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Biomedical subjects

P S Morahan

Publications and source records attributed to P S Morahan.

At least 19 recordsLinked to original sources

Effect of pyran on latency after herpes simplex virus infections.

The immunomodulator pyran protected mice against both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. In infections of the lip with HSV-1, prophylactic administration of pyran reduced the severity of the herpetic lesions and enhanced their resolution, but did not decrease the high incidence of development of latent HSV-1 infection of the trigeminal ganglia. In vaginal infections with HSV-2, prophylactic administration of pyran either systemically or locally reduced mortality, reduced the incidence of mice with vaginal HSV-2 infection, and did not alter the low incidence of latent infection of the spinal dorsal root ganglia. Pyran treatment before systemic herpetic infection after intravenous inoculation of HSV-2 also reduced mortality and virus replication, as evidenced by a decreased antibody response in the survivors, and it either reduced latent infection in the spinal dorsal root ganglia or did not predispose mice to latent infection. Treatment with the immunomodulator appeared to inhibit or reduce HSV infection early in viral pathogenesis in all three model systems, producing protection from clinical disease and resulting in less virus to induce a systemic antibody response, with either a reduction in latent virus infection or no enhancement of development of latency. In all of the HSV models, the development of latent herpetic infection was closely correlated with sufficient virus replication early in the infection to induce a systemic neutralizing-antibody response.

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Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus.

Previous investigations from our laboratories have demonstrated that cannabinoids possess immunosuppressive properties. The present studies were designed to determine whether these agents decrease host resistance to infections with Listeria monocytogenes and herpes simplex virus type 2. Host resistance was measured by changes in the 50% lethal dose of the pathogen in cannabinoid-treated and control mice. The effect of cannabinoids on resistance to L. monocytogens was dose dependent. Delta-9-tetrhydrocannabinol at doses of 38, 75, and 150 mg/kg suppressed resistance to infection by 10-, 17-, and 657-fold, respectively. Marijuana extract was less active but significantly reduced resistance to L. moncytogenes at all tested doses. Resistance to systemic herpes simplex virus type 2 infection was decreased 96-fold by delta-9-tetrahydrocannabinol, although marijuana extract was inactive. The doses and regimen of treatment with cannabinoids that produced significant decreases in host resistance were similar to those which caused suppression of delayed-type hypersensitivity to sheep erythrocytes. The possible mechanisms and public health aspects of the decreased host resistance produced by marijuana extract and its cannabinoids are discussed.

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Enhancement of erythroid target cells for Friend murine leukemia virus by intravenous pyran treatment.

Male BALB/c mice that received prophylactic iv treatment with pyran had significantly enhanced splenomegaly, an increased number of splenic foci induced by the spleen focus forming virus (SFFV) in the Friend murine leukemia virus (F-MuLV) complex, and a slightly decreased mean survival time as compared with untreated controls infected with F-MuLV. A corresponding increase in the lymphatic leukemia virus component of the F-MuLV complex was not observed, which suggests that the enhancement of the disease was due primarily to a selective increase in the SFFV component of the F-MuLV complex. That the enhancement was related to an increased number of target cells for SFFV was substantiated by data concerning erythropoiesis in iv pyran-treated animals. Increases in splenic hematocrits and in uptake of 59Fe in the spleens of animals treated iv with pyran provided quantitative evidence for the histologic finding of increased erythroid precursors in the spleens.

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Comparison of various macrophage-inhibitory agents on vaginal and systemic herpes simplex virus type 2 infections.

Pretreatment of mice intraperitoneally with silica, trypan blue, or dextran sulfate to inhibit macrophage function markedly increased the lethality of a systemic intravenous infection with herpes simplex virus type 2, but did not affect the lethality or local virus growth after vaginal infection of mice with herpes simplex virus type 2. Agents which inhibit macrophage function by different mechanisms decreased host resistance to herpes simplex virus type 2, but the effects of macrophage-inhibitory agents may vary according to the route of virus infection.

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Relationship of molecular weight to antiviral and antitumor activities and toxic effects of maleic anhydride-divinyl ether (MVE) polyanions.

The molecular weight (MW) and dose dependency of several of the toxic effects and antitumor and antiviral activities of a new series of five maleic anhydride-divinyl ether copolymers (MVE) were established. Each polyanion preparation was relatively homogeneous and exhibited a narrow MW range, from 12,500 (MVE-1) to greater than 52,000 (MVE-5). All of the polyanions were effective as adjuvants to surgery against the metastatic Lewis lung carcinoma, and also exhibited marked antitumor activity against the P815 mastocytoma. MVE-1 retained antitumor activity while losing considerable antiviral activity. This polyanion also exhibited the least toxicity with regard to criteria such as sensitization to the lethal effects of endotoxin, inhibition of reticuloendothelial function, and depression of the microsomal mixed functional oxidase system. The MVE-4 (MW, 32,000) and MVE-5 (MW, 52,600) polyanions exhibited potent antitumor and antiviral activity, but also demonstrated dose-dependent toxic effects.

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Herpes simplex virus vaccine: protection from stomatitis, ganglionitis, encephalitis and latency.

A mouse model system was developed for studying the pathogenesis of oral infection with herpes simplex virus type 1 and the protection offered by prior immunization with a nucleic acid-free vaccine. Of non-immunized mice, 95-100% developed ulcerative lesions 3-5 days following application of virus to abraded oral epithelial surfaces. Infection of the ipsilateral sensory (trigeminal) ganglion and the cerebellum occurred by day 2 and sequentially progressed to the contralateral ganglion by day 4 and to the cerebrum by day 5. Prior immunization of mice with an inactivated virus vaccine, and most importantly, with a vaccine free of nucleic acid, protected mice from subsequent oral virus infection. Protection was demonstrated by: (i) reduction in the incidence and severity of primary oral lesions; (ii) a decrease in the number of mice with acute ganglionic infection or dying of encephalitis; and (iii) a reduction in the incidence of latent trigeminal ganglionic infection.

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Immune responses to vaginal or systemic infection of mice with herpes simplex virus type 2.

Relationships among cell-mediated immune (CMI) responses, neutralizing antibody, and macrophages in host resistance to vaginal or systemic infection with HSV-2 were defined in BALB/c mice. The importance of T-lymphocytes in resistance to either systemic or vaginal infection was demonstrated by increased susceptibility of mice depleted of T-lymphocytes. A role for non-specific resistance against the systemic, but not vaginal, infection was demonstrated by increased susceptibility of mice depleted of macrophages. The temporal relationships among the serum antibody response, and the delayed-type hypersensitivity (DTH) and splenic proliferative CMI responses were defined in individual animals. Vaginal infection was associated exclusively with relatively transient CMI responses which appeared during the acute infection. After systemic infection, CMI responses appeared during the acute infection. After systemic infection, CMI responses appeared during the acute infection and persisted for approximately five weeks, while a humoral response appeared in surviving animals and persisted for at least four months. The results suggest that CMI is the predominant host response to vaginal HSV-2 infection, while both CMI and macrophage-mediated antiviral activity may be involved in recovery from primary systemic infection with HSV-2.

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Potential mechanism of macrophage-mediated tumor cell cytotoxicity.

Activated macrophages have been shown to inhibit the incorporation of 125IUDR into the DNA of Lewis lung (LL) tumor cells and to lead to the cytotoxicity of these target cells. Despite this apparent inhibition of DNA synthesis, the increase in the number of LL cells cultured with activated macrophages paralleled that of LL cells alone for the first 18 hours of culture (approximately one doubling of cells). To resolve this paradox, the DNA content of LL cells, which were cultured with activated macrophages for 16 hours, was analyzed by flow microfluorometry. These experiments indicated that subsequent to co-culture with activated macrophages, LL cells with a 50% reduction in their normal DNA content could be detected. Furthermore, after a 2-hour incubation with colcemid, a greater than 95% reduction in metaphase cells occurred in LL cells cultured with activated macrophages. However, dividing nuclei without chromosome condensation appeared to be a prominent feature of these cultures. This would suggest that the genotypic or phenotypic program for cell division in the tumor cells is such that under these unique circumstances of tumor cell-activated macrophage interaction, cell division can proceed in the absence of DNA synthesis. We suggest that this aberrant division may be related to the lethal event which leads to activated macrophage-mediated tumor cell cytotoxicity.

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Protection from oral herpes simplex virus infection by a nucleic acid-free virus vaccine.

The effect of immunization with inactivated herpes virus vaccines, including a vaccine free of all nucleic acid, was investigated in a mouse model system. Protection against oral lesions induced by herpes simplex virus type 1 was demonstrated by several criteria: (i) reduction in the incidence and severity of primary oral lesions; (ii) decrease in acute and latent infection of the regional sensory ganglia; and (iii) protection from viral encephalitis and death. The immune response of mice to the vaccine and to subsequent virus challenge was measured by following serum-neutralizing antibody titers.

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Immune responses to vaginal or systemic infection of BALB/c mice with herpes simplex virus type 2.

The temporal relationships among the humoral and cellular immune responses were defined in BALB/c mice after vaginal or systemic infection with herpes simplex virus type 2 (HSV-2). After vaginal infection, mice showed evidence of clinical vaginitis on days 4 to 6 and HSV-2 replication was detected locally in the vaginal secretions, cervix, vagina, and uterus before the virus subsequently spread to the central nervous system. Death from encephalitis occurred between 7 and 10 days after infection. Vaginal infection was associated with significant delayed type hypersensitivity and splenic proliferative cell-mediated immune responses which appeared during the acute infection and waned by 3 weeks. There was almost no evidence of a systemic neutralizing antibody response at any time after vaginal infection. In contrast to the local vaginal infection, systemic i.v. HSV-2 infection induced a humoral response as well as the two cellular immune responses. Although both cellular immune responses appeared during the acute infection (days 6 to 14) and persisted for approximately 5 weeks, the humoral response appeared in surviving animals and persisted for at least 4 months. Thus, vaginal HSV-2 infection was associated primarily with transient cellular immune responses, whereas i.v. HSV-2 infection induced prolonged systemic humoral and cellular immune responses.

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Cellular and serum involvement in protection against Friend leukemia virus.

Treatment of mice with the immunomodulator pyran copolymer inhibited leukemogenesis produced by Friend leukemia virus (FLV) complex, as evidenced by inhibition of the spleen focus-forming virus and lymphatic leukemia virus, as well as by a significant decrease in splenomegaly. In this report we present data suggesting that the protective effect of pyran is mediated by macrophages. Protection was conferred on normal recipient mice when peritoneal exudate cells from pyran-treated mice were transferred to recipient mice infected 24 hr later with FLV. Animals receiving pyran-activated peritoneal cells had a significant reduction of splenomegaly and of titers of spleen focus-forming virus and lymphatic leukemia virus than did control animals. In contrast, when glycogen-elicited peritoneal exudate cells were transferred, the mice were not protected. Pyran-activated peritoneal cells, but not normal peritoneal cells, also inhibited FLV growth in vitro. Serum from pyran-treated, but not glycogen-treated, mice also transferred resistance to FLV-infected mice.

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Macrophage activation and anti-tumor activity of biologic and synthetic agents.

Systemic administration of the synthetic immunopotentiator pyran, was as effective as the use of the biologic immunopotentiator BCG in activating macrophages and in inhibiting the Lewis lung carcinoma and MCA 2182 sarcoma. Several other synthetic polyanions also activated macrophages and exhibited some anti-tumor activity, but none were as effective as pyran. Cell-wall fractions such as the Ribi vaccine and MER were considerably less effective than BCG. The anti-tumor activity of pyran against the virtually non-immunogenic Lewis lung carcinoma involved non-specifically activated macrophages, and both anti-tumor activity and macrophage activating ability persisted over a 100-fold range of drug from 0.5 mg/kg to 50 mg/kg. The ability of activated macrophages to destroy tumor cells was abrogated by treatment with trypan blue, an inhibitor of macrophage lysosomal enzymes. In addition, preincubation of tumor cells with activated peritoneal cells at effector-cell:target-cell ratios of 20:1 and 5:1 markedly decreased tumor incidence and mortality. Glycogen-stimulated or unstimulated peritoneal cells were completely inactive in inhibiting tumor growth in vivo or exhibiting cytotoxicity in vitro, demonstrating the requirement for activated macrophages selective for tumor-cell destruction.

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