Showing papers in "Immunopharmacology and Immunotoxicology in 1992"

Effect of Bifidobacterium bifidum and Lactobacillus acidophilus on gut mucosa and peripheral blood B lymphocytes

Abstract: In 15 elderly individuals lyophilized Bifidobacterium bifidum (BB) and Lactobacillus acidophilus (LA) (Infloran®) were administered in capsules (two capsules 4 times per day) for 28 days, while in 10 elderly controls placebo were given the same posology and for an equal period of time. The effects of this treatment on the immune system both at the periphery or the intestinal level were investigated. Results show that BB and LA significantly reduced the colonic inflammatory infiltration, without altering T, B and Leu7+ cell percentage. At the same time, a significant increase of B cell frequency in the peripheral blood was noted, in comparison to controls. The overall results suggest that the regular administration of BB and LA leads to a modulation of the immunological and inflammatory response in elderly subjects.

Differential effects of morphine and naltrexone on the antibody response in various mouse strains.

Abstract: Morphine treatment has been shown to suppress several immunologic parameters. In this study, we examined the effects of morphine pellet implantation in vivo on the primary antibody response measured in vitro in various mouse strains. Effects of mouse strain and sex on morphine-induced suppression of the plaque-forming cell response, as well as spleen weight and mortality were determined. Morphine suppressed the primary antibody response in C3HeB/FeJ, C3H/HeJ and C57BI/6 mice, while Balb/cByJ and the (i-receptor-deficient strain CxBk/ByJ mice were not affected. There was no difference in the response to morphine between male and female C3HeB/FeJ mice. Naltrexone reversed the morphine-induced suppression in the C3H strains, but not in C57BI/6 mice. In addition, naltrexone caused significant mortality in Balb/cByJ mice. Spleen weight was decreased by morphine treatment in all the strains, but only the C3H strains were sensitive to the lethal effects of morphine. Thus, immune suppression did not corre...

Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. I. Suppression of T-cell activation.

Abstract: Considerable attention has been directed at defining the health deficits associated with exposure to mercurial compounds. While numerous studies have been conducted, the findings have been somewhat contradictory and have led to a confused understanding of the immunotoxicology of mercury. It is becoming clear, however, that the immunotoxic effects of heavy metals in general, and mercury in particular, are dependent upon the assays and source of cells. The major goal of our study was to assess whether low level mercury exposure modulates human T-cell function. Following treatment of T-cells with HgCl2 (0-1000 ng) and MeHgCl (0-100 ng), their activation by mitogens was evaluated. Both forms of mercury caused a dose dependent reduction in T cell proliferation, however, the effect was dependent upon the presence of monocytes. Moreover, in the absence of monocytes, HgCl2 enhance PMA induced T-cell proliferation. MeHgCl was approximately 5-10 times more potent than HgCl2. Mercury also inhibited the ability of these cells to synthesize and secrete IL-1. Analysis of the expression of activation markers on the cell surface indicated that one of the earliest markers of lymphocyte activation, CD69, was not effected by mercury. In comparison, T-cell expression of IL-2R and the transferrin receptor was impaired. Of particular interest, cells activated by mitogen for 24 hr became refractory to the immunotoxic effects of mercury. The results of this investigation clearly show that mercury-containing compounds are immunomodulatory; moreover, the decrease in T-cell function following exposure to mercury indicates that this metal is immunotoxic at very low exposure levels.

Serum tumor necrosis factor activity in inflammatory bowel disease.

Abstract: Serum tumor necrosis factor (TNF) levels in 33 patients with inflammatory bowel disease (IBD) were measured by using a sensitive enzyme immunoassay. Four of five Crohn's diseases (CD) and nine of twenty eight ulcerative colitis (UC) had elevated levels of serum TNF. In active CD or UC, a greater fraction of patients studied had significantly increased serum TNF levels (3/3 for CD and 8/11 for UC). Production of TNF by peripheral blood monocytes when stimulated by lipopolysaccharide was also increased in these patients and correlated with their serum TNF levels. These results suggest that TNF may have some pathoetiological meaning in IBD.

Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. II. Alterations in cell viability.

Abstract: The major goal of this investigation was to examine the cytotoxic properties of both HgCl2 and MeHgCl, in terms of their ability to alter human T-cell and monocyte viability. Following treatment with HgCl2 (0-20μ;g/ml) or MeHgCl (0-2μ;g/ml), there was minimal reduction in lymphocyte viability at 1-4 hr. However, after exposure to mercury for 24 hr, cell death was apparent. In comparison, monocytes exhibited significant loss of viability during the early exposure periods. MeHgCl was approximately 5-10 times more potent than HgCl2. Other indicators of cell death were also determined. Measurement of the energy charge ratio indicated profound changes in cellular energy conservation. Electron microscopic analysis of cells treated with mercury revealed early nuclear alterations characterized by hyperchromaticity, nuclear fragmentation and condensation of nucleoplasm. In concert with these nuclear changes, there was destruction of cytoplasmic organelles with loss of membrane integrity. Studies of phospho...

Effect of Zinc on Immune Functions and Host Resistance Against Infection and Tumor Challenge

Abstract: The effect of zinc treatment on immune function and resistance against infection and tumor challenge was studied in mice. Swiss albino mice were treated with zinc acetate (3 mg/kg body weight) in one or two intraperitoneal injections. Various immune function assays were performed in treated animals. Zinc treatment to normal animals caused potentiation of T-lymphocyte and macrophage functions. Zinc treatment was also found to increase host resistance against Candida albicans and Semliki Forest virus infections. Increased resistance against endotoxin shock and Ehrlich's ascites tumor challenge was also observed in zinc treated animals. It can be stated from this study that zinc treatment potentiates the cell mediated immunity and host resistance against infection and tumor challenge.

Anesthetic agents induce human mononuclear leucocytes to release cytokines.

Abstract: Studies were carried out on the ability of some anesthetic agents (Propofol, Dormicum, Ketalar and Penthotal) to induce the release of cytokines by human monocytes and lymphocytes in vitro. All anesthetic agents tested at hematic concentrations reached during anesthetic administration cause an increase in the production of Tumor necrosis factor (TNF) from human monocytes; the increase is 4–5 times greater than controls. The greatest Interleukin - 1α (IL-1α) production increase was induced by Propofol. The release of Interleukin -6 (IL–6) is notably increased by Ketalar (about 10 times greater than controls). In the presence of different anesthetic agents, human lymphocytes release Interleukin -4 (IL-4) and Interferon γ- (IFN-γ). Penthotal and Ketalar increase IL-4 production which appears quite high compared to that obtained with Con A used as standard challenge. Propofol induce IL-4 release which is about the same as that seen with Con A. IFN-γ is released in high quantities by lymphocytes treate...

Regulation of murine T-lymphocyte function by spleen cell-derived and exogenous serotonin.

Abstract: The modulatory effects of serotonin on T-cell activity were investigated. T-cell blastogenesis of normal spleen cells was slightly stimulated by the addition of low doses (1 and 10 ng/ml) of the inducer of serotonin release, fenfluramine. In contrast to the stimulatory effects of low doses of fenfluramine, high doses of fenfluramine (1 and 10 ug/ml) or of exogenously added serotonin (> or = 0.1 ug/ml) inhibited T-cell activation. Both the stimulation by low dose fenfluramine and the inhibition by high dose fenfluramine were accentuated by pretreating mice with tryptophan to heighten intracellular stores of serotonin and then inducing serotonin release. Pretreatment of mice with the serotonin inhibitor p-chlorophenylalanine (PCPA) abolished the fenfluramine inhibition of T-cell activation indicating that the fenfluramine inhibitory effect was mediated via endogenous spleen cell-derived serotonin. However, the PCPA treatment diminished T-cell activation. These results suggest that endogenous serotonin causes a biphasic dose-response effect on T-cell activity with serotonin being required for optimal T-cell function, low doses being immune stimulatory and higher doses being suppressive.

The impact of acemannan on the generation and function of cytotoxic T-lymphocytes.

Abstract: Acemannan, an antiviral agent with immune enhancement capabilities, was studied for its impact on cytotoxic T-lymphocyte (Tc) function generated in response to alloantigen. To investigate whether acemannan directly stimulated the generation of Tc from primary mixed lymphocyte cultures (MLC), the drug was added at the initiation of the MLC. There was a dose-related, statistical increase in killer T-cell generation produced by acemannan in the clinically relevant dose range. The lowest test dose of the drug (2.6 x 10(-9) M) increased chromium release nearly two-fold; the 2.6 x 10(-8) M dose gave a maximal 3.5 fold increase in cytotoxic T-cells. To study whether acemannan enhanced the capacity of Tc once generated to alloantigen to destroy targets bearing the sensitizing antigens, MLR were established in the absence of any drug. Acemannan at the two highest doses increased the functional capacity of Tc to destroy target cells to which they had been sensitized in the MLR. To control for the possibility that acemannan was directly cytotoxic to target cells, targets were incubated alone with drug and without sensitized killer T-cells. No dose of acemannan was found to be cytotoxic to these cells. In conclusion, acemannan did enhance the generation of cytotoxic T-cells when added at the initiation of the MLR. When acemannan was added at the completion of allostimulation, an increase of almost 50% killing by Tc was also observed. These effects can not be explained by direct drug related toxicity and suggest a functional correlate to the previously described immune enhancing properties of the agent. As this drug is being tested for the treatment of HIV infections, these data provide at least one immunologic mechanism by which acemannan may be clinically salutory.

Antiallergic effect of epinastine (WAL 801 CL) on immediate hypersensitivity reactions: (I). Elucidation of the mechanism for histamine release inhibition.

Abstract: Epinastine caused an inhibition of histamine release from rat peritoneal mast cells induced by both antigen-antibody reaction and compound 48/80. Epinastine was similarly effective in inhibiting compound 48/80-induced histamine release not only from isolated rat peritoneal mast cells but also from rat mesenterial pieces. Also, histamine release from lung pieces obtained from actively sensitized guinea pigs after exposure to antigen challenge was markedly inhibited by epinastine. The drug was effective in inhibiting not only Ca2+ uptake into lung mast cells in actively sensitized guinea pigs but also Ca2+ release from the intracellular Ca store of rat peritoneal mast cells exposed to both compound 48/80 and substance P. No significant changes were observed in phosphodiesterase activity in rat peritoneal mast cells treated with epinastine, while adenylate cyclase activity was augmented by epinastine. Epinastine has no inhibitory effect on histamine release induced by Ca2+ or IP3 from permeabilized m...

Immunomodulatory Effects of γ-HCH (Lindane) in Mice

Abstract: Mice were fed for 24 weeks with three different subtoxic dosages of γ-HCH (0.012, 0.12 and 1.2 mg/kg) mixed in powdered feed. The immunological profile was assessed at an interval of one month during the entire exposure period. Both the cell mediated and humoral components of immunity showed a biphasic response characterized initially by stimulation followed by suppression in a dose dependent manner. However, γ-HCH did not affect the functional properties of peritoneal macrophages. Histological changes in lymphoid organs were in accordance with the biphasic immunomodulatory effects of γ -HCH.

Antimicrobial Agents Induce Monocytes to Release IL-1α, IL-6, and Tnf and Induce Lymphocytes to Release IL-4 and TNFτ

Abstract: Evaluation was carried out on the action of different antibiotics on the release of cytokines. Experiments were done in vitro on monocytes and on human lymphocytes. Results show that the majority o...

Effect of a Traditional Chinese Medicine, Bu-Zhong-Yi-Qi-Tang (Japanese Name: Hochu-Ekki-To) on the Protection Against Listeria Monocytogenes Infection in Mice

Abstract: Effects of Bu-Zhong-Yi-Qi-Tang (Japanese name: Hochu-ekki-to) on the resistance against Listeria monocytogenes were observed in ICR mice orally administered this medicine daily for 10 days. Survival rates were increased by the pretreatment in mice inoculated i.v. with bacteria 1 day after the last administration and in mice inoculated i.p. 4 days after the last administration. After an i.v. inoculation of L. monocytogenes, the numbers of bacteria in the spleen and liver increased gradually to kill mice by day 5 in untreated group but the bacterial numbers increased slightly by day 3 and decreased from day 3 to day 8 in Hochu-ekki-to pretreated group. After an i.p. inoculation, the number of bacteria in the peritoneal cavity decreased very rapidly within 6h in Hochu-ekki-to treated group compared to that in untreated group. After the administration, number of polymorphonuclear cells increased in the peripheral blood, peritoneal cavity and spleen. In treated mice, macrophages increased in number in the peritoneal cavity and the spleen but decreased in the peripheral blood. Peritoneal macrophages from treated mice showed an enhanced activity to kill L. monocytogenes in vitro within 60 min after ingestion of bacteria. Hochu-ekki-to may augment the host defense against L. monocytogenes through the activation of macrophage series during an early phase of infection.

The effects of perfluorodecanoic acid (PFDA) on humoral, cellular, and innate immunity in Fischer 344 rats

Abstract: The in vivo effects of perfluorodecanoic acid (PFDA) exposure on antibody production, delayed type hypersensitivity (DTH), and natural killer (NK) cell activity were determined. Fischer 344 rats were injected with PFDA (20 mg/kg or 50 mg/kg, 8 days or 30 days prior to sacrifice) and were immunized with keyhole limpet hemocyanin (KLH). Pair-fed and ad libitum-fed control rats were included to evaluate effects of PFDA-induced anorexia. KLH-specific IgG2a production was significantly decreased (p < 0.05) in PFDA-treated rats when compared to ad libitum-fed and pair-fed controls at 8 days but not at 30 days following PFDA treatment. The DTH response of PFDA-treated rats was decreased 8 days and 30 days after PFDA treatment when compared to ad libitum-fed and pair-fed controls, however, the decrease was not statistically significant. NK activity 30 days after PFDA treatment was significantly elevated (p < 0.05) when compared to ad libitum-fed controls, but pair-fed controls had similarly elevated NK activity. NK activity at 8 days after PFDA treatment was not significantly altered. In conclusion, PFDA has been demonstrated to have immunomodulatory effects, some of which may be associated with drug-induced anorexia.

Pidotimod stimulates natural killer cell activity and inhibits thymocyte cell death.

Abstract: Experiments were performed to analyze the possible effect of the immunomodulating agent Pidotimod (3-L-pyroglutamyl-L-thiazolidine-4-carboxylic acid) on mouse Natural Killer (NK) cell activity and glucocorticoid hormone(GCH)-induced thymocyte apoptosis. The results indicate that in vivo treatment with Pidotimod (200 mg/Kg ip for 5 days) causes a significant increase in NK activity and in vitro treatment produces a significant reduction of dexamethasone-induced thymocyte apoptosis. This inhibition appears to be dose-dependent and is also evident against TPA or Ca(++)ionophore-induced apoptosis.

Induction of Immune Rejection of Tumors by Protein A in Mice Bearing Transplantable Solid Tissue Dalton's Lymphoma Tumors

Abstract: In a transplantable solid tissue Dalton's lymphoma tumor model in mice we have studied the mode of antitumor action of protein A, a well known biological response modifier. Protein A (15 ug) was administered intravenously in normal and solid tissue Dalton's lymphoma tumor bearimg mice on day 3 and 7 after tumor inoculation. Incidence of mortality was more in untreated tumor bearing group than that in PA treated tumor bearers. There was a significant decrease (p<0.001) in tumor diameter in PA treated group compared to untreated group. Protein A treatment significantly enhanced the delayed type hypersensitivity (p<0.01), T-cell number in spleens (p<0.001) and lymph nodes (p<0.05) as well as phagocytosis (p<0.001) of opsonized SRBC by peritoneal macrophages of tumor bearing animals. Apart from the nonspecific immunopotentiation, Protein A also activates natural Killer (NK) cell activity and also splenic lymphocytes mediated killing of autologous tumor targets in a significant (p<0.001) manner. These ...

Antiallergic effect of epinastine (WAL 801 CL) on immediate hypersensitivity reactions: (II). Antagonistic effect of epinastine on chemical mediators, mainly antihistaminic and anti-PAF effects.

Abstract: Anti-histamine and anti-PAF effects of epinastine were tested in rats, guinea pigs and rabbits. Epinastine showed a potent histamine Hi-blocking effect, but the potency was slightly less than that of ketotifen in histamine-induced contraction of guinea pig ileum and histamine-induced cutaneous reactions in rats. In histamine-induced dye leakage into the nasal cavity tested in rats, the drug was slightly more potent than ketotifen and azelastine. Epinastine as well as ketotifen suppressed rabbit platelet aggregation induced by PAF at higher concentrations compared with WEB 2086, a specific PAF-antagonist. In the bronchospasm induced by PAF in guinea pigs, epinastine was more effective than ketotifen in inhibiting the bronchoconstriction, while it showed no remarkable effect on the hypotension induced by PAF. Epinastine caused a potent antagonistic effect on LTC4-induced contraction of isolated guinea pig trachea. In conclusion, the potent anti-histamine, anti-PAF and anti-LT effects of epinastine m...

Decreased immunological responses by wortmannin-containing rice culture of Fusarium oxysporum and by purified wortmannin in avian species.

Abstract: Immunological assays were performed in young chicken and duck after they had been fed wortmannin-containing culture of Fusarium oxysporum or purified wortmannin for 2 weeks. The culture significantly decreased humoral response to sheep red blood cell, cell-mediated cutaneous hypersensitivity to phytohemagglutinin and phagocytic activity in isolated peritoneal exudate adherent cells, but only when the concentration was high enough to cause concurrent reduction in body weight gain and hematocrit. Increased dietary metabolizable energy and protein did not affect the toxicity of the culture. On the other hand, purified wortmannin (1 mg/kg diet) significantly inhibited the aforementioned immunological responses prior to the adverse effects on body growth and hematocrit. The data strongly indicate that wortmannin is an immunotoxic substance. The possibility that macrophage is the primary target cell type is discussed.

Nicotine enhances interleukin production of rat splenic T lymphocytes.

Abstract: Very little is known regarding the effects of nicotine, the most pharmacologically active component of tobacco products, on T lymphocyte activity or interleukin production. Therefore, rats were implanted subcutaneously with osmotic mini-pumps containing either physiological saline, nicotine (1.5 mg/kg/day) or a high dose of nicotine (4.5 mg/kg/day) for a period of 14 days. The ability of the splenic T lymphocytes to respond to the polyclonal T lymphocyte mitogens, Concanavalin A (ConA) or phytohemagglutinin (PHA), and the ability of mitogen stimulated splenic T lymphocytes to produce interleukin 2 (IL2) were determined. Treatment with nicotine suppressed, in a dose dependent fashion, the ability of splenic T lymphocytes to respond to mitogen, but dramatically enhanced the ability of mitogen stimulated lymphocytes to generate IL2.

Protein A potentiates lymphokine-activated killer cell induction in normal and melanoma patient lymphocytes.

Abstract: The effects of purified protein A from Staphylococcus aureus Cowan I strain on induction of lymphokine (IL-2) activated killer (LAK) activity were studied in normal as well as melanoma patient's lymphocyte. The coculture of peripheral blood mononuclear cells (PBMC) with various doses of protein A (0.001, 0.01 and 0.1 μmlg/ml) and IL-2 (100 U/ml) for 4 days produced synergistic effect on the LAK cells mediated cytotoxicity. The potentiation of cytotoxicity and lytic ability of LAK cells against NK sensitive (K-562) and NK-resistant (M1 4) tumor cells were observed. Further there was potentiation of DNA synthesis in PBMC after 4 days culture. Similar results were found when PBMC from melanoma patients were cultured with PA and IL-2. The potentiation of LAK cell induction associated with its cytotoxic and lytic potential by low doses of IL-2/PA regiment may be helpful in the development of LAK immunotherapy of the cancer patients.

The effects of volatile anaesthetic agents on human immune system function via occupational exposure.

Abstract: The immunological status of individuals occupationally exposed to low levels of halothane and nitrous oxide has been examined and compared with that of non-exposed controls. No differences in the serum concentrations of IgG, IgM, IgA, peripheral blood lymphocytes and lymphocyte subpopulations between the groups were observed.

Preventive Effect of A Synthetic Immunomodulator, 2-Carboxyethylgermantum Sesquioxide, on the Generation of Suppressor Macrophages in Mice Immunized with Allogeneic Lymphocytes

Abstract: The effect of 2-carboxyethylgermanium sesquioxide (Ge-132) on the generation of splenic suppressor macrophages (S-MO) in C3H/He mice (H-2k) immunized with allogeneic spleen cells from C57B1/6 mice (H-2b) was investigated. We have previously demonstrated that S-MO expressing I-J antigen, which appeared during alloimmunization, inhibited cytotoxic T lymphocyte (CTL) generation in the MLR and the elimination of these S-MO before subjection to the MLR resulted in more effective generation of CTL. The CTL activity, which was determined in vivo by the Winn's test, was markedly enhanced when immunized mice received a 100 mg/kg dose of Ge-132. The compound was found to be the most efficacious when injected simultaneously with the immunization. The activity of allospecific CTL co-cultured with MO fractions obtained from immunized mice in a 4-h 51Cr-release assay was shown to be 31% lysis of the target cells as compared with 90% lysis of the target cells in effector cells co-cultured with normal MO fraction...

Antitumor Activity Evaluation of Bromine-Substituted Analogues of Ifosfamide. I. Stereodifferentiaton of Biological Effects Amd Selection of the Most Potent Compounds

Abstract: The series of 9 compounds, including 3 racemates and 6 enantiomers of bromine-substituted analogues of ifosfamide (bromo-, chlorobromo- and dibromofosfamides) have been evaluated for antitumor activity against L1210 leukemia. Lewis lung carcinoma and B16 melanoma in mice. Effective and curative doses of tested compounds were estimated on the basis of computer-assisted elaboration of the dose-effect curves obtained from experimantal data. Two oxazaphosphorine drugs, ifosfamide and its congener cyclophosphamide, were used as referentials. Elementary toxicity studies were conducted in parallel in healthy animals and lethal doses were determined. Selection of the most potent compounds was based on the comparison of their therapeutic indices, calculated from the ratio of lethal to effective doses. In effect four compounds which have been shown therapeutically more effective than both referential drugs, were selected for further evaluation in mice bearing advanced tumours. Stereodifferentiation of evalu...

Immunological Consequences of Zidovudine Treatment in Control and Morphine or Methadone Treated Mice

Abstract: The effects of acute and chronic zidovudine (AZT) administration on immunologic test responses of mice were studied. The effects of AZT administration combined with morphine or methadone treatment, were also studied separately comparing the effects of each drug.We noted that AZT-treatment did not modify the T-lymphocyte subsets (L3T4/LyT2 rate), whereas morphine-treatment and AZT plus morphine treatment decreased the percentage of T helper cells.Acute and chronic AZT-treatment increased Natural Killer cell (NK) activity and also recovered the decreased NK cell activity produced by morphine-treatment.AZT-treatment, morphine-treatment, AZT plus morphine treatment and AZT plus methadone treatment strongly depressed the phagocytic physiological activity of Polymorphonuclear leukocytes (PMNs).Another evidence of immunologic responsiveness against AZT was the reduction of the mitogenic and antigenic response of lymphocytes.These results suggest a negative role of AZT-treatment especially on phagocytic a...

Effects of taxol on the macrophage function. Interactions with some immunological parameters.

Abstract: The effects of Taxol on some immunological parameters were investigated, in vitro, in the murine macrophage cell line J774.1. Mitochondrial dehydrogenase activity and (3H) TdR incorporation were shown to be increased in Taxol treated cells. Likewise, Taxol induced TNF alpha secretion. But Taxol seemed to be a weak inducer of the two interleukins IL-1 and IL-2, since their detection occurred late in the cell culture supernatants.

beta-Lactam antibiotic modulation of murine neutrophil cytokinesis.

Abstract: Fourteen cephalosporins, 11 penicillins and 1 monobactam were evaluated for their in vitro modulation of murine neutrophil cytokinesis. As a result, the beta-lactam antibiotics were placed into 6 groups based on their effect on random (R) and FMLP-directed (D) migration [Group 1 (no effect): cephalosporin C; Group 2 (R-->D decreases): cloxacillin, cefotaxime, ceftazadime, cefuroxime, cephalothin, cephapirin, cephadine, nafcillin, piperacillin, ticarcillin, ampicillin, oxacillin, aztreonam; Group 3 (R increases D-->): cephaloridine; Group 4 (R increases D increases): cefsulodin; Group 5 (R increases D decreases): cefoperazone, cefoxitin, ceftriaxone, 6-amino-penicillanic acid; Group 6 (R decreases D decreases): cefadroxil, cefazolin, penicillin G, methicillin]. Trypan blue exclusion studies showed that inhibition of R and D by Group 6 beta-lactam antibiotics is not due to overt cytotoxicity. beta-lactam antibiotics inhibiting D also increased neutrophil adherence to plastic at a concentration of 1000 microM. Finally, the [Ca++] inhibitor chlorpromazine significantly abrogates beta-lactam- and FMLP-directed migration at a test concentration of 1 microM.

Augmentation of Host Resistance to Listeria Monocytogenes Infection by A Traditional Chinese Medicine, Ren-Shen-Yang-Rong-Tang (Japanese Name: Ninjin-Youei-To)

Abstract: Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NIN), a traditional Chinese medicine, is a drug made of spray-dried powder of hot water extract obtained from twelve species of medical plants. An intraperitoneal (ip) injection with NIN 2 days before intravenous (iv) infection with Listeria monocytogenes (L. monocytogenes) accelerated elimination of viable bacteria in the spleen in the early stage of infection (from day 1) and protected mice from the lethal infection. It was suggested that the protective effect of NIN was mediated by the activation of nonimmune macrophages playing a principle role in resistance in the early stage of infection. Two days after ip injection with NIN just before infection, significantly increment in the number of monocytes in the peripheral blood was observed, though macrophage number in the spleen and their intracellular killing activity were unchanged. At 12 hours after infection with L. monocytogenes a significantly enhanced increase of splenic macrophage nu...

Immunomodulatory activity of a novel nucleoside, 7-thia-8-oxoguanosine: I. Activation of natural killer cells in mice.

Abstract: We reported recently that a novel immunomodulator, 7-thia-8-oxoguanosine (7T8OG)2 inhibited formation of pulmonary melanoma metastases (1), prevented against viral infection in mice (2) and potentiated the efficacy of a weakly immunogenic leukemia vaccine (3). Since certain tumor metastases and virus infected cells are targets to natural killer cells (NK cells), we now investigated whether 7T8OG is capable of activating NK cells in mice using NK cell sensitive YAC-1 and B16 and NK cell insensitive P815 targets. CBA/CaJ spleen cells incubated in vitro with 7T8OG at concentrations ranging from 0.005 to 0.5 mM responded with increased NK cell activity (32-62%) compared to controls (4-8%) to YAC-1 targets. Similar levels of augmentation in NK cell activity were observed when 40-168 mg/kg of 7T8OG was administered in vivo. In addition to the spleen, 7T8OG activated NK cells in the bone marrow (BM), the lungs, the liver, and in peritoneal exudate cells (PE). Although 7T8OG elicited activation of NK cells was observed as early as three hours after treatment, the maximal activity was observed after 24 h in the spleen; 12 h in the BM; 48 h in the lungs, and 72 h in PE. Administration of the drug by s.c., i.v., and i.p. routes all induced activation of NK cells in spleen, BM and PE. 7T8OG was found to activate NK cells in seven inbred and an outbred mouse strain, suggesting that the induced cytotoxicity against allogeneic and syngeneic tumor cells is not strain specific as well as independent of MHC restriction. C3H/He, CBA/CaJ and BDF/1 displayed higher levels of increased NK cell activity, whereas AKR mice were low responders. Low concentrations of IL-2 (0.25-5 U/ml) that induce little or no NK cell activity, when used in combination with 7T8OG, elicited significant enhancement of NK cell cytotoxicity. In contrast, IFN and 7T8OG showed no such synergism.

Contrasting Effects of thc on Adult Murine Lymph Node and Spleen Cell Populations Stimulated with Mitogen or Anti-CD3 Antibody

Abstract: Marijuana, and specifically its psychoactive component, THC, can up or down regulate lymphocyte proliferation in murine spleen cells depending in part on the method used to stimulate the cells. This study identifies a difference in THC induced disregulation using cells derived from two different secondary lymphoid organs, the spleen and the lymph node. It was found that THC treatment of mitogen (concanavalin A or phytohemagglutinin) stimulated cells derived from either organ resulted in suppression of the proliferative response. In contrast, spleen cells stimulated with anti-CD3 antibody and treated with low doses of THC displayed an enhanced proliferation whereas the response in lymph nodes did not change. The cell type involved with this THC immunoenhancement in spleen cells was found to be the Ly2 cell. Further differences in the THC modulation of Ly2 spleen cells as compared to lymph node cells were noted following stimulation with PHA. Proliferation of Ly2 cells of splenic origin was inhibited with low doses of THC whereas the Ly2 cells of lymph node origin were more resistant to this drug induced suppression. This study, therefore, demonstrates differences in the immunomodulatory capability of THC dependent upon the organ source of the lymphocytes.

Activation of CD4+ and CD8+ lymphocyte subsets by streptozotocin in the popliteal lymph node assay. II. Comparison with acute graft-vs-host reaction in H-2 incompatible F1 mouse hybrids.

Abstract: Changes in lymphocyte subsets during an acute GVH reaction were compared to STZ-induced PLN response in mice. The GVH reaction was induced locally by sc injection of parental C57Bl/6 [B6] spleen cells into (C57Bl/6 x DBA/2) F1 footpad [B6D2F1]. Early cell activation and time-related changes in T- and B-lymphocyte subsets were monitored during the onset of the GVH reaction by flow cytometry and immunophenotyping. Examination of cell size and chromatin decondensing for T- and B-cell subsets showed differences in activation profile during the early phase of the GVH reaction. The present study provides direct evidence for early in vivo activation of both CD4+ and CD8+ T-cells. Our data confirm the central role of T-cell activation in the induction of a GVH reaction and suggest that recirculatory host B-cells can play an important role in early GVH node enlargement. Overall, our comparative analysis supports the concept of polyclonal T-cell activation for both STZ-related and GVH-induced lymphoproliferation. Chemicals-induced lymphoproliferation leading to autoimmune reactions is a challenging issue. A number of drugs and chemicals have been tested in the PLNA assay for lymphoproliferative potential. We previously reported the activation and proliferation of T-cell subsets following STZ injection into murine footpads. The STZ-induced PLN enlargement and proliferation characteristics of T- and B-cell subsets were postulated to be similar to those of an acute allogeneic GVHR. In the present study, a cytometric analysis of T- and B-cell subsets in PLNs was performed during an acute allogeneic GVHR, for comparison purposes. Such a reaction results in a massive node enlargement five to ten times that seen after stimulation with conventional antigens. Acute GVHR is believed to be a direct consequence of the high frequency of alloreactive donor T-cells inducing a massive proliferation of B-cells, almost exclusively of host origin, in GVHR nodes. It is now widely accepted that donor T-cells activated as the result of exposure to foreign MHC antigens in the recipient, secrete various cytokines which assist the host B-cells and bypass the normal B-T cell cooperation. Induction of an acute GVHR, as in the parental B6--->recipient B6D2F1 model, requires the injection of CD4+ and CD8+ donor T-cells into an F1 recipient that differs from the parent at both MHC class I and II loci.(ABSTRACT TRUNCATED AT 400 WORDS)