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Biomedical subjects

R V House

Publications and source records attributed to R V House.

At least 37 records · Page 2Linked to original sources
PubMed1995

Suppression of immune function by non-peptidic delta opioid receptor antagonists.

Previous studies in this laboratory and elsewhere have provided evidence that compounds acting as delta opioid receptor agonists exhibit marked immunostimulatory potential. Conversely, the delta opioid receptor antagonists have previously been shown to demonstrate immunosuppressive effects as assessed by proliferation of T-cells following allogeneic or xenogeneic stimulation. The present study was performed to further characterize this immunosuppressive activity using the compounds benzylidene naltrexone (BNTX), naltrindole (NTI), and naltriben (NTB). In vitro exposure to BNTX resulted in an apparent dose-related suppression of B-cell proliferation, cytokine production by T-helper cells, and natural killer (NK) cell activity, with statistically significant suppression observed at concentrations between 1 and 10 microM. NTI was also immunosuppressive for all immune function parameters examined, although this compound was less active than BNTX. In vitro exposure to the structurally related compound NTB had no significant effect on any immune function examined in this study. In all cases, immunosuppression occurred in the absence of any detectable alteration in cellular viability, suggesting a specific immunosuppressive effect rather than overt toxicity.

Animals↗
PubMed1995

Effects of naltrexone on morphine-induced tolerance and physical dependence and changes in cellular immune function in mice.

The effects of naltrexone on tolerance/dependence, as well as alterations in cellular immune function induced by morphine administration, were determined. Mice were rendered tolerant to and physically dependent on morphine by subcutaneous implantation of pellets containing 75 mg of morphine. Implantation of naltrexone pellets (10 mg) blocked the development of tolerance to the analgesic action of morphine, as well as the development of physical dependence. Morphine suppressed lymphoid organ weights and cellularities, and this suppression was blocked by naltrexone. B-Cell proliferation was suppressed in morphine-tolerant but not in morphine-abstinent mice, and this suppression was exacerbated by naltrexone. Morphine tolerance and abstinence were associated with suppression of IL-2 production, which was completely blocked by naltrexone. NK cell activity was not significantly affected by either morphine or naltrexone exposure. The results suggest that the effects of morphine on the immune system are at least partially mediated through opioid receptors.

Animals↗
PubMed1995

Selective modulation of immune function resulting from in vitro exposure to methylenedioxymethamphetamine (Ecstasy).

Abuse of illicit analogs of methamphetamine (i.e., 'designer drugs') represents a growing problem. One of the most popular methamphetamine analogs is (+/-)-3,4-methylenedioxymethamphetamine (MDMA), commonly known as Ecstasy. The authors demonstrated previously that in vitro exposure to methamphetamine results in modulation of immune functional parameters necessary for host defense. The current study was performed to assess the potential direct (in vitro) immunomodulatory effect of exposure to a modified methamphetamine. Splenocytes or peritoneal macrophages from B6C3F1 mice were cultured in vitro at MDMA concentrations of 0.0001-100 microM. T-cell regulatory function was assessed by anti-CD3-mediated production of IL-2 and IL-4, B-cell function was assessed by quantitating cellular proliferation, natural immunity was assessed by quantitating natural killer (NK) cell activity, T-cell effector function was evaluated as a function of cytotoxic T-lymphocyte (CTL) activity, and macrophage function was assessed by IL-6 tumor necrosis factor (TNF) production. In vitro exposure to MDMA had no effect on B-cell proliferation at any concentration tested. In comparison, in the absence of direct cellular toxicity, production of IL-2 was enhanced at concentrations as low as 0.0001 microM. IL-4 production was not affected by exposure to any concentration of MDMA examined, suggesting a differential alteration in T-helper cell function by this compound. Basal and augmented NK cell function were enhanced at MDMA concentrations between 0.0001 and 1.0 microM when examined at an effector:target ratio of 100:1. CTL induction was significantly suppressed at a concentration of 100 microM. Finally, macrophage production of TNF was slightly suppressed at 10 and 100 microM MDMA, although this inhibition was not statistically significant.

Adjuvants, Immunologic↗
PubMed1995

Local versus systemic immunotoxicity of isobutyl nitrite following subchronic inhalation exposure of female B6C3F1 mice.

Female B6C3F1 mice were exposed to isobutyl nitrite (IBN) by inhalation at 0, 37.5, 75, or 150 ppm for 6 hr per day, 5 days per week for 15 weeks. The potential of this compound to induce immunotoxicity was assessed during the 3rd, 13th, 14th, and 15th week of exposure and after 2 weeks of recovery following the 15 weeks of exposure. Both systemic and lung immune functions were examined, including body and lymphoid organs weights, pulmonary macrophage function and host defense, expression of splenic lymphocyte cell-surface markers, natural killer cell function, mixed lymphocyte reaction, and induction of specific antibody to a T-cell-dependent antigen. There was a dose-related suppression of T-cell-dependent antibody-forming cell responses in the spleen following IBN exposure; however, other measures of T-cell and nonspecific immunity were not significantly affected. A dose-related increase of H202 production by alveolar macrophages was present after 12 but not after 68 exposures to IBN. In contrast, pulmonary host defense mechanisms against Klebsiella pneumoniae were unaffected. These results suggest that in the absence of changes in host resistance, IBN may have selective and partially reversible effects on the immune system.

Administration, Inhalation↗
PubMed1995

In vitro evaluation of fentanyl and meperidine for immunomodulatory activity.

Exposure to drugs, either ethical pharmaceuticals or illicit street drugs, often results in medical complications, including alterations in the immune system. Among the drugs associated with immunomodulatory potential are the analgesics fentanyl and meperidine. The purpose of this study was to determine the potential of these drugs to alter immunological parameters subsequent to in vitro exposure at a range of concentrations. This potential immunotoxicity was assessed using a series of in vitro assays measuring B-lymphocyte proliferation, cytokine production by T-helper lymphocytes, T-lymphocyte cytolytic function, natural killer (NK) cell function, and macrophage function. Exposure to these analgesics was associated with a differential suppression of interleukin-4 production by T-cells, as well as a more generalized suppression of cytokine production by macrophages. In addition, T-cell cytolytic activity was suppressed at high drug concentrations. B-cell proliferation and NK cell activity were also inhibited, but to a lesser degree than noted with T-cell function. Addition of naltrexone to the cultures did not reverse these alterations in immune function, suggesting that these changes are not mediated via opioid receptors.

Adjuvants, Immunologic↗
PubMed1995

Direct cellular immunomodulation produced by diacetylmorphine (heroin) or methadone.

1. Abuse of the narcotic drug diacetylmorphine (heroin), as well as methadone, a drug for treating heroin addiction, has been associated with alterations in immune function in humans. The current study was performed to assess the direct (in vitro) immunomodulatory effect of exposure to these drugs, in view of the very limited studies reported thus far on this effect. 2. Murine splenocytes or peritoneal macrophages were cultured in vitro at concentrations of 0.0001-100 microM heroin or methadone. B-cell function was assessed by quantitating cellular proliferation in response to stimulation with an antigen analog; T-cell regulatory function was assessed by culturing splenocytes with or without drugs in the presence of anti-CD3 antibody and subsequently quantitating cytokine production; and T-cell effector function was evaluated by culturing lymphocytes with or without drugs during a 5-day induction culture followed by assessment of specific cytotoxic T-lymphocyte (CTL) activity. Natural immunity was assessed by quantitating basal and IL-2 augmented natural killer (NK) cell function, and macrophage function was assessed by cytokine production. 3. In vitro exposure to heroin resulted in decreased B-cell proliferation at concentrations of 1-100 microM, and methadone had a similar effect at concentrations of 0.1-100 microM. 4. Production of IL-2 was suppressed by 0.1-100 microM of heroin, whereas exposure to methadone appeared to result in a generalized modulation, with suppression of IL-2 at most concentrations. In contrast, IL-4 production was only affected at the 100 microM concentration of both drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Immunomodulatory effects of in vitro exposure to morphine and its metabolites.

Both in vivo and in vitro exposure to morphine have been reported to produce a number of immunomodulatory effects in both laboratory animals and humans. The current study was performed to assess the direct in vitro effect of exposure to morphine or morphine metabolites on immune response parameters. Murine B6C3F1 splenic lymphocytes or peritoneal macrophages were cultured in vitro at concentrations of 0.0001-100 mumol/l morphine sulfate, morphine-3-glucuronide, morphine-6-glucuronide, or normorphine. B cell proliferation was significantly suppressed following exposure to all drugs. Production of interleukin (IL)-2, IL-4, and IL-6 was affected only moderately by all drugs except morphine-6-glucuronide, which produced a marked suppression at 100 mumol/l. Both basal and augmented natural killer (NK) cell function were unaffected by any drug except morphine-6-glucuronide, which enhanced NK cell activity at concentrations between 0.0001 and 1.0 mumol/l. In contrast, both morphine-3-glucuronide and morphine-6-glucuronide significantly inhibited cytotoxic T lymphocyte induction at concentrations between 0.0001 and 100 mumol/l, whereas morphine and normorphine were inactive in this assay. In summary, in the absence of direct cellular cytotoxicity, a differential immunomodulation was observed following in vitro exposure to morphine and its metabolites.

Adjuvants, Immunologic↗
PubMed1995

Comparison of the hallucinogenic indole alkaloids ibogaine and harmaline for potential immunomodulatory activity.

The immunomodulatory potential of the indole alkaloids ibogaine and harmaline was examined in a panel of in vitro immune function assays. These assays were chosen to assess T-cell regulatory and effector function, B-cell function, macrophage function, and natural killer-cell function. The in vitro exposure to either ibogaine or harmaline resulted in a dose-related suppression of all immune functions examined except macrophage function. This suppression was noted at various concentrations in different assays, but was generally only associated with high concentrations (10-100 mumol/l).

Adjuvants, Immunologic↗
PubMed1994

Effects of morphine tolerance and abstinence on cellular immune function.

Female B6C3F1 mice were rendered tolerant-dependent on morphine by a combination of injections and pellet implantation. Mice were injected with morphine sulfate (20 mg/kg, s.c.) twice a day on day 1. On day 2, they were implanted s.c. with a 75 mg morphine pellet for 3 days. On day 5, the pellets were either left intact (tolerant) or removed 8 h prior (abstinent) to carrying out the immune function tests. A high degree of tolerance to the analgesic and hypothermic effect of morphine developed as a result of this procedure. Similarly, physical dependence also developed as evidenced by the signs of the abrupt and naltrexone-precipitated abstinence syndrome. Implantation with morphine pellets resulted in a profound, statistically significant reduction in spleen and thymus weight and cellularities, with the greatest degree of reduction noted in abstinent animals. Morphine tolerance was associated with suppressed B-cell proliferation following in vitro stimulation, as well as interleukin-2 (IL-2) and interleukin-4 production by T-cells. NK cell activity was significantly reduced in morphine-tolerant, but not in morphine-abstinent, mice following a 24 h incubation in the presence or absence of IL-2. In comparison, the in vitro induction of cytotoxic T-cells was significantly depressed in morphine-abstinent, but not morphine-tolerant, animals. Exposure to morphine apparently had limited effect on macrophage function as assessed by production of tumor necrosis factor. These studies demonstrate a differential effect on immune effector and regulatory mechanisms in morphine tolerance and abstinence processes.

Animals↗
PubMed1994

Screening petrochemicals for contact hypersensitivity potential: a comparison of the murine local lymph node assay with guinea pig and human test data.

Over the last few years, the Murine Local Lymph Node Assay (MLLNA) has received considerable attention as a more quantitative, less expensive alternative to the guinea pig assays currently employed to identify potential human contact allergens. At this time, several companies are involved in both independent and joint efforts to validate the MLLNA with their products. This report describes the preliminary results of an Exxon-sponsored research effort to validate the assay with selected materials that are representative of our company's diverse chemical and petroleum product groups. Nine test materials were chosen for which there already existed guinea pig and/or human patch sensitization data. When the MLLNA results were compared to those data obtained from currently used predictive tests (guinea pig, human patch test), the MLLNA showed good agreement for moderate and strong sensitizers. However, the assay may be prone to the potential confounding effects of irritation (false positives), may be insensitive to weak sensitizers, and may be influenced by vehicle selection.

Animals↗
PubMed1994

Comparison of immune functional parameters following in vitro exposure to natural and synthetic amphetamines.

The potential of synthetic and natural amphetamines to modulate cellular immune effector and regulatory mechanisms was evaluated in an in vitro exposure system. Murine splenic lymphocytes and elicited peritoneal macrophages were cultured with 0.0001-100 microM of amphetamine sulfate, methamphetamine hydrochloride, or the (S) or (R) isomers of cathione hydrochloride. T-lymphocyte regulatory function was assessed by quantitating the production of cytokines, and T-lymphocyte effector function was assessed by the induction of cytotoxic T-lymphocytes (CTL). B-lymphocyte function was measured by proliferation, and natural immunity was assessed by quantitating basal and IL-2 augmented natural killer (NK) cell activity. None of the compounds tested had any direct effect on cellular viability. Exposure to amphetamine resulted in a significant suppression of IL-2, but not IL-4, production by T-lymphocytes, as well as a suppression of B-lymphocyte proliferation only at the highest amphetamine concentration examined. NK cell function was slightly suppressed by amphetamine exposure, but was enhanced by methamphetamine exposure. Conversely, exposure to either (S) or (R) isomers of cathinone resulted in stimulation of IL-2 production, B-lymphocyte proliferation, and CTL induction. No significant effect of cathione was noted on NK cell function. These data suggest that natural and synthetic amphetamines exhibit differential immunomodulatory activity following in vitro exposure.

Amphetamines↗
PubMed1994

Immunological consequences of in vitro exposure to lysergic acid diethylamide (LSD).

The ability of lysergic acid diethylamide (LSD) to alter immune function after direct in vitro exposure was examined. It was demonstrated that LSD is able to suppress the proliferation of B-lymphocytes; the production of the cytokines IL-2, IL-4, and IL-6; and the induction of cytotoxic T-lymphocytes at a concentration of 100 microM. In vitro exposure to LSD had differential effects on natural killer (NK) cell activity, with significant enhancement of both basal and IL-2-augmented NK cell function at concentrations between 0.0001 and 0.1 microM, and suppression of NK response at 100 microM. These results demonstrate that LSD may have a direct effect on components of the immune system at concentrations that may be reached upon human exposure.

Animals↗
PubMed1993

Phencyclidine exposure alters in vitro cellular immune response parameters associated with host defense.

Phencyclidine hydrochloride (PCP) was tested for its ability to alter a variety of immune effector and regulatory functions in vitro. B6C3F1 murine splenic lymphocytes or elicited peritoneal macrophages were cultured in vitro with medium only or medium containing 10(-10)-10(-4) M PCP. Macrophages cultured with or without PCP were stimulated with lipopolysaccharide, and production of interleukin 6 (IL-6) and tumor necrosis factor (TNF) was assessed by bioassay. Cytotoxic T-cell effector function was determined following 5-day lymphocyte co-culture with tumor stimulator cells in the presence of PCP. In addition, the ability of T-lymphocytes to produce specific immunoregulatory cytokines IL-2 and IL-4 in the presence of PCP was quantitated by bioassay. B-lymphocyte function was determined by quantitating lymphocyte proliferation following stimulation with anti-IgM antibody and murine IL-4. Natural immunity was assessed by culturing lymphocytes with or without PCP for 24 h, then quantitating basal and IL-2 augmented natural killer (NK) cell activity. In the absence of effects on cell viability, significant suppression of IL-2 production by T-cells was noted at pharmacologically relevant PCP concentrations (1 microM). In vitro concentrations of 10 microM suppressed the generation of specifically sensitized cytotoxic T-cells. In addition, PCP significantly suppressed both IL-2-augmented NK function as well as B-lymphocyte proliferation. By comparison, macrophage IL-6 production was not affected by any concentration of PCP examined in this study.

Animals↗
PubMed1993

Cytokine technology in basic and applied research on the hematopoietic system.

Cytokines are polypeptide molecules important for the regulation and maintenance of immunity and hematopoiesis. Their central role in the control of a number of physiological mechanisms makes them an important area of both basic and applied biomedical research. This review presents an overview of basic and applied biology, and introduces the term cytokine technology to denote the use of cytokines as research tools for understanding the cellular and molecular regulation of hematopoiesis. A number of frontier technologies are reviewed, including fusion toxins, fusion proteins, and animal models of cytokine expression and regulation.

Animals↗
PubMed1992

Chemical allergy: molecular mechanisms and practical applications.

Allergic reactions can be defined as the adverse, tissue-damaging, and sometimes fatal consequences of specific immune responses, usually to exogenous antigens. In the context of toxicology it is allergic reactions resulting from immune responses to chemicals and drugs which are of greatest relevance. The allergy may take a variety of forms including contact hypersensitivity (allergic contact dermatitis), respiratory hypersensitivity (with symptoms ranging from mild rhinitis to severe asthma), and various types of comparatively ill-defined reactions which in many respects resemble autoimmunity. Of these contact hypersensitivity is the most frequently encountered health problem resulting from the interaction of chemicals with the immune system. A wide variety of chemicals are able to induce contact sensitization. Some of these are, in addition, known to cause respiratory hypersensitivity, a less frequent, but no less important, form of chemical allergy.

Animals↗
PubMed1992

Examination of the local lymph node assay for use in contact sensitization risk assessment.

The purpose of this study was to evaluate the utility of the murine local lymph node assay (LLNA) for contact sensitization risk assessment. Cellular proliferative activity in draining lymph nodes was determined for individual animals on Day 5 following four daily epicutaneous applications of the test chemical to the ears. Seventeen chemicals were tested, covering a range of materials including preservatives, drug actives, and perfume raw materials. The assay was found to be useful for identifying strong, moderate, and some weak sensitizers as defined by other testing methods (guinea pig, human). For evaluating the antigen specificity of the LLNA proliferative response, an in vitro blastogenesis assay was used. Dendritic cells (DC) isolated from lymph nodes of mice treated 24 hr earlier with trinitrochlorobenzene (TNCB) were capable of in vitro stimulation of lymphocytes from TNCB-sensitized mice, but not lymphocytes from mice sensitized to the preservative mixture of 5-chloro-2-methylisothiazolinone plus 2-methylisothiazolinone (MCI/MI). Conversely, DC from mice treated 24 hr earlier with MCI/MI were capable of stimulating lymphocytes from MCI/MI-sensitized mice, but were unable to stimulate lymphocytes from TNCB-sensitized mice, demonstrating the specificity of the response. The results of these studies support the use of the murine LLNA for both investigative and predictive contact sensitization testing. The LLNA offers the advantages of requiring less time for completion, incorporating an objective endpoint, requiring approximately half the number of animals, and being less costly than most currently employed guinea pig test methods. In addition, we believe the murine LLNA is a useful test to incorporate into a scheme for contact sensitization risk assessment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Examination of immune parameters and host resistance mechanisms in B6C3F1 mice following adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Adult female B6C3F1 mice were given a single ip dose of 0, 01, 1.0, or 10.0 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and examined for immune function and host resistance 7-10 d later. Exposure to TCDD resulted in a significant dose-related decrease in induction of both IgM and IgG antibody-forming cells. This suppression was noted for both T-dependent and T-independent antigens. TCDD at a dosage of 10 micrograms/kg was shown to suppress production of antibody to viral hemagglutinin. In contrast, TCDD exposure had no significant effect on natural killer cell function, production of interferon, or various parameters of macrophage function. Assessment of host resistance revealed a significant increase in susceptibility to fatal infection with influenza virus, but no significant alteration in susceptibility to infection with the bacterium Listeria monocytogenes.

Animals↗