picibanil and Cytomegalovirus-Infections

Seven chemically diverse biological response modifiers (BRM) were compared for antiviral activity in intact and NK cell-depleted CD-1 mice. Both spontaneous and BRM-induced splenic NK cell cytotoxicity were depleted for at least 5 days following treatment with the monoclonal antibody NK1.1. Antiviral protection of standard doses of MVE-2, pIC, pICLC, rmIFN-tau and CL246,738 against lethal MCMV or HSV-2 infections was not abrogated by NK cell depletion, demonstrating that NK cells are not required for BRM-induced antiviral activity against these herpesviruses. When mice were treated with 100,000 U of rHuIFN-alpha B/D, NK cells were not required for activity against MCMV, while at a dose of 25,000 U, NK cells appeared to be partially required against MCMV. At lower doses, the activity of rHuIFN-alpha B/D against MCMV appeared dependent upon the presence of NK cells. A similar dose-related requirement for NK cells was observed for activity of OK-432. Thus, at higher doses of rHuIFN-alpha B/D and OK-432, elements of the natural immune system in addition to or other than NK cells are apparently involved, while at lower doses NK cells appear to play a more important role in antiviral protection against MCMV infection.

Topics: Adjuvants, Immunologic; Animals; Cytomegalovirus Infections; Cytotoxicity, Immunologic; Female; Herpes Simplex; Herpesviridae Infections; Immunity, Innate; Interferon-alpha; Killer Cells, Natural; Lymphocyte Depletion; Mice; Mice, Inbred Strains; Picibanil; Specific Pathogen-Free Organisms; Spleen

The susceptibility of congenitally anemic W/WV mice to infection with murine cytomegalovirus (MCMV) was examined. W/WV mice showed a higher mortality rate and shorter survival time after MCMV infection than did their +/+ littermate mice. In addition, W/WV mice showed a lower plaque-forming unit (PFU) per 50% lethal dose (LD50) and produced higher titers of infectious virus in various organs. The mortality rate and survival time of W/WV mice which received a bone marrow graft 4 weeks before infection was completely restored to the level for +/+ mice, suggesting the importance of the cells of myeloid origin. Although natural killer (NK) activity of W/WV mice was comparable to that of +/+ mice before infection, marked reduction was observed after MCMV infection. Furthermore, OK-432 treatment failed to enhance NK activity of W/WV mice. Impaired NK response was also completely restored by bone marrow grafting 4 weeks before infection. The level of serum interferon (IFN) of infected or uninfected W/WV mice was comparable to that of +/+ mice. Therefore, impaired NK inducibility seems to be responsible, at least in part, for the high susceptibility of W/WV mice to MCMV infection.

Topics: Animals; Bone Marrow Transplantation; Cytomegalovirus Infections; Disease Susceptibility; Female; Genotype; Interferons; Killer Cells, Natural; Mice; Picibanil

Host-mediated antiviral effect of 2 biological response modifiers (BRM), OK-432, and PS-K, against murine cytomegalovirus (MCMV) was evaluated in chronically or latently infected mice. In the early stage of chronic MCMV infection, the BRM-induced resistance was evidenced by decrease in infectious viruses replicated in the salivary glands and by augmented cytotoxic activity of the spleen cells against YAC-1 cells and MCMV-infected mouse embryonic fibroblasts (MEF). In the late stage of chronic MCMV infection, the BRM treatment did not eliminate MCMV from the mice, but did prevent exacerbation of MCMV infection in the salivary glands induced by administration of cyclophosphamide (CY). In mice latently infected by MCMV, BRM treatment suppressed CY-induced reactivation of MCMV in the salivary glands. It was suggested that the antiviral effect of BRM against MCMV in chronically or latently infected mice was based on activation of natural killer (NK) cells and cytotoxic T lymphocytes (CTL).

Topics: Animals; Antibodies, Viral; Antiviral Agents; Biological Products; Cell Line; Cells, Cultured; Chronic Disease; Cyclophosphamide; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxicity, Immunologic; Female; Immunosuppression Therapy; Interferons; Killer Cells, Natural; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Picibanil; Proteoglycans; Salivary Glands; T-Lymphocytes, Cytotoxic; Virus Replication

The presence of HCMV-infected cells inhibits the killing of mouse tumor cells by adherent PEC in an antibody-dependent cell-mediated cytotoxicity (ADCC) test system. The effect of HCMV-infected cells on ADCC is mediated by the binding of IgG to the Fc receptors of infected cells.

Topics: Antibody-Dependent Cell Cytotoxicity; Cytomegalovirus; Cytomegalovirus Infections; Macrophages; Monocytes; Peritoneal Cavity; Picibanil; Receptors, Fc

The host-mediated antiviral effect of two biological response modifiers (BRM), OK-432 and PS-K, against murine cytomegalovirus (MCMV) was evaluated in normal and immunologically deficient mice of the same litters. In normal littermate mice, BALB/c (nu/+) or C57BL/6 (bg/+), the BRM-induced resistance against MCMV infection was evidenced by increase in fifty percent lethal doses, decrease in titers of viruses replicated in the target organs and augmentation of natural killer (NK) cell activity of the spleen cells. In T cell-deficient, athymic nude mice, BALB/c (nu/nu), the protective effect was manifested by prolongation of the survival, decrease in the virus titers, and increase in the NK-cell activity, but without decrease in mortality. In NK cell-deficient, beige mutant mice, C57BL/6 (bg/bg), the BRM-induced protection was nullified or minimized, and there was little difference in those parameters between BRM-treated and untreated mice. However, with higher doses of OK-432, but not PS-K, or with sublethal doses of MCMV, the NK cell activity was slightly augmented in the beige mutant mice. Thus both NK cell and T cell activity are essential for mice to overcome acute MCMV infection and it is likely that the protective effect of BRM manifests itself fully, at least in immunologically intact mice.

Topics: Adjuvants, Immunologic; Animals; Antiviral Agents; Basidiomycota; Biological Products; Cytomegalovirus Infections; Immunity, Cellular; Killer Cells, Natural; Mice; Mice, Mutant Strains; Mice, Nude; Picibanil; Proteoglycans; Spleen; T-Lymphocytes

Pretreatment with two biological response modifiers (BRM), OK-432 and PS-K, protected mice from lethal infection by murine cytomegalovirus (MCMV). This was evidenced by an increase in 50% lethal doses and a decrease in titers of infectious viruses replicated in the liver and spleen. Spleen cells from the BRM-treated mice augmented the natural killer (NK) cell activity and suppressed the replication of MCMV in vitro. During MCMV infection, the NK cell activity of the spleen cells was maintained at a high level in the BRM-treated mice, whereas it was severely impaired in untreated mice. The BRM-induced protection was nullified by concomitant administration of antiasialo GM1 antibody. Interferon was neither induced by BRM treatment nor enhanced in BRM-pretreated and MCMV-infected mice. Thus, the protective effect of OK-432 and PS-K seems to be based on activation of NK cells and prevention of MCMV-induced inhibition of the NK cell activity.

Topics: Animals; Antibiotics, Antineoplastic; Biological Products; Cytomegalovirus; Cytomegalovirus Infections; Female; Interferon Inducers; Interferons; Killer Cells, Natural; Macrophages; Mice; Picibanil; Proteoglycans; Spleen; Virus Replication