Biomedical subjects

J D Morrey

Publications and source records attributed to J D Morrey.

29 records · Page 2Linked to original sources

PubMed1992

Suppression of murine retroviral disease by 2',3'-didehydro-2',3'-dideoxythymidine (D4T).

The thymidine analog, 2',3'-didehydro-2',3'-dideoxythymidine (D4T), and 3'-azido-3'-deoxythymidine (AZT) were evaluated for activity against Friend virus complex (FV) in Mus dunni cells using a focal immunoenzyme assay. The 50% effective doses were, respectively, 1.2 and 0.1 microM for the two compounds; the 50% cytotoxic doses using trypan blue dye exclusion were 25.4 and > 100 microM. Four FV inhibition experiments with D4T were run in F1 hybrid mice containing the Rfv-3r/s genotype. This mouse strain allows the study of treatment effects on development of specific neutralizing antibodies and on splenomegaly, splenic and plasma virus titers, and splenic viral RNA. In the first experiment, D4T was given by oral gavage (p.o.) three times daily (t.i.d.) for 14 days beginning 4 h post-virus inoculation. All dosages used (187.5, 375, 750 mg/kg/day) significantly inhibited all viral parameters. Other experiments used D4T p.o. twice daily, with dosages of 46.9, 93.8, 187.5 and 375 mg/kg/day or four times daily with a dose of 375 mg/kg/day. No significant disease inhibition was seen using the twice daily treatment schedule, but efficacy was apparent using the four times daily treatment. The final experiment repeated the initial study, extending the t.i.d. treatments to 25 days and using dosages of 46.9, 93.8, 187.5 and 375 mg/kg/day. All but the lowest dose reduced each virus parameter. None of the D4T treatment regimens caused death in toxicity controls, although moderate host weight loss or less weight gain was seen, and variable hematocrit decreases occurred, particularly in mice receiving the highest drug dosage. Inhibition of natural killer (NK) cell activity also was seen in these same animals, but in infected mice, FV-induced decrease in NK cell activity was prevented by D4T treatment. Virus-specific neutralizing antibodies developed in all infected, treated animals. These data indicate D4T has potential as a possible candidate for anti-human immunodeficiency virus evaluations in the clinic.

Animals↗

PubMed1992

Elucidation of mode of retroviral-inhibitory effects of imexon through use of immune competent and severe combined immune deficiency (SCID) mice.

Mice infected with various tumor retroviruses have been used as models for evaluating therapeutic substances for the treatment of some cancers, and more recently, for human immunodeficiency virus (HIV) infection, the causative agent of acquired immune deficiency syndrome (AIDS). Consequently, there is a need to determine the ability of biological response modifiers (BRMs) to specifically reduce virus-infected cells, as compared to their non-specific anti-proliferative effects. To address this need, a BRM, imexon, was evaluated in this study using three strains of mice having different Friend virus (FV)-specific immunological capabilities. The first strain, (B10.A x A/WySn)F1, was genetically capable of producing FV-specific neutralization and cytotoxic antibodies, the second, Balb/c, was not, and the third, SCID mice, lacked functional T and B cell immunity. Imexon treatment reduced virally-induced splenomegaly in all 3 strains; however, the concentration of splenic viral infectious centers (IC) were not affected. Since imexon was efficacious in reducing splenomegaly in SCID mice, the mode of action was concluded to not require functional T or B cell immunity. The observation that imexon did not affect splenic IC titers also suggested that imexon did not specifically eliminate virally infected cells, but may have functioned by other mechanisms. This study also demonstrated the use of various mouse strains as a strategy for delineating the modes of action of BRMs against murine retroviral infections.

Animals↗

PubMed1992

Murine retroviral disease-enhancing effects of a pyrimidinone immunomodulator.

(B10.A x A/WySn)F1 mice, infected with the Friend virus (FV) complex, were used as a predictive therapeutic model for AIDS. These infected mice exhibit many of the viral and immunologic manifestations of AIDS. Bropirimine (2-amino-5-bromo-6-phenyl-4[3H]pyrimidinone, ABPP) is an immunomodulating compound which has been shown to inhibit other viral infections. Oral (per os treatment) dosages of ABPP ranging from 50 to 400 mg/kg/day for 3 days resulted in increased numbers of infectious centers in the infected mice and increased splenomegaly and percentage of Ig+ (B cells) in spleens of infected and uninfected mice. Decreased percentages of total Thy-1.2+ (total T) cells and L3T4+ (T-helper) cells were seen in both uninfected and infected mice and a slightly decreased percentage of Ly-2+ (T-suppressor/cytotoxic) cells was observed in spleens of the infected mice. No effect on Ly2+ cells in spleens of uninfected mice was found. Intraperitoneal injection, single or multiple, of 20-200 mg/kg ABPP prior to FV injection resulted in increased spleen weights but had no effect on numbers of infectious centers in the spleens or on FV antibody titers in the plasma. Intraperitoneal treatment of uninfected mice with ABPP resulted in slight or no changes in percentages of Thy-1.2+, L3T4+ and Ly-2+ cells. Mice receiving multiple exposures of ABPP had an increase in percentage of splenic B cells and a depressed response to the T cell mitogen PHA. Treatment with ABPP induced the production of interferon (IFN); however, a state of hyporesponsive IFN production was seen following multiple administrations of ABPP. These data suggest that the immunomodulator ABPP may have an enhancing effect on this retroviral disease.

Acquired Immunodeficiency Syndrome↗

PubMed1992

HIV-1 LTR activation model: evaluation of various agents in skin of transgenic mice.

Mice containing the HIV-1 long terminal repeat (LTR) regulating the expression of firefly luciferase reporter gene were investigated for their use as a model for activation of the LTR. As a limited test of this model, a number of different factors were screened for their ability to affect reporter gene activities in the skin. Reporter gene levels were increased in the skin by topical treatment of dimethylsulfoxide, retinoic acid, phorbol ester, ultraviolet light, and hydrogen peroxide, all of which have previously been shown to cause increased HIV production in cultured human cells. Topically applied arachidonic acid, histamine, ethanol, acetone, and methanol did not increase reporter gene activities. A lack of published reports on activation of HIV-1 in human cells by these agents suggests that they do not activate viral expression in human cells, which corroborates with the findings of this report. Minor forms of skin wounding and intraperitoneally administered psoralen plus ultraviolet light also increased reporter gene activities in skin. Control and test treatments could be performed on the same mouse and repetitive samples could be obtained from each treatment area. These transgenic mice might be useful as predictive models for regulation of the LTR in epidermal or dendritic cells.

Administration, Topical↗

PubMed1991

Effect of imexon treatment on Friend virus complex infection using genetically defined mice as a model for HIV-1 infection.

Imexon (4-imino-1,4-diazobicyclo-3.1.0-hexan-2-one) was moderately effective in the treatment of a retroviral infection in a genetically defined murine model. The animal model consisted of a Friend virus complex (FV) infection in a hybrid mouse strain, (B10.A x A/WySn)F1, which has similarities with acquired immune deficiency syndrome (AIDS). Intraperitoneal imexon initiated 1 or 3 days after FV inoculation and continued through 13 days after inoculation significantly reduced splenomegaly, splenic cell-free virus titers and viral RNA. Viral infectious centers/10(6) splenocytes and FV titers in the plasma were reduced, though not to a statistically significant level. The effect of imexon on survival was not statistically significant which suggested that the antiviral effects were only transiently effective. Phytohemagglutinin-induced blastogenesis and percent of total T cells, T helper cells and T suppressor/cytotoxic cells in the spleens were increased, and the percentage of B cells decreased by imexon treatment of both FV-infected and uninfected mice. The splenic natural killer cell activity and interleukin-1 production were not markedly affected. Virus specific neutralizing antibody developed in both imexon- and placebo-treated FV-infected mice, although titers were lower in the imexon-treated animals.

Acquired Immunodeficiency Syndrome↗

PubMed1991

In vivo activation of human immunodeficiency virus type 1 long terminal repeat by UV type A (UV-A) light plus psoralen and UV-B light in the skin of transgenic mice.

UV irradiation has been shown to activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) in cell culture; however, only limited studies have been described in vivo. UV light has been categorized as UV-A (400 to 315 nm), -B (315 to 280 nm), or -C (less than 280 nm); the longer wavelengths are less harmful but more penetrative. Highly penetrative UV-A radiation constitutes the vast majority of UV sunlight reaching the earth's surface but is normally harmless. UV-B irradiation is more harmful but less prevalent than UV-A. In this report, the HIV-1 LTR-luciferase gene in the skin of transgenic mice was markedly activated when exposed to UV-B irradiation. The LTR in the skin of transgenic mice pretreated topically with a photosensitizing agent (psoralen) was also activated to similar levels when exposed to UV-A light. A 2-h exposure to sunlight activated the LTR in skin treated with psoralen, whereas the LTR in skin not treated with psoralen was activated after 7 h of sunlight exposure. The HIV-1 LTR-beta-galactosidase reporter gene was preferentially activated by UV-B irradiation in a small population of epidermal cells. The transgenic mouse models carrying HIV-1 LTR-luciferase and LTR-beta-galactosidase reporter genes have been used to demonstrate the in vivo UV-induced activation of the LTR and might be used to evaluate other environmental factors or pharmacologic substances that might potentially activate the HIV-1 LTR in vivo.

Animals↗

PubMed1991

Early-initiated zidovudine therapy prevents disease but not low levels of persistent retrovirus in mice.

An F1 hybrid mouse strain containing the Rfv-3r/s genotype was inoculated with Friend virus complex (FV) and treated with zidovudine (ZDV) intraperitoneally three times daily for 20 days beginning as early as 10 min after initial viral exposure. This strain of mice develops FV-specific neutralizing antibodies that aid in reducing viremia and splenic virus titers but do not prevent splenomegaly and eventual FV-associated death. The virally exposed mice treated with ZDV did not develop splenomegaly or have detectable viremia after the last drug treatment. On day 21, a single animal had demonstrable virus in the spleen as determined by a focal immunoenzyme assay; 57% had detectable virus at 5 weeks, but non displayed splenic virus after 35 weeks. None of the animals died after the 35-week holding period, compared to 38% dying in placebo-treated mice. To detect low levels of the virus, or potentially latent virus, splenocytes were cocultivated with a cell line known to readily propagate FV, and the cells were subsequently passaged four times to amplify replication of the virus. After amplification, a significant increase was seen in the number of mice testing positive for virus. Thus, ZDV treatment initiated early after virus exposure was effective in preventing FV-induced splenomegaly and death, but did not prevent low levels of persistent retrovirus in the mice.

Animals↗

PubMed1990

Effects of zidovudine on Friend virus complex infection in Rfv-3r/s genotype-containing mice used as a model for HIV infection.

Infection with the Friend virus complex (FV) in (B10.A x A/WySn)F1 mice containing the Rfv-3r/s genotype results in several disease manifestations analogous to those seen in patients with acquired immune deficiency syndrome, predominantly high levels of specific antibody and low levels of infectious virus with eventual retroviral disease-induced death of the host. Other immunologic manifestations of FV infection in this murine host included inhibition of percent total T, T-helper, and T-suppressor/cytotoxic cells of total splenic lymphocytes and phytohemagglutinin-induced response of spleen cells. Interleukin-1 production was not affected but the numbers of splenic B cells were increased by the infection. 3'-Azido-3'-deoxythymidine (zidovudine, AZT) administered (a) intraperitoneally three times daily for 24 days beginning 4 h after virus inoculation in doses of 60 to 480 mg/kg/day, (b) in drinking water for 22 days beginning 4 h after virus inoculation in doses of 22 to 216 mg/kg/day, or (c) in drinking water for 29 days beginning 6 days after virus inoculation in doses of 22 to 216 mg/kg/day markedly inhibited FV-induced disease. In the mice receiving early-initiated AZT therapy, FV-induced splenomegaly and hematocrit values were inhibited and infectious centers in the spleen and FV titers in the plasma were reduced to below detectable levels at the higher AZT dosage levels. The percent of total T cells in splenic lymphocytes was increased in the infected, AZT-treated mice. In the intraperitoneal experiment, FV disease-induced death was prevented by treatment with all doses of AZT. Neutralizing antibody to FV was significantly reduced in all AZT-treated groups. Toxicologic manifestations of these AZT treatments included splenic enlargement and reduced hematocrit, although all treated, uninfected mice survived the treatments, gained weight, and displayed no significant effects on enumeration of T and B cells.

Animals↗

PubMed1987

Tissue-specific replication of Friend and Moloney murine leukemia viruses in infected mice.

We have studied the replication of ecotropic murine leukemia viruses (MuLV) in the spleens and thymuses of mice infected with the lymphocytic leukemia-inducing virus Moloney MuLV (M-MuLV), with the erythroleukemia-inducing virus Friend MuLV (F-MuLV), or with in vitro-constructed recombinants between these viruses in which the long terminal repeat (LTR) sequences have been exchanged. At 1 week after infection both the parents and the LTR recombinants replicated predominantly in the spleens with only low levels of replication in the thymus. At 2 weeks after infection, the patterns of replication in the spleens and thymuses were strongly influenced by the type of LTR. Viruses containing the M-MuLV LTR exhibited a remarkable elevation in thymus titers which frequently exceeded the spleen titers, whereas viruses containing the F-MuLV LTR replicated predominantly in the spleen. In older preleukemic mice (5 to 8 weeks of age) the structural genes of M-MuLV or F-MuLV predominantly influenced the patterns of replication. Viruses containing the structural genes of M-MuLV replicated efficiently in both the spleen and thymus, whereas viruses containing the structural genes of F-MuLV replicated predominantly in the spleen. In leukemic mice infected with the recombinant containing F-MuLV structural genes and the M-MuLV LTR, high levels of virus replication were observed in splenic tumors but not in thymic tumors. This phenotypic difference suggested that tumors of the spleen and thymus may have originated by the independent transformation of different cell types. Quantification of polytropic MulVs in late-preleukemic mice infected with each of the ecotropic MuLVs indicated that the level of polytropic MuLV replication closely paralleled the level of replication of the ecotropic MuLVs in all instances. These studies indicated that determinants of tissue tropism are contained in both the LTR and structural gene sequences of F-MuLV and M-MuLV and that high levels of ecotropic or polytropic MuLV replication, per se, are not sufficient for leukemia induction. Our results further suggested that leukemia induction requires a high level of virus replication in the target organ only transiently during an early preleukemic stage of disease.

Animals↗

PubMed1984

Effects of folic acid malnutrition on rotaviral infection in mice.

A study was undertaken to determine if dietary deficiencies of folic acid would influence rotaviral diarrheal disease in infant mice. Female mice were fed diets containing essentially no folic acid, 25% of a normal quantity of folic acid, or a normally recommended quantity of folic acid, beginning at time of breeding and continuing through periods of gestation and lactation. Two-day-old infants from these dams were exposed to purified murine rotavirus or to sterile virus diluent and the severity of the rotaviral infection monitored. Infants from the low folic acid group had significantly lower folate levels in their livers, indicating a deficiency was achieved, and developed more severe disease manifestations than those infants from the dams receiving the normal folic acid levels in their diet. The infection enhancement was seen as increased incidences of diarrhea and a significantly greater number of mice exhibiting high intestinal rotaviral antigen titers. Serum rotavirus antibody titers were below detectable levels in a significant number of these same infants.

Animals↗

PubMedDate not supplied

Staphylococcosis of turkeys. 1. Portal of entry and tissue colonization.

Staphylococcus aureus and various coagulase-negative staphylococci were isolated from turkeys with staphylococcosis. Virulent S. aureus adhered well (averaged more than 100 bacteria per tissue cell) in vitro to cells from tissues of the respiratory tract but did not adhere well (averaged fewer than 12 bacteria per tissue cell) to cells from tissues of the alimentary tract. Some avirulent coagulase-negative staphylococci also adhered well to cells from the respiratory tissues. Lungs and livers of turkeys became colonized with virulent S. aureus following experimental aerosol exposure. Tracheas, livers, and hock joints of some market-age turkeys were naturally colonized with S. aureus and various species of coagulase-negative staphylococci.

Aerosols↗