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PubMed1987

The effects of immunomodulating peptidoglycan monomer and muramyl dipeptide on hepatic microsomal UDP-glucuronyltransferase and beta-glucuronidase.

The effects of immunomodulating peptidoglycans, peptidoglycan monomer (PGM) and muramyl dipeptide (MDP), on hepatic microsomal UDP-glucuronyltransferase (uridine diphosphoglucuronate glucuronosyl transferase, EC 2.4.1.17) and beta-glucuronidase (beta-D-glucuronide glucuronohydrolase, EC 3.2.1.31) were tested in female C57Bl mice. 4-Methylumbelliferone and p-nitrophenol were used as representative substrates for one functional form of UDP-glucuronyltransferase (GT1) and testosterone for the second functional form (GT2) of the enzyme. Both PGM and MDP were found to transiently inhibit the activity of UDP-glucuronyltransferase. There was no significant difference in the magnitude of inhibition of the two functionally different enzyme forms. The activity of microsomal beta-glucuronidase was tested using 4-methylumbelliferyl glucuronide and p-nitrophenyl glucuronide as substrates. Time dependent transient inhibition of beta-glucuronidase activity was observed with both peptidoglycans. In addition, the effect of MDP on cytochrome P-450 was tested, since we have shown previously that PGM affected this system. MDP decreased the content of cytochrome P-450 and inhibited the activity of related enzymes.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1987

Immunomodulation of local and systemic immunity after subchronic pulmonary exposure of mice to benzo(a)pyrene.

A single intratracheal (i.t.) instillation of 3H-BaP (2.5 mg/kg) cleared rapidly from the lung with a half life of approximately 8 h. In contrast, the amount of 3H-BaP (expressed as counts/min/mg tissue) in the lung-associated lymph nodes (LALN) continued to increase over a 6 day period while a low, persistent level of BaP was detected in the spleen. To determine whether humoral immunity was affected by BaP accumulation in lymphoid organs, B6C3F1 mice were given seven daily i.t. instillations of 0.4, 4.0 or 40 mg BaP/kg, and immunized with sheep red blood cells (SRBC) 1 day after the last BaP instillation. When antigen was given by i.t. instillation, the number of antigen-specific, antibody-forming cells (AFC) decreased in the LALN after BaP exposure. Interestingly, the number of AFC in the LALN from BaP-exposed mice were significantly increased after intraperitoneal (i.p.) immunization. However, these same mice had lower numbers of AFC in the spleen. When 51Cr-SRBC were instilled in the lung, the pulmonary clearance of radiolabeled antigen was slowed in BaP-exposed mice. When 51Cr-SRBC were placed in the peritoneal cavity, the amount of radiolabeled antigen that reached the LALN was similar in BaP-exposed and vehicle mice. However, four times more radiolabeled antigen translocated from the peritoneal cavity to the lung in BaP-exposed mice, while significantly less antigen reached the spleen and liver. Thus, BaP-induced immunomodulation of the humoral immune response appears to be influenced by the route of immunization, as well as by the proximity of the responding lymphoid tissue to the site of BaP deposition.

Animals↗

PubMed1988

In vitro and in vivo immunomodulation by LF 1695 of human and rat macrophages and platelets in schistosomiasis.

The activity of the synthetic immunomodulator LF 1695 on the efficiency of two effector cell populations--macrophages and blood platelets--involved in IgE-dependent cytotoxic processes against parasites, was evaluated. Oxygen metabolite production and anti-parasite cytotoxic properties of both macrophages and platelets were increased following LF 1695 treatment in vivo (in rat) or in vitro (in rat and in man). The phagocytic properties of rat peritoneal macrophages were also potentiated by their in vitro incubation with the drug. In addition to these effector functions, the lysosomal enzyme content and the migration ability of rat peritoneal macrophages were stimulated after incubation with LF 1695. In the presence of the drug, rat macrophages were also shown to produce increased level of IL-1--measured by the mitogen-induced proliferation of murine thymocytes--when compared to unstimulated phagocytes. Finally, the oral treatment of rats with LF 1695, in the course of an experimental infection with schistosome parasites, induced a higher degree of immune protection (80%) against a challenge infection than untreated, infected control rats (40%). These results bring evidence of a stimulatory role for LF 1695 on immune effector functions of cells participating to defense mechanisms against multicellular pathogens.

Adjuvants, Immunologic↗

PubMed1988

Comparative study of various immunomodulators for macrophage and natural killer cell activation and antiviral efficacy against exotic RNA viruses.

Several immunomodulators were compared for immunomodulatory and antiviral activity in B6C3F1 female mice. Our results demonstrate that murine recombinant gamma interferon (rIFN-G), human recombinant alpha A/D interferon (rIFN-A), ampligen (a polyribonucleotide) and CL246,738 modulate nonspecific immunity and are effective antiviral agents in vivo. Administration of each of these agents 1 day before cell harvest induced high levels of splenic natural killer (NK) cell activity against YAC-1 target cells. rIFN-G was also a potent activator of peritoneal macrophages (M phi), as evidenced by high levels of antitumor activity and changes in ectoenzyme phenotype that is characteristic of tumoricidal M phi. rIFN-A, ampligen and CL246,738 induced moderate to low levels of M phi activation by these criteria. In vivo protection experiments showed that repeated therapeutic treatment with rIFN-A protected mice against i.p. infection with Venezuelan equine encephalitis (an alpha togavirus, VEE), Banzi (a flavivirus) and herpes simplex virus type 2 (HSV-2). Similar treatment with rIFN-G was effective against VEE and HSV-2, but ineffective against Banzi virus. A single prophylactic i.p. dose of ampligen 1 day before virus challenge was very effective against Banzi virus, moderately effective against HSV-2, and ineffective against VEE and Caraparu (a bunyavirus) infection. A single prophylactic oral dose of CL246,738 provided almost complete protection of mice against VEE, Banzi, and HSV-2, and also increased the mean survival time for Caraparu infected mice. Collectively, these results indicate that rIFN-A, r-IFN-G, ampligen and CL246,738 may be useful in prophylactic or early therapeutic treatment of several serious virus infections. Since these agents stimulate NK cells and M phi, their antiviral activity may result, in part, from the alterations they induce in the natural immune system.

Adjuvants, Immunologic↗

PubMed1988

Immunomodulating properties of cianidanol on responsiveness and function of human peripheral blood T-cells and K-cells.

Cianidanol (Ci) [(+)-catechin] is a lipophilic compound which interacts with membrane lipids and affects responsiveness and function of immunocompetent cells. We therefore studied the immunomodulating properties of Ci on the proliferative response of human peripheral T-cells in one-way mixed lymphocyte reaction (1-MLR) and autologous mixed lymphocyte reaction (AMLR); on the generation of cytotoxic T-cells (Tc-cells), suppressor T-cells (Ts-cells, comprising radiosensitive as well as radioresistant suppressor T-cells) and radioresistant suppressor T-cells (rrTs) in 1-MLC; and on the cytolytic activity of Tc-cells and K-cells. In 1-MLR we observed a small stimulation of cell proliferation at Ci concentrations up to 108 microM whereas higher concentrations led to a marked suppression (100% at 435 microM). The generation of Ts-cells and rrTs-cells in 1-MLR was clearly suppressed at Ci-concentrations above 435 microM and 108 microM, respectively. The timing of Ts-cell formation was not influenced. The Tc-cell generation in 1-MLR was inhibited at high doses, and at 870 microM 59% suppression was observed. A similar dose-dependent suppressive effect of Ci was seen by testing for the cytolytic activity of ADCC-reactive K-cells and of CML-reactive Tc-cells generated in 1-MLR in the absence of Ci. At the highest concentration used (870 microM) the CML was suppressed by 45% and the ADCC by 46%. Our investigation on Ci's influence on the efferent and afferent part of immune responses in vitro demonstrated both stimulatory and inhibitory effects usually occurring at low and high concentrations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody-Dependent Cell Cytotoxicity↗

PubMed1989

Effects of the immunomodulator PSK on growth of human prostate adenocarcinoma in immunodeficient mice.

Tumor growth alterations were studied using an immunomodulator, PSK. Four human prostate tumor lines were grown in two types of immunodeficient mice. Two of the lines were selected because they are able to metastasize to lungs in host animals. Outbred NIH Swiss athymic mice having normal natural killer cells and athymic Beige mice deficient in natural killer cells were used as animal hosts. PSK treatment was given to tumor-bearing hosts to some animals soon after solid tumors were injected and to others after solid tumors were well-established. Low dose cyclophosphamide was given to some animals to decrease host natural killer cells and polyinosinic-polycytidylic acid (poly I:C) was given to other animals to increase natural killer cell activity. Measurement of tumor doubling times, host survival and metastatic capabilities showed that either poly I:C or PSK treatment in NIH Swiss animals soon after tumor cells were injected significantly increased tumor doubling times and host survival and decreased the incidence and number of metastatic lung lesions. Two of the tumor lines incapable of metastasizing in NIH Swiss mice were metastatic in the Beige athymic, natural killer-cell-deficient animals.

Adenocarcinoma↗

PubMed1990

Lack of immunomodulating effect of disulfiram on HIV positive patients.

Disulfiram (Antabuse (R)) is metabolized to two molecules of diethyldithiocarbamate, which has been reported to be an immunomodulating agent. In a double blind trial, 15 HIV antibody positive homosexual men were given daily doses of 100 mg or 400 mg of disulfiram or placebo, for 4 weeks. All had a CD4-count below 500 X 10(6)/l and/or a pokeweed mitogen response in a lymphocyte proliferation assay less than 50% of normal controls. None suffered from opportunistic infections. No significant effect of disulfiram on immunological, haematological, biochemical or clinical variables was observed in this short-term trial.

Adjuvants, Immunologic↗

PubMed1991

The mechanism of action of a synthetic immunomodulator, 3,6-bis(2-piperidinoethoxy)acridine trihydrochloride (CL 246,738), in natural killer cell activation in animals.

CL 246,738 is a low molecular weight, synthetic immunomodulator. The present study was done to determine the interaction among interferon (IFN), macrophages, and natural killer (NK) cells in mice following oral administration of CL 246,738. Splenic NK activity as evidenced by lysis of YAC-1 lymphoma cells in vitro was found to be augmented by the compound not only in normal mice, but also in immunodeficient beige and nude mice. Lytic activity remained elevated from one to seven days after a single treatment and the peak activation varied depending on the source of NK cells. NK cell activity associated with the peritoneal exudate cell population peaked at day 1 and returned to normal by day 2, whereas NK cell activity of peripheral blood lymphocytes peaked at day 3 and remained significantly elevated until day 7. Liver associated NK activity peaked at day 4 and remained significantly elevated at day 7 after treatment with CL 246,738. Lung associated NK activity was elevated by day 1 after treatment, peaked at day 4 and returned to normal by day 7 after drug administration. The drug was also effective in inducing IFN in all mouse strains tested. When these drug-treated mice were given antibody to IFN-(alpha + beta) but not to IFN-(beta), both IFN levels and NK cell activity decreased, suggesting the importance of IFN-(alpha) in this system. Furthermore, mice that had received carrageenan prior to, but not after CL 246,738 administration showed reduced serum IFN titers as well as decreased NK cell activity, indicating that macrophages played an intermediate role in immune enhancement by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Acridines↗

PubMed1991

A new immunomodulator, LF 1695--II. Effects on allogenic and antigenic responses.

LF 1695, a chemically defined immunomodulator has been shown to induce in vitro T-cell differentiation and to potentiate mitogenic proliferation. The effects of LF 1695 on antigenic and allogenic responses were studied in vitro and lymphocyte proliferation was estimated by 3H-thymidine uptake for 5 and 6 days, respectively. Human peripheral blood lymphocytes (PBL) from tuberculin sensitive donors were significantly stimulated by purified protein derivative (PPD) in the presence of LF 1695. Optimal lymphocyte proliferation with PPD was obtained at 0.5 micrograms/ml LF 1695. The ability of LF 1695 to enhance proliferation of PBL in an allogenic reaction was also examined. LF 1695 (0.2 micrograms/ml) enhanced the proliferation of PBL from two individuals with different HLA DR loci in the bilateral mixed lymphocyte reaction (MLR). Moreover, LF 1695 was tested in vivo in the experimental graft vs host reaction (GvHR) in mice. CBA, H2k mice receiving a lethal dose of irradiation were injected with spleen cells from LF 1695-treated or untreated C57 Bl/6, H2b mice via different routes. CBA mice were found to have a spleen weight x 1000/body ratio up to 1.5 when injected with cells from untreated C57 Bl/6 mice. Mice treated intraperitoneally with LF 1695 at 2.5 or 5 mg/kg/day showed an increase of GvHR intensity with splenic index of 1.71 and 1.80, respectively. When the animals were treated continuously through drinking water containing LF 1695 (4 mg/kg, 10 mg/kg or 100 mg/kg), these ratios were: 1.82, 1.10 and 1.37, respectively. Finally, LF 1695 enhanced GvHR significantly when used at low doses, while high doses induced a decrease of GvHR intensity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Methyl inosine monophosphate (MIMP), a new purine immunomodulator for HIV infection.

Prior work has documented the thymomimetic and immunotherapeutic activity of purine molecules related in structure to inosine. Synthesis of a series of new structures has yielded a stable methylated form of IMP resistant to hydrolysis by 5' nucleotidase. With both human peripheral blood lymphocytes and murines splenocytes, Methyl Inosine Monophosphate (MIMP) augments proliferative responses to T-cell mitogens like phytohemagglutinin (PHA), but less so, or not at all, to B-cell mitogens like pokeweed or endotoxin (LPS). MIMP does not directly stimulate lymphocytes alone in the absence of mitogen. The optimal effects of MIMP parallel the optimal effects of PHA. The magnitude of the effect is greater and more consistent than with other purine immunomodulators. MIMP is non-toxic in vitro and in vivo and is orally active in mice. Significant effects are observed as low as 0.1 and 1 micrograms/ml in vitro and 0.1 or 1 mg/kg in vivo. MIMP is a candidate third generation purine under development for immunotherapeutic purposes.

Adjuvants, Immunologic↗

PubMed1991

Immunomodulator, LZ-8, prevents antibody production in mice.

LZ-8, a new and recently discovered immunomodulator from Ganoderma lucidum, has been shown to have immunosuppressive activity in vivo and to be a member of the immunoglobulin superfamily. In this paper we examined the in vivo effect of LZ-8 on antibody production using the hepatitis B surface antigen (HBs Ag) in mice. LZ-8 had mitogenic activity in vitro towards spleen cells of C57BL/10 (B10) and C57BL/10BR (B10BR) as previously shown towards those of DBA/2 mice. B10 and B10BR mice produced anti-HBs Ag antibody by the twice sensitization of the antigen while intraperitoneal administration of LZ-8 twice weekly into the mice (8 and 12 mg/kg) greatly prevented the production of antibody to HBs Ag (83.3-96.8% inhibition). We further examined the effect of LZ-8 administration on mitogen responsibility of spleen cells and on the T-cell subset population in both the spleen and lymph node but no significant differences were observed between the LZ-8 treated and untreated mice. These results suggest that the immunosuppressive activities of LZ-8, previously shown, such as the prevention of systemic anaphylaxis and the Arthus reactions, were caused by the blocking of antigen-specific antibody production.

Adjuvants, Immunologic↗

PubMed1992

The immunomodulator AS101 administered orally as a chemoprotective and radioprotective agent.

AS101 [ammonium-trichloro (0,0' dioxyethylene)tellurate] is a new immunomodulator shown previously to stimulate the production of various cytokines in vitro and in vivo, and to have minimal toxicity. In the present study we explore the possibility of oral administration of AS101 to mice via cannulation in lieu of interperitoneal or intravenous administration reported to date. Our studies show that oral administration of AS101 at a dose ranging between 50 and 100 micrograms/mouse promotes hemopoietic regeneration after treatment with sublethal doses of cyclophosphamide (CYP) and protects mice from the lethal effects of this compound. In addition, AS101 administered orally confers a strong radioprotective effect upon mice when given before irradiation.

Adjuvants, Immunologic↗

PubMed1993

A characterization of the in vivo immunomodulation by Met-enkephalin in mice.

Single intraperitoneal injections of Met-enkephalin (MENK) into CBA mice decreased the phagocytic activity of peritoneal macrophages, Con-A-induced proliferation and NK-activity of spleen cells. Conversely, in mice which had been immunized with sheep erythrocytes, treatment with MENK was associated with enhancement of phagocytosis, and no effect on lymphoid proliferation and NK-cytotoxicity of spleen cells. MENK-induced inhibition of cellular functions in nonimmunized mice was associated with a decrease of plasma ACTH level, whereas MENK-induced stimulation of phagocytosis in immunized mice was paralleled with an elevation of ACTH, suggesting a role of corticoids in immunomodulation by MENK. MENK-induced modulation (suppression and stimulation) of phagocytosis, as well as inhibition of spleen cell proliferation, was not observable in adrenalectomized mice, although a reduced NK-cytotoxicity was still present.

Adrenal Glands↗

PubMed1993

Pharmacokinetics of an immunomodulator peptidoglycan monomer in mice after intravenous administration.

A 14C labeled low molecular weight immunomodulator, peptidoglycan monomer (14C-PGM), was injected intravenously (i.v.) into mice. At various time intervals thereafter (15 min-6 h), radioactivity in the urine, whole blood, plasma, kidneys, liver, spleen, lungs, intestines and the brain of the mice was determined. Shortly after injection, 14C-PGM was very rapidly excreted from the organism, so that 1 h following administration, 80% of the radioactivity was found in the urine (62% as unchanged PGM and the rest as the metabolites pentapeptide and disaccharide). At the same time, around 2% of the injected material was found in the blood. Six hours after injection, equal quantities were found in the intestines, liver and blood (0.5%), slightly less in the kidneys, lungs and spleen (0.2-0.3%) and the least quantity in the brain (0.04%). However, the dynamics of retention in the organs was evidently different. In the kidneys, lungs and spleen, radioactivity steadily decreased over the studied period. In the liver following an initial decrease, radioactivity remained the same 3 and 6 h after injection. On the other hand, in the intestines and brain PGM seemed to accumulate rather than disappear following i.v. administration. This fact should be considered when explaining different biological activities of low molecular weight bacterial peptidoglycans.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1995

Low molecular weight immunomodulators produced by microorganisms.

In order to develop a new class of low molecular weight immunomodulators for the treatment of incurable diseases involving cancer, hematologic diseases and inflammation, we have sought cytokine inducers and inhibitors of cell adhesion to the extracellular matrix among the low molecular compounds produced by microorganisms. Cytogenin, cytoblastin (a monokine inducer), conagenin (a lymphokine inducer) and delaminomycins and IC-101 (inhibitors of cell adhesion to extracellular matrices) have been recently found in our institute. In this report, we describe the principles of screening and structures, and discuss their biological activities.

Actinobacteria↗

PubMed1995

Immunomodulating effects of the new anti-rheumatic drug tenidap on collagen-induced arthritis.

We investigated the in vivo action of the newly developed anti-rheumatic agent tenidap, CP-66,248 (Pfizer Inc., New York), on arthritis in collagen-induced arthritic mice. The inhibitory effect of tenidap on the development of arthritis was statistically more significant than piroxicam. The serum anti-type II collagen antibody titer was markedly inhibited in the mice treated by tenidap. These results suggest that, unlike NSAIDs, tenidap inhibits the progress of collagen-induced arthritis through its immunomodulating effect.

Animals↗

PubMed1995

Experimental investigations on the immunomodulating activity of polybacterial preparation for peroral immunotherapy and immunoprophylaxis of uroinfections.

The immunomodulating effect of a polybacterial immunostimulator Urostim in experimental animal models was investigated. The preparation was created for immunotherapy and immunoprophylaxis of uroinfections. It consists of killed bacterial cells and their lysates of four microbial species: Escherichia coli expressing type 1 pili, Rc mutant of E. coli, Klebsiella pneumoniae, Proteus mirabilis and Enterococcus faecalis, BALB/c mice and guinea-pigs were treated orally with Urostim for 5 or 10 days, respectively. A stimulatory effect of Urostim on phagocytosis (increased phagocytic index and phagocytic number) of mice peritoneal exudate cells was observed. An increased number of plaque-forming cells and elevated titres of haemagglutinating antibodies in mice demonstrated activation of humoral immunity. Lymphoproliferative studies showed a significant response to phytohaemagglutinin (PHA) and Urostim, especially after the second application of the preparation. At the same time no changes in the absolute number of peripheral blood lymphocytes were found. An active protection of mice against a systemic infection and of guinea-pigs against uroinfection caused by Gram-negative bacteria was obtained. In conclusion, the results obtained characterize Urostim as an effective immunostimulator. Its peroral application leads to the activation of innate resistance, cell-mediated, humoral and local immunity.

Adjuvants, Immunologic↗

PubMed1995

Mechanisms of conditioned immunomodulation.

This article presents some recent work from our laboratory indicating that multiple physiological systems play a role in conditioned immunomodulation. The first study shows that naltrexone, but not N-methylnaltrexone, blocks the suppressive effects of an aversive conditioned stimulus on Con-A-induced proliferation and natural killer cell activity of splenic lymphocytes. This finding indicates that central opioid activity is involved in the conditioned effects. The second study shows that the beta-adrenergic antagonists atenolol and ICI-118,551 block of the suppressive effects of an aversive conditioned stimulus on Con-A-induced proliferation, but have no effect on natural killer cell activity. This result indicates the involvement of the adrenergic system in a subset of the conditioned effects. Collectively, these experiments provide evidence that both the opioid system and the sympathetic nervous system are involved in conditioned immunomodulatory changes elicited by an aversive conditioned stimulus.

Animals↗