Biomedical subjects

W C Koff

Publications and source records attributed to W C Koff.

At least 37 records · Page 2Linked to original sources

PubMed1988

Development and testing of AIDS vaccines.

Recent advances in delineating the molecular biology of human immunodeficiency virus type 1 (HIV-1) have led to innovative approaches to development of a vaccine for acquired immunodeficiency syndrome (AIDS). However, the lack of understanding of mechanisms of protective immunity against HIV-1, the magnitude of genetic variation of the virus, and the lack of effective animal models for HIV-1 infection and AIDS have impeded progress. The testing of AIDS vaccines also presents challenges. These include liability concerns over vaccine-related injuries; identification of suitable populations for phase 3 efficacy studies; balancing the ethical obligation to counsel research subjects to avoid high-risk behavior with the necessity to obtain vaccine efficacy data; and the effect of vaccine-induced seroconversion on the recruiting and welfare of trial volunteers. Several candidate AIDS vaccines are nevertheless currently under development, and some are undergoing phase 1 clinical trials. Rapid progress will depend on continued scientific advancement in conjunction with maximum use of resources, open information and reagent exchange, and a spirit of international collaboration.

Acquired Immunodeficiency Syndrome↗

PubMed1987

Interleukin 1 release by human monocytes treated with liposome-encapsulated lipopolysaccharide.

Liposome therapy offers a unique method of delivering antifungals, antiprotozoans, and macrophage-activating factors directly to reticuloendothelial cells. Although liposomes are entering clinical trials, their effect on Il 1 synthesis and release has yet to be determined. The beneficial, as well as possible pathological, effects of liposome therapy may be due to IL 1 released by reticuloendothelial cells. This study examined the effects of multilamellar phospholipid vesicles on the synthesis and release of IL 1 from human peripheral blood monocytes. Liposomes consisting of phosphatidylcholine and phosphatidylserine in molar ratio of 7:3 did not stimulate IL 1 release, and did not diminish the level of IL 1 release when monocytes were subsequently stimulated with LPS or Staphylococcus aureus. Surprisingly, LPS encapsulated in liposomes failed to stimulate IL 1 release from monocytes. This defect was limited to the release of IL 1, because monocytes stimulated with liposomes containing LPS had control levels of intracellular (cytosolic) and membrane IL 1. By contrast, LPS associated with lyophilized liposomes induced the secretion of IL 1 and behaved similarly to free LPS. These findings indicate that LPS activation of monocytes may involve not only the synthesis of IL 1 but activation of the secretory mechanism for IL 1, and that these two events could be independent, that the density of LPS molecules at the surface of the liposome may influence the degree of monocyte activation as measured by intracellular IL 1 synthesis, membrane accumulation, and secretion into the medium, and that intracellular lipids may not interfere with the secretory mechanism, because liposomes made with phospholipids differing in acyl chain length or the headgroup behaved identically.

Cell Membrane↗

PubMed1987

Herpes simplex virus-induced suppression of macrophage-mediated tumoricidal activity in murine macrophages.

Herpes simplex virus (HSV) infections can enhance the progression of neoplastic diseases. Since macrophages can be activated to become tumorilytic and may figure prominently in host defense against cancer, the ability of HSV to modify macrophage-mediated tumoricidal functions was evaluated. Murine peritoneal macrophages treated with HSV could not be activated to a tumoricidal state by mouse recombinant gamma-interferon (IFN-gamma). Addition of HSV 4 h after treatment with IFN-gamma, at a time when the macrophages are fully committed to developing the cytotoxic phenotype, blocked macrophage-mediated lysis of syngeneic melanoma target cells. This inhibition of activation and cytotoxicity was not due simply to uptake of virus particles, because treatment with heat-inactivated HSV at 4-h posttreatment with IFN-gamma had no effect. In addition, HSV did not undergo a productive infection within macrophages, suggesting that the observed inhibitory activity might be due to a virus-induced product. In this regard, treatment of macrophages with recombinant alpha-interferon suppressed the activation of these cells by IFN-gamma, suggesting that virus-induced alpha-interferon may be mediating all or part of the suppressive activity. These studies suggest that enhancement of tumor progression following HSV infection may be related to the virus-induced suppression of macrophage-mediated tumoricidal activity.

Animals↗

PubMed1986

Regulatory effects on macrophages of human recombinant interferons-alpha.

The regulatory effects of human recombinant and hybrid interferons-alpha (IFN-alpha) on macrophage-mediated tumoricidal activity were examined. Recombinant hybrid IFN-alpha-A/D suppressed the capacity of murine interferon-gamma (IFN-gamma) to activate mouse peritoneal macrophages to a tumorilytic state, and blocked the killing of syngeneic syngeneic melanoma target cells by macrophages previously committed to the cytotoxic phenotype with a 4-h pretreatment with IFN-gamma. This suppressive activity was limited to IFN-alpha-A/D, as IFN-alpha-A and IFN-alpha-D were not effective. In contrast, IFN-alpha-A, -D, and -A/D were all capable of activating human peripheral blood monocytes to lyse human tumor cells. When encapsulated in liposomes, only IFN-alpha-A/D maintained its monocyte activating efficacy. These findings suggest that the immunomodulatory effects of IFN-alpha subtypes and hybrid molecules are dependent on species of monocytes/macrophages, subtype, and nature of presentation to effector cells.

Adjuvants, Immunologic↗

PubMed1986

Neuroendocrine hormones suppress macrophage-mediated lysis of herpes simplex virus-infected cells.

Herpes simplex viruses (HSV) remain latent in sensory and peripheral ganglia and can be reactivated to cause recurrent HSV infections. Recent evidence has suggested that stress can induce an immunosuppressive state and increase the frequency and severity of recurrent herpes infections. Because macrophages play a central role in the host defense against HSV, the effects of stress-related neuroendocrine hormones on macrophage-HSV interactions were examined. Norepinephrine and epinephrine blocked the capacity of recombinant interferon-gamma (IFN-gamma) to activate murine macrophages to a cytotoxic state capable of selectively killing HSV-infected cells. In contrast, ACTH, dopamine, serotonin, and beta-endorphin had no effect. The suppression of IFN-gamma-induced, macrophage-mediated lysis of HSV-infected cells occurred concomitantly with a marked increase in macrophage intracellular cyclic AMP levels. Moreover, exogenous administration of dibutyryl cyclic AMP blocked induction of macrophage-mediated cytotoxicity, suggesting that the neurohormones were modulating macrophage function via an adrenergic receptor-mediated system. These findings demonstrate that selective stress-related neurohormones modify the cytolytic activity of macrophages against virus-infected cells and suggest a possible neuroendocrine-immunologic basis for the recurrence of HSV infection.

Adrenocorticotropic Hormone↗

PubMed1986

Catecholamine-induced suppression of interleukin-1 production.

Recent evidence indicates that stress can suppress immune responses and thus increase the severity of viral and neoplastic diseases. Although, the mechanisms for stress-induced modulation of immunologic competence are unclear, neuroendocrine hormones are thought to be involved. A direct suppressive effect could result from the action of neuroendocrine hormones on lymphokine and monokine release. The central role of interleukin-1 (IL-1) in regulating cellular immune responses to infection and neoplasms stimulated the present study evaluating the effects of neuroendocrine hormones on IL-1 production. Norepinephrine and epinephrine inhibited the capacity of gamma interferon and lipopolysaccharide to stimulate IL-1 production from mouse peritoneal macrophages. Moreover, when intracellular and extracellular levels of IL-1 were quantitated, the studies demonstrated a catecholamine-mediated block in IL-1 synthesis without effect on its release. We also observed that exogenous cyclic AMP (cAMP) administered to mouse macrophages suppressed IL-1 production. This, coupled with the capacity of norepinephrine and epinephrine to enhance intracellular cAMP levels in macrophages, strongly suggested that the catecholamine-induced suppression of IL-1 production may be mediated by elevated intracellular cAMP levels. These findings demonstrate that selected stress-related neuroendocrine hormones can modulate IL-1 production by macrophages and further support the hypothesis that alteration of macrophage function by neuropeptides and neurohormones is a significant feature of stress-induced enhancement of viral and neoplastic disease.

Animals↗

PubMed1986

Human tumor necrosis factor-alpha kills herpesvirus-infected but not normal cells.

Human recombinant tumor necrosis factor-alpha (TNF) was found to recognize and destroy herpes simplex virus-infected cells while leaving uninfected cells unharmed, as determined by a 51Cr-release microcytotoxicity assay. In contrast, recombinant interleukins 1 and 2, alpha interferon and gamma interferon were not cytotoxic for virus-infected cells. The ability to discriminate between herpes virus-infected and uninfected cells suggests that TNF may be a beneficial antiviral agent.

Animals↗

PubMed1985

Protection of mice against fatal herpes simplex type 2 infection by liposomes containing muramyl tripeptide.

Intravenous administration of liposomes containing muramyl tripeptide phosphatidylethanolamine, a lipophilic derivative of muramyl dipeptide that activates macrophages to a cytolytic state in situ, significantly protected mice against lethal challenge with herpes simplex virus type 2. These findings suggest that the systemic activation of macrophages by liposomes containing an immunomodulator can lead to prophylaxis of severe infections caused by herpesviruses.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1985

Human monocyte-mediated cytotoxicity against herpes simplex virus-infected cells: activation of cytotoxic monocytes by free and liposome-encapsulated lymphokines.

Human peripheral blood monocytes were incubated with free or liposome-encapsulated human lymphokines containing macrophage-activating factor (MAF) and tested for their effect on herpes simplex virus (HSV)-infected target cells. Activated monocytes lysed allogeneic HSV type 2 (HSV-2)-infected whole human embryo cells and xenogeneic BALB/c mouse embryo cells (10E2) without any significant effect on uninfected cells, as measured by release of 51Cr from target cells after 18 h of cocultivation. Kinetic studies revealed that lysis of virus-infected cells occurred by 10 h following cocultivation with activated monocytes. The inability of free MAF or supernatants from MAF-activated monocytes to lyse HSV-2-infected cells suggested that direct monocyte-target cell contact is required for monocyte-mediated cytotoxicity of the virus-infected cells. Monocytes activated with MAF suppressed the production of HSV-2 and HSV-1 from virus-infected cells more than control monocytes did. In addition, monocytes treated with liposome-encapsulated MAF selectively destroyed HSV-2-infected cells but left uninfected cells unharmed. The capacity of liposome-encapsulated immunomodulators to activate human monocytes to selectively lyse HSV-2-infected cells has potential therapeutic benefit and should be evaluated in vivo.

Cells, Cultured↗

PubMed1985

Efficient activation of human blood monocytes to a tumoricidal state by liposomes containing human recombinant gamma interferon.

Human recombinant gamma interferon (INF-gamma) activated human peripheral blood monocytes to a cytotoxic state capable of lysing adherent tumorigenic cells without harming normal cells. The efficiency of INF-gamma activation of monocytes is enhanced by encapsulating INF-gamma within liposomes: The minimum effective dose (MED) of free INF-gamma for monocyte activation was found to be 1-10 U/ml, per 10(5) monocytes, whereas the minimum dose for IFN-gamma encapsulated in liposomes was less than 0.0025 U. Monocytes treated with liposome-encapsulated INF-gamma retained their cytotoxic phenotype for much longer than do monocytes treated with free INF-gamma. Since liposomes can be passively targeted to cells of the reticuloendothelial system following IV administration, these findings suggest that liposome-encapsulated INF-gamma may have therapeutic potential that should be evaluated in vivo.

Cells, Cultured↗

PubMed1985

The potential use of liposome-mediated antiviral therapy.

The natural targeting of liposomes to cells of the reticuloendothelial system should be exploited to examine whether selective delivery of antiviral or immunomodulatory agents could be beneficial for the treatment of virus diseases. In this review we discuss the potential use of liposomes in the treatment of virus diseases, the targeting of liposome-encapsulated immunomodulators to macrophages in order to render these cells cytolytic for virus-infected cells, and the targeting of liposome-encapsulated antiviral drugs to macrophages to achieve direct suppression of virus replication with in these cells.

Adjuvants, Immunologic↗

PubMed1985

Modulation of macrophage-mediated tumoricidal activity by neuropeptides and neurohormones.

Recent evidence has suggested that stress may suppress the immune system and increase the frequency and severity of viral and neoplastic disease. The mechanisms for stress-induced modulation of immune function are unclear, but several neuropeptides are thought to be involved. Because macrophages play an important role in the host defense against infection and neoplasia, several stress-related neuropeptides were screened in efforts to determine whether these substances affect macrophage-mediated tumoricidal activity. Adrenocorticotropin and noradrenaline each completely blocked the capacity of mouse recombinant interferon-gamma (INF-gamma) to activate murine peritoneal macrophages to a tumoricidal state as measured by the lysis of 125I-UdR-labeled melanoma target cells. Vasoactive intestinal peptide significantly potentiated the suppressive effects of noradrenaline. In contrast, neurotensin markedly enhanced the cytolytic capability of peritoneal macrophages activated with INF-gamma. Several other neuropeptides, including substance P, alpha-endorphin, beta-endorphin, Leu-enkephalin, and Met-enkephalin, had no effect on macrophage activation. These findings demonstrate that selected stress-related neuropeptides and neurohormones significantly modulate the capacity of macrophages to attain a tumoricidal state and suggest that alteration of macrophage function by neuropeptides may be a prominent feature of stress-induced enhancement of neoplastic disease.

Adjuvants, Immunologic↗

PubMed1984

Human monocytes activated by immunomodulators in liposomes lyse herpesvirus-infected but not normal cells.

Highly purified peripheral blood monocytes from normal human donors were activated in vitro by incubation with liposomes containing immunomodulators such as recombinant human gamma interferon, human lymphokines, or muramyl dipeptide. The ability of liposomes containing immunomodulators to activate monocytes to a cytotoxic state capable of discriminating between virus-infected and uninfected cells was shown by activated monocytes recognizing and destroying herpes simplex virus type 2-infected cells while leaving uninfected cells unharmed .

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1983

Treatment of intracranial dengue virus infections in mice with a lipophilic derivative of ribavirin.

Rimantadine, ribavirin, and 6-mercapto-9-(tetrahydro-2-furyl)purine, administered intraperitoneally every 8 h for 7 days starting minutes after virus challenge, had no effect on survival and mean survival time of BALB/c mice inoculated intracranially with dengue virus type 2. In contrast, intraperitoneal treatment with ribavirin 2',3',5'-triacetate, a lipophilic analog of ribavirin, effected significant increases in both mean survival time and survival rate, suggesting that ribavirin 2',3',5'-triacetate may be superior to rabavirin for treatment of viral diseases of the brain.

Adamantane↗

PubMed1983

Lysis of herpesvirus-infected cells by macrophages activated with free or liposome-encapsulated lymphokine produced by a murine T cell hybridoma.

Thioglycolate-induced mouse peritoneal macrophages were activated in vitro by the lymphokine designated macrophage-activating factor (MAF) produced by a murine T cell hybridoma to lyse herpes simplex virus type 2 (HSV-2)-infected murine target cells. Comparison of uninfected BALB/c 10E2 cells with HSV-2-infected 10E2 cells showed that macrophages activated with MAF selectively destroyed HSV-2-infected cells and left uninfected cells unharmed, as measured by an 18-h 51Cr-release assay. In contrast, macrophages treated with medium were as efficient as MAF-activated macrophages in suppressing the production of HSV-2 from virus-infected cells. These findings suggest that macrophages must attain an activated state to lyse HSV-2-infected cells. Finally, incubation of macrophages with liposomes containing MAF was shown to be a highly efficient method for activation of macrophages against HSV-2 infected cells. The ability to selectively destroy herpesvirus-infected cells in vitro by macrophages activated with liposome-encapsulated MAF suggests that the therapeutic efficacy of this treatment in vivo should be evaluated.

Animals↗

PubMed1983

Cell-mediated immune response to respiratory syncytial virus infection in owl monkeys.

The suitability of owl monkeys as experimental models to study the cellular immune response to respiratory syncytial virus (RSV) infection was examined. Seronegative owl monkeys inoculated intranasally with RSV shed large quantities of virus and developed clinically evident upper respiratory disease. RSV infected monkeys had significant lymphoproliferative responses to RSV antigen by 4 weeks post-infection. In contrast, no positive blastogenic responses were elicited during the acute phase of illness. An in vitro 51Cr release assay was developed to study owl monkey antibody-dependent cellular cytoxicity (ADCC) against RSV infected Hep-2 cells. Peripheral blood mononuclear cells from owl monkeys in the presence of RSV specific antibody caused lysis of RSV infected target cells. The effector cell for ADCC was found to be non-adherent to plastic. The owl monkey RSV ADCC system was found to closely parallel RSV specific ADCC observed with human effector cells. In addition, it was found that heterologous matches of human effector cells with monkey sera and monkey effector cells with human sera were equally efficient in mediating RSV specific ADCC. These studies demonstrate the value of the owl monkey as a model to study the pathogenesis or RSV infections.

Animals↗

PubMed1982

Antiviral effects if ribavirin and 6-mercapto-9-tetrahydro-2-furylpurine against dengue viruses in vitro.

The antiviral effects of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) and 6-mercapto-9-tetrahydro-2-furylpurine (6-MPTF) against dengue viruses were examined in vitro. Ribavirin significantly reduced the growth of dengue virus types 1-4 in LLC-MK2 cells at concentrations well below cytotoxic levels (cell viability was determined by trypan blue dye exclusion) Addition of guanosine to ribavirin-treated dengue virus-infected cell cultures completely reversed the antiviral effect of the drug. In contrast, ribavirin had no effect on dengue virus replication in human peripheral blood leukocytes (PBL). 6-MPIF, a specific inhibitor of hypoxanthine-guanine phosphoribosyltransferase, did not significantly reduce the growth of dengue viruses in either LIC-MK2 cells or human PBL. However, synergistic effects of 6-MPTF and ribavirin were observed, as combined treatment of the drugs markedly suppressed the replication of dengue viruses in human PBL. The successful demonstration that dengue virus replication in mononuclear leukocytes is markedly suppressed by the combined treatment of ribavirin and 6-MPTF signals a need to evaluate the efficacy of this treatment against dengue virus infections in vivo.

Animals↗

PubMed1981

Suppression of dengue virus replication in vitro by rimantadine hydrochloride.

The effects of rimantadine on dengue virus replication were examined in a variety of tissue culture systems. The growth of dengue virus type 2 in human peripheral blood leukocytes (PBL) was completely suppressed when rimantadine was included in the culture medium at a concentration of 25 microgram/ml. Similarly, rimantadine caused a significant inhibition of dengue virus replicaton in cultures of rhesus monkey PBL. Addition of drug into virus-infected LLC-MK2 cell cultures caused a decrease in the production of all four types of dengue virus. Maximal inhibition of dengue virus replication by rimantadine was observed when the drug was added immediately following the viral adsorption period. Rimantadine did not induce may cytopathic effects on either LLC-MK2 cells or PBL at concentrations less than 75 microgram/ml. These findings demonstrate that rimantadine is an effective inhibitor of dengue virus replication in vitro, and indicate a need for further examination of the efficacy of rimantadine against severe dengue virus disease.

Adamantane↗