance against Sendai virus and Escherichia coli infections by chitin derivatives in mice

The efficacy of chitin derivatives on non-specific host resistance to Sendai virus and Escherichia coli infections was studied in mice. Seventy percent deacetylated chitin (DAC-70) and N-trimethylated DAC-70 [DAC-70(Me)3] showed protective activity against Sendai virus infection; however, carboxymethyl-chitin (CM-chitin) did not. DAC-70 also showed protective activity against E. coli infection.

Effect of muramyl dipeptide and its stearoyl derivatives on resistance to Sendai virus infection in mice

The efficacy of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), 6-O-stearoyl-MDP (L18-MDP), N alpha-acetylmuramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl-L-lysine (MDP-Lys-L18) and N-stearoylmuramyl-L-alanyl-D-isoglutamine (2N-L18-MDP) for augmenting host-resistance to viral infection was examined in Sendai virus infected mice. L18-MDP and MDP-Lys-L18 augmented the non-specific host-resistance to infection with Sendai virus. MDP showed a slight enhancement of host-resistance to this infection but 2N-L18-MDP was ineffective. The protective effect of MDP-Lys-L18 was seen only when the drug was administered a few days before the virus challenge. The intranasal administration of MDP-Lys-L18 was effective at 1 microgram but only slight activity was observed in mice treated intravenously or intraperitoneally even at the 100 microgram dose level. MDP-Lys-L18 treatment preceding infection augmented interferon production in the lung of the mice but MDP-Lys-L18 treatment alone induced no interferon.

Protective activity of recombinant cytokines against Sendai virus and herpes simplex virus (HSV) infections in mice

The efficacy of recombinant cytokines such as murine interferon-gamma (IFN-gamma), human granulocyte colony-stimulating factor (G-CSF), mouse granulocytic-macrophage colony-stimulating factor (GM-CSF) and human interleukin-1 beta (IL-1 beta) has been examined for augmentation of host resistance against Sendai virus and herpes simplex virus (HSV) infections. All four cytokines were found to protect mice against Sendai virus infection. IFN-gamma afforded protection when administered intranasally but not intravenously several days before the infection. Intranasal administration of G-CSF one day before the infection was the most effective administration route and timing. Intranasal administration of GM-CSF was found to afford protection 1 or 3 days before the infection. IL-1 beta demonstrated therapeutic activity against Sendai virus infection after intranasal administration on the same day as the infection. When each of the cytokines was administered subcutaneously four times daily into cyclophosphamide-treated mice before intravenous infection with HSV, only GM-CSF revealed any protective activity.

Suppression of Sendai virus growth by treatment with Nα-acetylmuramyl-l-alanyl-d-isoglutaminyl-Nϵ-stearoyl-l-lysine in mice

Mice that received Nα-acetylmuramyl-l-alanyl-d-isoglutaminyl-Nϵ-stearoyl-l-lysine [MDP-Lys(L18)] were resistant to Sendai virus infection. In these protected mice, a significant growth inhibition of the virus was confirmed repeatedly at 100.2 to 100.4 of haemadsorbing units at an early non-specific phase but not at a late virus-eliminating phase of the infection. Virus growth was enhanced by treatment with silica but not by treatment with anti-asialo GM1 serum in MDP-Lys(L18)-treated mice. Peritoneal adherent cells activated by MDP-Lys(L18) showed an enhanced uptake and ability to inactivate Sendai virus in vitro. Excess interferon production in MDP-Lys(L18)-treated mice was seen on day 1 but not on days 2 to 7 of the infection. The possible role of macrophages and interferon in providing non-specific protection against Sendai virus in the MDP-Lys(L18)-treated mice is discussed.

Effect of Nα-acetylmuramyl-l-alanyl-d-isoglutaminyl-Nϵ-stearoyl-l-lysine on resistance to herpes simplex virus type-1 infection in cyclophosphamide-treated mice

Abstract The restoration of resistance by N α -acetylmuramyl- l -alanyl- d -isoglutaminyl-N ϵ -stearoyl- l -lysine [MDP-Lys(L18)] on herpes simplex virus (HSV) type-1 infection was examined in cyclophosphamide (CY)-treated mice. MDP-Lys(L18) was shown to restore the resistance to HSV infection in CY-treated mice when it was injected either subcutaneously, intravenously, or intraperitoneally before infection. Treatment with MDP-Lys(L18) in CY-treated mice restored impaired activity for inhibiting HSV growth in the liver.

Effect of stearoyl-N-acetylmuramyl-L-alanyl-D-isoglutamine on host resistance to Corynebacterium kutscheri infection in cortisone-treated mice.

Opportunistic corynebacteriosis was induced successfully by infection with Corynebacterium kutscheri in cortisone-treated mice and the ability of stearoyl-N-acetylmuramyl-L-alanyl-D-isoglutamine derivatives in phosphate buffered saline (PBS) solution or encapsulated into liposomes for restoring impaired resistance was examined. 6-O-Stearoyl-N-acetylmuramyl-L-alanyl-D-isoglutamine (L18-MDP) in liposomes and N alpha-acetyl muramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl-L-lysine (MDP-Lys-L18) both in PBS solution and in liposomes were shown to restore depressed resistance to infection of C. kutscheri when injected intravenously before infection. Treatment with L18-MDP in cortisone-treated mice inhibited growth of C. kutscheri in the liver and kidney for as long as three days after infection.

Stimulation of Host-Defense Mechanism with Synthetic Adjuvants and Recombinant Cytokines Against Viral Infection in Mice

The efficacy of synthetic immunoadjuvants and recombinant cytokines for the potentiation of host-resistance against virus infection was investigated using mouse models infected with Sendai virus and herpes simplex type 1 virus (HSV). The synthetic MDP derivative, MDP-Lys(L18), and recombinant cytokines, IL-1 beta, IFN-gamma, G-CSF and GM-CSF were shown to be effective for the stimulation of nonspecific protection against Sendai virus infection in mice. Both MDP-Lys(L18) and GM-CSF were effective for the protection against HSV infection in cyclophosphamide (CY)-treated mice. B30-MDP was suggested to be useful as an immunoadjuvant for the potentiation of antigenicity of recombinant or component vaccines.

Prophylactic activity against Sendai virus infection and macrophage activation with lipophilic derivatives of N-acetylglucosaminylmuramyl tri- or tetrapeptides

The efficacy of N-acetylglucosaminyl-beta (1----4)-N-acetylmuramyl tri- or tetrapeptides (GM) and the lipophilic derivatives for host augmentation against Sendai virus infection and for macrophage activation in vitro was examined. The anti-infectious activities of GM derivatives were shown to increase with the chain length of the fatty acid combined with the diaminopimelyl group. When the macrophages were activated with 1 U ml-1 murine interferon gamma (IFN-gamma) and 0.001 microgram ml-1 GM derivatives, the cytocidal ability of macrophages depended on the length of the side chain, and exhibited a positive relationship with the anti-infectious activity of GM derivatives against Sendai virus infection. These results indicated that the increment of lipophilicity of GM derivatives would play an important role in the anti-infectious activity and macrophage activation in vitro.

Prophylactic activity of dihydro-heptaprenol, a synthetic polyprenol derivative, against Sendai virus infection in mice

Abstract The effect of a chemically synthesized polyprenol derivative, dihydroheptaprenol (DHP), on the non-specific resistance of mice to Sendai virus infection was investigated. The mice that received 200 μg of DHP intranasally twice, at 3 days and 1 day before the infection, showed a significant protection against Sendai virus infection. Treatment of mice twice even with as much as 2000 μg of DHP through the subcutaneous route, however, had no protective effect against infection. Excess interferon and tumour necrosis factor production in intranasally DHP-treated mice was seen 1 day after the infection when compared with Sendai virus alone controls or with DHP alone controls. Variance analysis of these findings indicates a prophylactic activity of DHP in pulmonary viral infections.