Showing papers in "Immunopharmacology and Immunotoxicology in 1991"
TL;DR: The inhibition of the production of proinflammatory mediators by extremely low concentrations of mometasone furoate suggests that this steroid should be highly effective in various disorders.
Abstract: Mometasone furoate (9α, 21 dichloro-11β, 17α dihydroxy-16α methyl-1, 4 pregnadiene-3, 20 dione-17–[2′] furoate) was an unexpectedly potent inhibitor of the in vitro production of three inflammatory cytokines, IL-11, IL-6, and TNF-α. the potency of mometasone furoate in inhibiting cytokine production was compared to that of hydrocortisone, betamethasone, dexamethasone, and beclomethasone.IL-6 and TNF-α were both produced by WEHI-265.1 (murine myelomonocytic leukemia) cells following stimulation by lipopolysaccharide (LPS). Twenty-four hours after stimulation by LPS, the cell-free supernatant fluids were removed. Their cytokine content was analyzed using ELISAs specific for each cytokine.IL-1 synthesis was induced in the harvested peritoneal macrophages of BALB/c mice by incubation with LPS for twenty-four hours. the IL-1 content in the cell-free supernatant fluids was determined by the thymocyte-costimulator bioassay.Using these systems, mometasone furoate was found to be the most potent steroid te...
78 citations
TL;DR: The four agents inhibited chemotaxis efficiently and in a concentration-dependent manner but had only weak effects on the release of BGL, whereas the effect of procaine was blunt.
Abstract: This study examined the effects of four typical local anesthetics, lidocaine, prilocaine, procaine and tetracaine, on the functioning of human polymorphonuclear leukocytes (PMN). PMN were stimulated by fMet-Leu-Phe (FMLP) or phorbol myristate acetate (PMA) to elicit chemotaxis, extracellular release of beta-glucuronidase (BGL) and superoxide anion (SOA) production. the four agents inhibited chemotaxis efficiently and in a concentration-dependent manner but had only weak effects on the release of BGL. the effect of tetracaine was strongest, followed by lidocaine, then prilocaine, whereas the effect of procaine was blunt. the 50% inhibitory concentrations (IC50 in molarity) of the four local aesthetics for chemetaxis were as follows: tetracaine=4.1×10−4, lidocaine=3.2×10−3, prilocaine=3.6×10, procaine=4.9×10−3, those for SOA production induced by FMLP were : tetraaine=3.1×10−4, lidocine=5.9×10−3, prilocaine=1.9×10−2, procaine=1.2×10−2, those for SOA production indced by PMA were : tetracaine=1.1×10−...
72 citations
TL;DR: The results suggest that the proliferative responses of fish lymphocytes to mitogens may be a potentially sensitive biomarker of exposure to, and effects of xenobiotics.
Abstract: The marine fish spot, Leiostomus xanthurus, was collected from five sites in the lower Chesapeake Bay system representing a gradient of sediment polycyclic aromatic hydrocarbon (PAH) concentrations. The proliferative responses to mitogens by anterior kidney lymphocytes were assessed using [3H]-thymidine uptake by replicating DNA. The data shows two different mitogen-dependent lymphocytic responses as the sediment PAH levels increase at the sampling sites; a suppression of the response to the T cell mitogens, concanavalin A (Con A) and phytohemagglutinin, and a sharp augmentation of the response to B cell mitogen, lipopolysaccharide (LPS), as well as to poke weed mitogen and peanut agglutinin. The magnitude of the lymphoproliferative responses correlated strongly with the total sediment PAH concentrations (r2 greater than 0.8). A similar correlation was also observed with 15 selected individual PAH compounds regardless of their molecular weights. By maintaining the fish in clean York River water for up to 24 weeks, it was possible to reverse the augmented proliferative responses to LPS of fish from all sampling sites and to increase the reduced responses to Con A, in fish from three sites, and partially in two sites where sediments were highly contaminated with PAH. These results suggest that the proliferative responses of fish lymphocytes to mitogens may be a potentially sensitive biomarker of exposure to, and effects of xenobiotics.
45 citations
TL;DR: It is concluded that in humans inhalation of volatile nitrites causes cycles of modest immunosuppression, particularly in NK activity, followed by gradual recovery when the drug is not inhaled for several days.
Abstract: Effects on the human immune system of volatile nitrite inhalation were studied in 18 male volunteers. While nitrite inhalation decreased the absolute number of CD3+ T lymphocytes during the period of inhalation, cell numbers returned to pre-treatment levels within one week after cessation of the drug. Nitrite inhalation did not alter the percentage of CD3+, CD4+, CD8+ or CD19+ lymphocytes. Natural killer (NK) cell activity against K562 target cells was depressed by nitrite administration but returned to pre-inhalation or greater levels after nitrite discontinuation. Cell proliferation following cell activation by PHA, ConA and PWM was unaffected by amyl nitrite inhalation. We conclude that in humans inhalation of volatile nitrites causes cycles of modest immunosuppression, particularly in NK activity, followed by gradual recovery when the drug is not inhaled for several days.
30 citations
TL;DR: The data suggest that nicotinamide and 3-aminobenzamide suppress antigen presenting function of class II MHC positive endothelial cells and fibroblasts at the site of tissue inflammation.
Abstract: We investigated the effects of nicotinamide and 3-aminobenzamide, known as inhibitors of poly (ADP-ribose) synthetase, on the expression of interferon- gamma (IFN-gamma)-induced class I and II major histocompatibility complex (MHC) molecules on the surface of cultured human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF). Indirect immunofluorescent staining on HUVEC and HDF was performed using monoclonal antibodies against class I MHC (HLA-A,B,C) and class II MHC (HLA-DR, HLA-DP and HLA-DQ) molecules, and then the expression of these molecules was determined using a fluorescence flow cytometry. Human recombinant IFN-gamma (100 U/ml) increased the expression of HLA-A,B,C molecules, and induced the expression of HLA-DR molecules and, to a lesser extent, of HLA-DP on both HUVEC and HDF. HLA-DQ molecules were not induced by IFN-gamma on either cell type. Nicotinamide and 3-aminobenzamide in the concentration greater than or equal to 1 mM reduced the IFN- gamma -induced expression of HLA-DR and HLA-DP on both HUVEC and HDF, whereas neither agent in the concentration of up to 10 mM affected the IFN- gamma -induced increase in HLA-A,B,C molecule expression. These data suggest that nicotinamide and 3-aminobenzamide suppress antigen presenting function of class II MHC positive endothelial cells and fibroblasts at the site of tissue inflammation.
29 citations
TL;DR: It is demonstrated that cocaine is immunosuppressive and that it acts on human MNC during early stages of cellular activation, and that illicit cocaine use may compromise the integrity of the immune system.
Abstract: Because of the national epidemic of cocaine abuse and the increasing prevalence of infectious diseases among drug abusers, we investigated the effects of cocaine and cocaine metabolites on human cellular immune functions. Mononuclear cells (MNC) were isolated from blood of healthy adult volunteers. MNC were stimulated in vitro with mitogens with and without various concentrations of cocaine. Because of cocaine's poor stability in vitro, we found it necessary to replenish cocaine daily to MNC cultures. Under these conditions, cocaine, in a dose response fashion, significantly inhibited MNC proliferation: Metabolites of cocaine did not alter MNC proliferative responses significantly from control cultures. Polymorphonuclear leukocyte chemotaxis was also significantly impaired by cocaine. Our data demonstrate that cocaine is immunosuppressive and that it acts on human MNC during early stages of cellular activation. These data further suggest that illicit cocaine use may compromise the integrity of the...
26 citations
TL;DR: It is concluded that the dose-dependent suppressive effects of arecoline on DTH response to SRBC and on certain in vitro lymphocyte functions are more clear than the host resistance to endotoxin shock.
Abstract: Arecoline, a major alkaloid of arecanut was screened to explore its modulatory influence on cell-mediated immune response in a murine model system. the in viva and in vitro effects were evaluated at subtoxic concentrations of arecoline. Delayed type hypersensitivity (DTH) reactions to sheep red blood cells (SRBC) were evaluated in male mice. When treated subcutaneously with 20 mg/kg bw (1/5 of LD50) dose of arecoline for 1, 2 or 3 weeks, the DTH reactions were significantly suppressed. At arecoline concentration of 10 mg/kg bw, there was a moderate reduction in DTH response, while no appreciable change was observed at a dosage of 5 mg/kg bw. the effects were not dependent on the duration of treatment. In contrast, treating with arecoline continuously for 4 days following SRBC immunization showed significant suppression in DTH reactions at both 10 and 20 mg/kg bw doses. When treated after 12 h following immunization with 20 mg/kg bw arecoline, significant reduction in DTH reactions were seen. While...
25 citations
TL;DR: The data suggest that the host's immune responses to M. tuberculosis infection can be selectively modulated by drugs acting on the neuroendocrine axis.
Abstract: Acetyl-L-carnitine (ALC), a drug for the treatment of ageing-related neuroendocrine dysfunctions, was orally administered -2 gm/day for 30 days -to 10 patients with active pulmonary tuberculosis (TBC). Lymphocyte-mediated antibacterial activity and serum levels of tumor necrosis factor (TNF)-U were evaluated before and after treatment, comparing the values with those of 10 TBC patients receiving placebo.Results show that by day 30, antibacterial activity remained unmodified or increased in ALC-treated subjects, while decreased in the placebo group. No influence of ALC on TNF-U levels was detectable.These data suggest that the host's immune responses to M. tuberculosis infection can be selectively modulated by drugs acting on the neuroendocrine axis.
20 citations
TL;DR: Although macrophage depletion of cultures impaired proliferation induced by Con A, tocopherol supplementation continued to stimulate proliferation at optimal and sub-optimal levels of mitogen.
Abstract: The effect of α-tocopherol on in vitro proliferation of murine splenic lymphocyte cultures supplemented with various concentrations of the vitamin has been measured at sub-optimal, optimal and supra-optimal levels of the T-cell mitogen Concanavalin A (Con A). In the concentration range (1–25 μg/ml), tocopherol enhanced proliferation when administered up to 24 hours after exposure to sub-optimal and optimal concentrations of Con A; however, at supra-optimal levels of the mitogen, it appeared to inhibit proliferation. In the concentration range 50–100 μg/ml, tocopherol supplementation only enhanced proliferation in response to sub-optimal concentration of Con A. the spontaneous proliferation of lymphocytes in the absence of mitogens was increased by tocopherol supplementation at all concentrations tested. In contrast, there appeared to be only slight stimulation of B-cell proliferation in response to optimal concentration of bacterial lipopolysaccharide (LPS) by lower levels of vitamin E. Tocopherol...
16 citations
TL;DR: Similarities in their modes of action, as measured by these biophysical and cell biological tests, indicate the possibility that these three immunosuppressors will show similarities in their clinical performance.
Abstract: The immunosuppressive drugs FK-506 and mycophenolic acid (MPA) have recently been described, but their mode(s) of action are not well understood. We have compared them to cyclosporine A (CsA) in several assays. We have shown that CsA (1 μg/ml), MPA (0.1 μg/ml), and FK-506 (0.5 μg/ml) all induce a state of unresponsiveness to anti-CD3 stimulation as measured by [3H]-thymidine uptake. This suggests that the target of these drugs may be present only after mitogenic stimulation. These drugs also cause a hyperpolarization of the plasma membrane of lymphocytes. This effect is blocked by quinine or verapamil. All three immunosuppressors only slightly modulate the increase in intracellular Ca++ caused by Con-A or by anti-CD3 stimulation but do not affect Ca++ levels alone. They also decrease expression of IL2 receptors on αCD3-stimulated lymphocytes. Similarities in their modes of action, as measured by these biophysical and cell biological tests, indicate the possibility that these three drugs will show ...
15 citations
TL;DR: A relatively very high radioactivity was found in liver, kidney, thymus, spleen and brain very soon which suggest a very good penetration into tissues, an agreement with the high apparent distribution volume of peripheral compartment and higher lipophilicity of AdDP as compared to MDP.
Abstract: A pharmacokinetic profile of 14C-AdDP with uniformly labelled alanine was investigated. It was shown that the distribution phase after an i.v. administration is very short with a half-life of 2.1 min. the half-life of elimination phase after the i.v. administration is about 2.85 hours, that is longer than those of MDP and its derivatives. the total body clearance (30 ml/min/kg) is caused predominantly by metabolism of the compound. All the radioactivity found in urine in a 48 hours interval after a s.c. administration represents only 3.1% of the administered dose. Only a smaller part of the excreted radioactivity is formed by unmetabolised AdDP. the concentration curve after a S.C. administration is characterized by a very fast absorption with a half-life shorter than 1 minute. the distribution and elimination phases are prolonged (20 min, 11 hours respectively) in comparison with an i.v. injection. the decreased absolute bioavailability after a s.c. administration (65%) is probably not biological...
TL;DR: Observations suggest that there is a correlation between membrane depolarization and initiation of DNA synthesis in PU5-1.8 cells and PKC may be acting as a modulator in this transducing pathway.
Abstract: The role of membrane potential (Em) on the initiation of DNA synthesis in murine macrophage cell line PU5-1.8 was investigated with fluorescent probes bis-oxonol and diS-C3-(5). Incubation of PU5-1.8 cells in high K(+)-HEPES buffer or with gramicidin at 37 degrees C for 1h that depolarized the membrane induced [3H]-thymidine incorporation and expression of early response gene such as c-myc and c-fos. When PU5-1.8 cells were treated with a number of agents including fetal calf serum (FCS), lipopolysaccharide (LPS), epidermal growth factor (EGF), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and bradykinin (BK), only FCS caused DNA synthesis and membrane depolarization. Other agents had no effect on these events. The FCS-mediated DNA synthesis in PU5-1.8 cells was inhibited by clamping the membrane potential with valinomycin. Moreover, intracellular alkalinization induced by nigericin at pH 7.9, which is believed to be a permissive signal for mitogenesis, caused membrane depolarization. On the other hand, challenge of cells with phorbol 12-myristate 13 acetate (PMA) suppressed the K(+)-mediated DNA synthesis. However, the treatment of cells with PMA did not change the membrane potential but suppressed the gramicidin-mediated membrane depolarization. These observations suggest that there is a correlation between membrane depolarization and initiation of DNA synthesis in PU5-1.8 cells. PKC may be acting as a modulator in this transducing pathway.
TL;DR: It is suggested that a decrease in the size of the pool of T cell precursors able to produce IL-2 is responsible for the impairment of Tcell function observed in HLA-B8,DR3 positive subjects.
Abstract: The activity of recombinant interleukin-2 (rIL-2) on the in vitro lymphocyte proliferative response to phytohemagglutinin mitogen was investigated in healthy HLA-BB, DR3 positive and negative subjects. the response to mitogen, significantly decreased in HLA-BB, DR3 positive subjects, was completely restored by adding rIL-2. Moreover, in HLA-BB, DR3 positive subjects the in vitro treatment with rIL-2 significantly increased the reduced frequency of mitogen responsive T lymphocyte precursors, as assessed by limiting dilution analysis. These data suggest that a decrease in the size of the pool of T cell precursors able to produce IL-2 is responsible for the impairment of T cell function observed in HLA-BB, DR3 positive subjects. Since in autoimmune diseases it is possible to show the same impairment(s) of T cell functions which can be observed in HLA-BB, DRB positive subjects, these results could be of practical value for the understanding of pathogenetic mechanismts) of autoimmune diseases and, in c...
TL;DR: This study considered the possibility of modifying the functional response of human neutrophils, of mouse lymphocytes and macrophages treated with phospholipids having different polar groups, different isomerisms with saturated and unsaturated fatty acids from C12 to C20 carbon atoms.
Abstract: Our study considered the possibility of modifying the functional response of human neutrophils, of mouse lymphocytes and macrophages treated with phospholipids having different polar groups, different isomerisms with saturated and unsaturated fatty acids from C12 to C20 carbon atoms. the results are as follows.a) Most of the phospholipids containing fatty acids from C12 to C20 cause inhibition of the blastogenic capacity of the polyclonal activators tested.b) the phospholipids tested cause a decrease in adherence of polymorphonuclear leukocytes with the exception of the phosphatidyl-choline containing saturated and unsaturated fatty acids.c) A decrease in polymorphonuclear leukocytes migrational capacity almost always occurs.d) the cells treated with L-phosphatidyl-ethanolamine having fatty acids from C14 to C17 show an increase in chemiluminescence; those treated with phosphatidyl-choline and L-phosphatidyl-glycerol show a decrease of the chemiluminescence; L-phosphatidic acid and L-phosphatidyl-...
TL;DR: Patients treated with AZT are especially likely to benefit from IVIG prophylaxis, and the cumulative probabilities of developing an opportunistic infection over the 12 months of treatment were significantly higher than in the Group B subjects.
Abstract: 30 patients with HIV infection were enrolled to evaluate the clinical efficacy and toxicity of zidovudine (AZT), 0.5 g/day p.o. (Group A) vs. AZT 0.5 g/day p.o. plus intravenous immunoglobulins (IVIG), 0.4 g/kg of body weight for three consecutive days, followed by one treatment of 0.6 g/kg of body weight every fourth week (Group B), over a period of one year. the study was open and randomized. 'The treatment groups were compared using the following study variables: 1) type of infections, recurrences and severity; 2) change in CD4+ T and CD8+ T cell count; 3) change in platelet count; 4) change in TNFa serum levels; 5) the probability of not developing an opportunistic infection over a period of 12 months. Patients from Group B developed less pathological events in comparison to Group A. No significative differences were evident with regard to values of T cell subsets obtained before and after treatment in each group and between the two groups. On the contrary, in 12 out of 15 patients from Group ...
TL;DR: The hypothesis that the macrophage is an important target cell in the mediation of AmB-induced immunomodulation is supported, as it is shown that in vitro incubation with AmB can stimulate AKR (AmB-high responder strain) macrophages and produce a greater inhibition of protein synthesis in C57BL/6 peritoneal Macrophages.
Abstract: Lymphoid cells from most inbred mouse strains respond to amphotericin B (AmB)-induced immunostimulation. However, C57BL/6 mice and related strains display low or absent lymphoid cell stimulation by AmB and enhanced susceptibility to AmB toxicity. Experiments reported here show that in vitro incubation with AmB can stimulate AKR (AmB-high responder strain) macrophage proliferation. Intraperitoneal injection of AKR mice with AmB also elicits a population of macrophages primed for enhanced oxidative burst activity after triggering by zymosan particles. Under the same experimental conditions, AmB elicits a population of very weakly responsive macrophages from C57BL/6 mice. The low responsiveness of C57BL/6 macrophages correlates with previous observations that AmB is a potent immunoadjuvant and B cell mitogen in most inbred strains, but it selectively lacks immunoadjuvant effects in C57BL/6 mice and it also fails to induce polyclonal B cell stimulation in their spleen cell suspensions. Similarly, in measurements of protein synthesis in vitro, high concentrations of AmB produce a greater inhibition of protein synthesis in C57BL/6 peritoneal macrophages than in parallel cultures of AKR macrophages. These findings support the hypothesis that the macrophage is an important target cell in the mediation of AmB-induced immunomodulation.
TL;DR: The results show UDMH caused significant suppression of the T helper cell population derived from the thymus at the 75 mg/kg dose in vivo, but did not affect other lymphocyte subpopulations isolated from mesenteric lymph node, spleen or thymUS at this or any other dose.
Abstract: 1,1-Dimethylhydrazine or unsymmetrical dimethylhydrazine (UDMH) is a highly volatile and reactive compound used primarily as a liquid rocket propellant. Previous studies found UDMH to possess immunomodulatory activity similar to other hydrazine derivatives. Modulation of T lymphocyte subpopulations and Major Histocompatibility Complex Class II or Ia antigen were evaluated as possible mechanisms for this UDMH-induced immunomodulation. Murine lymphoid cell populations were examined by flow cytometry for changes in their cell surface marker percentages or relative number upon exposure to UDMH either in vitro or in vivo. The results show UDMH caused significant suppression of the T helper cell population derived from the thymus at the 75 mg/kg dose in vivo, but did not affect other lymphocyte subpopulations isolated from mesenteric lymph node, spleen or thymus at this or any other dose. In vivo exposure of mice at all doses of UDMH did not significantly alter expression of Ia antigens on adherent cell populations and expression of the Ia antigen following in vitro UDMH exposure was not affected as well. Results indicate that the immunomodulatory effects of UDMH are not mediated by phenotypic alteration of T lymphocyte subpopulations or Ia antigen.
TL;DR: The results are consistent with the hypothesis that intact PK-C activity is essential for neutrophil superoxide production, but that differences exist in the initial pathways induced by these neutrophils activators.
Abstract: Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) induced significant superoxide production in human neutrophils within 30 minutes after addition of stimulus and the response was complete within 2 hr. Other agents known to prime neutrophils, including LPS and tumor necrosis factor-alpha, lacked activity under the experimental conditions employed. Using a panel of pharmacologic inhibitors, we sought to compare GM-CSF-induced neutrophil superoxide to that produced by cells exposed to N-formyl methionyl-leucyl-phenylalanine (fMet-Leu-Phe) and phorbol 12-myristate 13-acetate (PMA). Each stimulant displayed a different profile. Rolipram, a peak IV phosphodiesterase inhibitor, specifically inhibited neutrophil activation by GM-CSF and fMet-Leu-Phe, while superoxide production stimulated by PMA was unaffected. Staurosporine, a protein kinase C (PK-C) inhibitor, suppressed superoxide production induced by all three neutrophil stimulants. Cytochalasin B totally inhibited superoxide induced by GM-CSF under conditions that promote the fMet-Leu-Phe-induced response. Cytochalasin B did not markedly affect PMA-induced superoxide. The results are consistent with the hypothesis that intact PK-C activity is essential for neutrophil superoxide production, but that differences exist in the initial pathways induced by these neutrophil activators. Superoxide secretion from GM-CSF-treated neutrophils appears to be a direct, delayed response that requires assembly of microfilaments during exposure to the cytokine.
TL;DR: Findings indicate that several mechanism are involved in the elderly-related decline of T lymphocyte activation structures during lectin stimulation, including a partial involvement of iron overload in the depressed function.
Abstract: During the last few years, several observations outline that the impaired T lymphocyte proliferative capacity in the elderly is due to a reduced interleukin 2 (IL-2) release. To further investigate the activation process during lectin stimulation, aged peripheral blood mononuclear cells (PBMC) were stimulated with phytohemagglutinin (PHA) and assessed for CD25 (IL-2 receptor) and CD71 (transferrin receptor) expression at different intervals of time. Our results provided evidence for a significant decline of both structure induction, above all in the later phase of culture. Indomethacin (INDO) treatment gave rise to an enhancement of CD71 antigen expression only, while prostaglandin E2 (PGE2) supplementation to culture media further decreased either CD25 or CD71 receptor induction. Interferon (IFN)-alpha and IFN-gamma treatment failed to modulate the frequency of CD25+ and/or CD71+ cells. Finally, the expression of CD71 receptor was increased by deferoxamine supplementation, this suggesting a partial involvement of iron overload in the depressed function. Although further studies are required to evaluate at a molecular level the decreased antigen expression, these findings indicate that several mechanism are involved in the elderly-related decline of T lymphocyte activation structures during lectin stimulation.
TL;DR: It is suggested that TNF plays a major role in the pathogenesis of galactosamine/LPS hepatitis in mice and that IL-lα acts synergistically with TNF to enhance the hepatotoxic effect of recombinant murine TNF in galacto-sensitized mice.
Abstract: The possible involvement of interleukin-lα (IL-lα) in the pathogenesis of murine hepatitis model induced with galactosamine and lipopolysaccharide (LPS) was investigated. the injection of 10 ng/mouse of LPS in combination with 10 mg/mouse of galactosamine into mice induced hepatic damage at 24 hours. Treatment with anti-mouse IL-1α antiserum 30 min before galactosamine/LPS injection showed a tendency to reduce the liver injury, while pretreatment with anti-mouse tumor necrosis factor-α (TNF) antiserum significantly protected mice from liver injury. the use of recombinant murine TNF, instead of LPS, in combination with galactosamine could elicit hepatic damage, whereas recombinant murine IL-lα could not substitute for LPS. However, recombinant murine IL-lα enhanced the hepatotoxic effect of recombinant murine TNF in galactosamine-sensitized mice. These results suggest that TNF plays a major role in the pathogenesis of galactosamine/LPS hepatitis in mice and that IL-lα acts synergistically with TNF ...
TL;DR: The spectrum of lung NK cell response to BRM is smaller than that previously reported for NK cells from other anatomic compartments, which is important for the responsible and effective use of BRM.
Abstract: Natural killer (NK) activity plays an important role in host defense against tumors, especially once augmented by immunomodulators. It is likely that the modulation of NK cells is a reflection of the environment in which they reside. the current study was undertaken to characterize the response profile of lung interstitial lymphocyte natural killer (LLNK) activity to various biological response modifiers (BRM) in vitro after short term incubation (18h). the presented data show that treatment of lung lymphocytes with human recombinant interleukin 2 (rlL-2), purified rat interferon alpha/beta (IFN-α/s), or murine recombinant tumor necrosis factor alpha (rTNF-α) resulted in a dose-dependent increase in LLNK activity. the maximum stimulation was similar for rlL-2 and IFN-α/s, although a much higher concentration of IFN-α/s was required to reach this level of stimulation. the maximum response to rTNF-α treatment was about half that seen with rlL-2 or IFN-α/s and it, too, required a high concentration. ...
TL;DR: Cultures containing AmB and murine peritoneal macrophages showed synergistic anticryptococcal activity and the antifungal activity was associated with AmB-stimulated macrophage cultures and with their culture supernatants.
Abstract: Amphotericin B (AmB) and its methyl ester derivative (AME) are immunoadjuvants with macrophage stimulating properties. Cultures containing AmB and murine peritoneal macrophages showed synergistic anticryptococcal activity. The antifungal activity was associated with AmB-stimulated macrophages and with their culture supernatants. Photoinactivation of the residual AmB in the macrophage culture supernatant did not result in the loss of antifungal activity. AmB-stimulated macrophage culture supernatants inhibited the growth of C. neoformans in a dose responsive manner and the activity was destroyed by incubation at 100 degrees C but not at 60 degrees C.
TL;DR: The results suggest that previously observed increases in anti-microbial action by M phi from DMN-exposed animals are due in-part to enhanced ROI production.
Abstract: Previous results demonstrated that mice exposed in vivo to DMN were more resistant to both bacterial and tumor challenges. Furthermore, macrophages (M phi) isolated from these animals demonstrated increased functional properties. As reactive oxygen intermediates (ROI) represent a key mechanism of anti-microbial action, it was important to determine whether ROI levels in M phi were related to augmented anti-microbial action in animals exposed to DMN in vivo. Peritoneal exudate M phi elicited with either thioglycollate (TG), Con A or C. parvum (CP) were examined for the production of ROIs. TG-M phi, Con A-M phi and CP-M phi obtained from animals exposed to DMN showed increased superoxide anion (O2-) production in vitro following stimulation with either phorbol myristate acetate (PMA) or opsonized zymosan (Op-zym) when compared to vehicle M phi. ROI production by bone marrow-derived macrophages (BMDM) produced by either GM-CSF or CSF-1 was also determined. BMDM from DMN-exposed animals obtained using either growth factor, had increased ROI production at 3, 5, 7 and 9 d of culture compared to vehicle BMDM. There was no shift in the kinetics of ROI production during differentiation of these BMDM. Analysis of extracellular anti-listericidal activity of TG- and CA-elicited M phi demonstrated that only TG-M phi obtained from DMN-exposed animals had enhanced killing capacity. There were no differences in intracellular anti-microbial activity in TG- and CA-elicited M phi obtained from either vehicle or DMN-exposed animals. TG-elicited M phi from either vehicle or DMN-exposed animals were examined for anti-microbial activity and H2O2 production following in vitro exposure to PMA. M phi from both vehicle and DMN treatment groups had enhanced killing and H2O2 production following PMA treatment, while PMA-stimulated TG-M phi from DMN-exposed animals demonstrated significantly higher levels of H2O2 production and cell killing as compared to all other treatment groups. These results suggest that previously observed increases in anti-microbial action by M phi from DMN-exposed animals are due in-part to enhanced ROI production.
TL;DR: The effects on chemotaxis and NADPH oxidase appear to be reversible and not due to metabolic transformation of the dihydrofolate reductase inhibitor.
Abstract: The effect of the dihydrofolate reductase inhibitor 10-deazaaminopterin on several neutrophil functions was tested in vitro. At 100 uM it inhibited chemotaxis by 50% and reduced the generation of superoxide by 30%. It had no influence on phagocytosis and did not significantly change the secretion of s-D-glucuronidase, a marker enzyme of degranulation. After preincubation of white cells with various concentrations of 10-deazaaminopterin, followed by resuspension in drug-free medium, no inhibition of chemotaxis or superoxide generation was seen. Therefore, the effects on chemotaxis and NADPH oxidase appear to be reversible and not due to metabolic transformation of the dihydrofolate reductase inhibitor.
TL;DR: Data suggest that BCR enhances 3MC-induced tumorigenesis, and is apparently not mediated by suppression of the immune system since BCR-treated rats had selectively enhanced immune function.
Abstract: Seven-week-old male Sprague-Dawley rats were given a single injection of 1.5 mg of 3–methylcholanthrene (3MC) to induce in situ fibrosarcomas. the rats were also treated with the dopamine agonist bromocriptine (BCR) from two days prior to 14 days after 3MC treatment and again for 14 consecutive days beginning at week 5. Tumor incidence was markedly increased and latency decreased in BCR-3MC rats compared to 3MC controls. Natural killer (NK) cell cytotoxicity responses and production of interleukin 2 (IL2) was enhanced at two weeks in rats treated with only BCR. Natural killer cell activity was suppressed at two weeks in rats treated with only 3MC. This effect was reversed by BCR treatment. Rats treated with 3MC and BCR had suppressed NK cell responses and production of IL2 and interferon-γ (IFN) at 12 weeks.In another study, rats injected with 1, 3 or 5 mg/kg BCR for 14 consecutive days had increased NK cell activity and IL2 production at all doses and increased IFN production at the two high dose...
TL;DR: It is thought that SA3443 may assist in the elimination of hepatitis viruses from the liver in patients with chronic active hepatitis, by the activation of NK and/or CTL activities.
Abstract: (4R)-Hexahydro-7, 7–dimethyl-6–oxo-1, 2, 5–dithiazocine-4–carboxylic acid (SA3443) is a newly synthesized cyclic disulfide compound which offers potential hepatoprotective properties.The effect of SA3443 on the induction of natural killer (NK) and cytotoxic T lymphocyte (CTL) activities was investigated. NK activity in BALB/c mice splenic cells was investigated using YAC-1 cells as target cells. SA3443, at a dose range of 30–300 mg/kg/day, augmented NK activity significantly when administered orally once daily for 4 days before the assay. Alloantigen-specific CTL activity in splenic cells from BALB/c mice was detected 9 days after sensitization with C57BL/6 mice splenic cells. SA3443, at a dose of 100 mg/kg/day, augmented CTL activity significantly when administered orally, once daily for 4 days beginning after the sensitization and for 2 days before the assay, while a high dose of SA3443, at 300mg/kg, suppressed CTL activity.From these results, it is thought that SA3443 may assist in the eliminat...
TL;DR: NFS60, a murine leukemia cell line, responds to both interleukin 3 and 6 by proliferating, apparently by different signal transduction pathways, and the effect of various arachidonic acid metabolites on the response to cytokine was different.
Abstract: NFS60, a murine leukemia cell line, responds to both interleukin 3 and 6 by proliferating, apparently by different signal transduction pathways. Although stimulation by both cytokines increases the uptake of 3H-arachidonic acid, the response to IL-6 was much faster. Furthermore, the effect of various arachidonic acid metabolites on the response to cytokine was different. PGE2 inhibited IL-6-induced proliferation and potentiated the response to IL-3. Additionally the G proteins which coupled the IL-3 and IL-6 receptor to the proliferative response are probably different, based on the ability of cholera toxin to inhibit the IL-3 but not the IL-6 response. These data are evidence of two pathways of signal transduction.
TL;DR: It is observed that in vitro treatment of macrophages with cisplatin, rIFN-gamma and LPS show increased activity of the protein kinase-C (PK-C), which suggests that this activation is energy dependent.
Abstract: A single i.p. injection of cisplatin (10 mg/kg body weight) into mice results in a significant increase in chemiluminescence and ATP contents of the peritoneal exudate cells (PEC) than that of PEC from untreated mice. It is also observed that in vitro treatment of macrophages with cisplatin, rIFN-gamma and LPS show increased activity of the protein kinase-C (PK-C). The activation of PK-C could result in stimulation of NADPH-oxidase resulting in increased levels of chemiluminescence. Increased contents of ATP in PEC after cisplatin treatment also suggests that this activation is energy dependent.
TL;DR: The difference between the action of mechloretamine and levamisole used in immunostimulating doses on the increased anti-SRBC antibodies or on the E-rosette forming lymphocytes was revealed.
Abstract: The effect of the following doses of mechloretamine: 1, 5, 10, 25, 50, 100, 250 and 500 μg/kg on the immunological response in mice immunized with sheep red blood cells (SRBC) was investigated. the number of plaque forming cells (PFC) to SRBC, the serum hemagglutinins level and the number of lymphocytes forming E or EAC-rosettes were determined. Depending on mechloretamine dose the following effects on the tested parameters were obtained : (i) only stimulating -1 and 5 pg/kg, (ii) stimulating or suppressive according to the test -10–100 pg/kg, (iii) only suppressive -250 and 500 μg/kg. Mechloretamine (5 μg/kg) induced the increase in PFC in comparison with levamisole (2 mg/kg). the difference between the action of mechloretamine and levamisole used in immunostimulating doses on the increased anti-SKBC antibodies or on the E-rosette forming lymphocytes was revealed.
TL;DR: Exogenous PGE2 strongly inhibits the response of human lymphocyte cultures to SRBC and indomethacin, which inhibits in this system lymphocyte endogenous P GE2 synthesis increases the in vitro immune response.
Abstract: Exogenous PGE2 strongly inhibits the response of human lymphocyte cultures to SRBC. This effect is mediated through a T cell inhibition since non-T cells are not significantly affected. Indomethacin, which inhibits in this system lymphocyte endogenous PGE2 synthesis increases the in vitro immune response. the effect of indomethacin is overcame by exogenous PGE2. These data may be relevant for explaining the immunomodulatory role of PGE2 following antigen challenge.