Showing papers in "Immunopharmacology and Immunotoxicology in 1989"
TL;DR: The data indicate that TNF plays a central role in the phenomenon of the enhanced susceptibility of animals to endotoxin after exposure to lead, caused by an enhanced susceptibility to TNF and possibly by a prolonged exposure to a higher level of TNF.
Abstract: Heavy metals administered to animals, at doses which appear relatively innoxious by themselves, enhance susceptibility to endotoxin. The mechanisms which underly this phenomenon are not yet fully understood. In this study we investigated the role of the cytokine Tumour Necrosis Factor (TNF), an important mediator of the effects of endotoxin, in this phenomenon. First it was studied whether lead enhances sensitivity of mice to endotoxin and to TNF. Lead appeared to enhance sensitivity to both endotoxin and TNF resulting in mortality of mice at low endotoxin and TNF doses. Next we studied the influence of lead on serum TNF levels after stimulation by endotoxin. Lead treated mice showed lower TNF blood levels two hours after injection of endotoxin and lead. Six and eight hours after injection TNF levels of lead treated mice were higher compared to those of mice injected with endotoxin only. In the last part of our investigation, we studied the influence of a monoclonal hamster anti TNF antibody on the effect of combined lead-endotoxin exposure. Administration of the antibody prevents lethality completely. Our data indicate that TNF plays a central role in the phenomenon of the enhanced susceptibility of animals to endotoxin after exposure to lead. The enhanced susceptibility to endotoxin is caused by an enhanced susceptibility to TNF and possibly by a prolonged exposure to a higher level of TNF.
42 citations
TL;DR: Results demonstrate that Broncho-Vaxom is an immunomodulator affecting multiple immunological mechanisms including the activation of natural killer cells, of monocytes and of T cells through direct mechanisms or through the cytokine cascade.
Abstract: Broncho-Vaxon (OM-85 BV) is a bacterial extract of eight bacterias usually involved in the respiratory tract infections. Since Broncho-Vaxom is clinically active in decreasing the incidence of such infections, its immunological effect was investigated, in vitro, using peripheral blood mononuclear cells (PBMC). The experimental data indicate that Broncho-Vaxom can modulate various immune functions. It was shown, using a radioimmunoassay for these cytokines, that Broncho-Vaxom will spontaneously enhance TNF alpha and IL-2 production whereas it has no action on IF gamma production. However, when the PBMC are stimulated with PHA, an increased production for IF gamma, TNF alpha and IL-2 was observed suggesting that, under appropriate conditions, Broncho-Vaxom enhances the production of these cytokines. In other experiments, Broncho-Vaxom was shown to markedly increase the natural killer activity of PBMC. All these results demonstrate that Broncho-Vaxom is an immunomodulator affecting multiple immunological mechanisms including the activation of natural killer cells, of monocytes and of T cells through direct mechanisms or through the cytokine cascade.
41 citations
TL;DR: The in vitro effect of X-ray irradiation on the human natural killer (NK) system was studied and the possible use of low doses ofX-rays in combination with biological response modifiers for treatment of cancer is suggested.
Abstract: The in vitro effect of X-ray irradiation on the human natural killer (NK) system was studied. When K562 cells were irradiated with X-rays and cultured for 18 hours, they showed increased sensitivity to lysis by blood lymphocytes and purified large granular lymphocytes (LGL). The X-ray-induced augmentation was observed as little as 2 Gy irradiation, reaching maximum at 5 to 20 Gy. The doses of X-rays did not influence the viability and spontaneous release of the target cells. On the other hand, irradiation with X-rays of NK cells at 5 to 15 Gy resulted in a transient increase in NK activity at 1 hour, and then the activity declined and was completely lost after 24 hours. However, when LGL were cultured with interferon immediately after irradiation, they maintained elevated NK activity. These results suggest the possible use of low doses of X-ray irradiation in combination with biological response modifiers for treatment of cancer.
36 citations
TL;DR: The data indicate that wortmannin inhibits immune function in rats and mice and suggest that metabolic modification of the toxin is necessary for toxicity.
Abstract: In order to assess the effects of the fungal toxin wortmannin on the immune system, rats and mice were fed wortmannin-containing cultures of Fusarium oxysporum for 1 or 2 weeks. Wortmannin caused significant decreases in thymic weight, thymic lymphocyte numbers, serum IgG and IgM levels, the primary humoral response to T-dependent and T-independent antigens and the proliferative response of spleen cells to pokeweed mitogen. In vitro administration of wortmannin did not produce evidence of cytotoxicity to spleen or thymus cells. The data indicate that wortmannin inhibits immune function in rats and mice and suggest that metabolic modification of the toxin is necessary for toxicity.
34 citations
TL;DR: The measurement of pulmonary natural killer activity was evaluated as a method to assess pulmonary immunocompetence and whether exposure to phosgene resulted in local pulmonary or systemic immune dysfunction, both of which are important to evaluate systemic immune functions.
Abstract: Phosgene, also known as carbonyl chloride, carbon oxychloride, and chloroformyl chloride, is a toxic air pollutant and a potential occupational health hazard Studies were initiated (a) to evaluate the measurement of pulmonary natural killer (NK) activity as a method to assess pulmonary immunocompetence, and (b) to determine whether exposure to phosgene resulted in local pulmonary or systemic immune dysfunction Fischer-344 male rats were exposed either to filtered air or to 10 ppm phosgene gas for four hours The effect of phosgene on lung NK activity was quantified at different times after acute phosgene exposure Pulmonary NK activity was measured by mincing lung tissue into small pieces prior to incubation with collagenase Whole-lung homogenate was assayed for NK activity utilizing a 4 hour 51-Cr-release assay with YAC-1 cells as target cells Acute phosgene exposure resulted in a suppressed pulmonary NK activity on days 1, 2, and 4 after exposure; however, normal levels of biological activi
29 citations
TL;DR: Results of this study indicated that continuous ozone exposure for 1, 5, or 7 days resulted in a significant decrease in pulmonary NK activity, and the suppressed pulmonary NK response was thus attenuated and returned to normal values in the continued presence of ozone gas.
Abstract: Ozone is an oxidant gas and an ubiquitous oxidant air pollutant with the potential to adversely affect pulmonary immune function with a consequent increase in disease susceptibility. Pulmonary natural killer (NK) activity was measured in order to assess the pulmonary immunotoxicity of continuous ozone exposure. Continuous ozone exposures at 1.0 ppm were performed for 23.5 hours per day for either 1, 5, 7, or 10 consecutive days. Pulmonary immune function was assessed by measuring natural killer (NK) activity from whole-lung homogenates of male Fischer-344 rats. Results of this study indicated that continuous ozone exposure for 1, 5, or 7 days resulted in a significant decrease in pulmonary NK activity. This suppressed pulmonary NK activity returned to control levels after continuous exposure to ozone for 10 days. The suppressed pulmonary NK response was thus attenuated and returned to normal values in the continued presence of ozone gas. This attenuation process is dynamic, complex, and doubtless ...
29 citations
TL;DR: The effect of a benzodiazepine (BDZ), diazepam on human polymorphonuclear cell (PMN) and monocyte phagocytosis and killing from healthy volunteers and in vitro both functions exerted by PMN and monocytes are evaluated.
Abstract: The effect of a benzodiazepine (BDZ), diazepam on human polymorphonuclear cell (PMN) and monocyte pha gocytosis and killing from healthy volunteers has been evaluated. Diazepam is able to inhibit in vitro both functions exerted by PMN and monocytes at 10−5 and 10−6 M concentrations/ 4 × 106 phagocytes. 10−7 M con centration was not effective in all the instances.These results are discussed for their possible clinical implications, since previous studies have shown that in patients with phobic disorder there is evidence for reduced phagocytosis and killing capacities.
25 citations
TL;DR: It is suggested that CGRP inhibits NK cell activity by increasing the intracellular cyclic AMP concentration and may be implicated in the regulation of NK function.
Abstract: The effect of calcitonin gene-related peptide (CGRP) on natural killer (NK) cell activity in spleen cells from Ba1b/c mice and nude mice was studied. CGRP dose-dependently (10 to 10 M) inhibited NK activity of spleen cells from both strains of mice. This inhibitory effect was observed at the effector to target ratios of 12.5:1 to 100:1. Maximum inhibition by 10−7 M CGRP was about 60 %. The inhibition of NK activity by CGRP was also observed in anti-Thy 1.2 plus complement treated Ba1b/c spleen cells. Furthermore, when cells were treated with 10 to 10−7 M CGRP the concentration of intracellular cyclic AMP increased in spleen cells of nude mice. The characteristics of these cells were similiar to those of NK cells, (1) being petri dish and nylon wool nonadherent, (2) expressing asialo GM1 antigen, and (3) lacking readily detectable Thy 1 antigen and immunoglobulin. In addition, the intravenous injection of asialo GM1 completely abolished NK activity in spleen cells from nude mice and the increase in...
24 citations
TL;DR: Results of this study have shown that treatment with recombinant human interleukin-2 induced increased cellular TNF activity in lymphoid organs and this activity was abrogated by an anti-TNF antibody.
Abstract: Interleukin-2 has been tested as an anti-cancer agent, either alone or in combination with immune cells, but severe dose limiting adverse toxic effects have been observed. Because the pathogenesis c the toxicity has remained uncharacterized, it has not been possible to determine whether the therapeutic and the toxic events could be separated. We have examined immunopharmacologic regulation of IL2 induced mediator induction and toxicity syndrome and have compared this data with our earlier information on IL2 enhancement of immune function in murine systems. The results of this study have shown that treatment with recombinant human interleukin-2 induced increased cellular TNF activity in lymphoid organs and this activity was abrogated by an anti-TNF antibody. Additionally, continuous daily treatment with interleukin-2 also induced increases in serum corticosterone but no detectable increases in serum IL1 or TNF. The increases in serum corticosterone occured later in the treatment process and coincid...
19 citations
TL;DR: The effects of arecoline on lymphoid organs, which may be due to its direct action or through the elevation of corticosterone, are demonstrated.
Abstract: Arecoline, a suspected carcinogenic/cocarcinogenic alkaloid was screened to explore in detail its immunomodulatory influence in murine model system. The oral LD50 value for male mice was 371 mg/kg bw whereas it was 309 mg/kg bw for female mice. The subcutaneous LD50 value for both sexes was 97 mg/kg bw. Only a marginal difference was observed in intraperitoneal LD50 values between male (120 mg/kg bw) and female (109 mg/kg bw) mice. Arecoline was administered subcutaneously to male mice at subtoxic dose levels (5, 10, and 20 mg/kg bw) for 1, 2 and 3 weeks on a daily basis. In groups where significant decreases in body weight were present (at 20 mg/kg bw for both sexes), reductions in thymus weight were also noted. Spleen, mesenteric lymph nodes (MLN), liver, and kidney showed moderate reductions in their weights. Histopathological effects at 20 mg/kg bw included lymphocyte depletion of the thymic cortex, and the B and T lymphocyte areas in spleen and MLN. In concordance with the zona fasciculate hy...
15 citations
TL;DR: Angiotensin II or its breakdown products modulate the production of monocyte cAMP in spite of the inability to demonstrate classical cell surface receptors.
Abstract: Serum angiotensin converting enzyme activity is elevated in certain human granulomatous diseases. Angiotensin II modestly suppresses thymidine incorporation and augments gamma interferon production from human blood mononuclear cells. This suggests that angiotensin II may play an immunoregulatory role in human granulomatous inflammation. For this reason, the binding of angiotensin II to human peripheral blood mixed mononuclear cells, and to the human monocyte-like cell line, U-937, was studied. Angiotensin II binding to U-937 cells reveals a low level of saturable specific binding (Kd = 3 x 10(-10) M). However, binding to human cells is not easily reversible and is poorly inhibited in a competitive manner. In addition, the molecular integrity of the radioligand is not maintained following binding. Therefore, the definition of classical receptor binding cannot be fulfilled. Since binding is decreased by low temperatures and various metabolic inhibitors, it appears likely that endocytosis occurs, perhaps along with receptor binding. Angiotensin II or its breakdown products modulate the production of monocyte cAMP in spite of the inability to demonstrate classical cell surface receptors.
TL;DR: The peripheral blood lymphocytes, serum immunoglobulins, C3 and C4 complement protein concentrations of 20 patients with idiopathic epilepsy who were receiving phenytoin were examined and compared with 30 healthy controls in order to obtain a detailed profile of the effects of the drug on the humoral and cellular immune systems.
Abstract: The peripheral blood lymphocytes, serum immunoglobulins, C3 and C4 complement protein concentrations of 20 patients with idiopathic epilepsy who were receiving phenytoin were examined and compared with 30 healthy controls in order to obtain a detailed profile of the effects of the drug on the humoral and cellular immune systems. The T-lymphocyte subsets were identified using monoclonal antibodies. A significant decrease in suppressor T-cells (p<0.05) and an increase in the ratio of T-helper to T-suppressor lymphocytes (p<0.01) have been found. Furthermore, an increase in B-lymphocytes (p<0.01) and a significant rise in serum Ig M concentrations (p<0.05) have been observed. No significant changes in serum concentrations of Ig G, Ig A and complement proteins were detected.
TL;DR: It is concluded that ascorbic acid supplementation might partially restore peripheral, monocyte function and help the monocyte-macrophage system to mount an effective immune response against chronicity of brucella infection.
Abstract: In 14 patients suffering from relapsing chronic brucellosis who were anergic to brucella antigens, we have studied peripheral blood monocyte random migration and chemotaxis against non-specific and specific leukoattractants, as well as plasma and monocyte ascorbic acid levels.We found that all parameters studied, were significantly beneath normal, when compared to normal subjects.After the oral administration of ascorbic acid at a daily dose of 1gr for 15 conseguetive days, random and directed migration against a non-specific stimulus (casein)returned to normal. Directed migration against disease associated leukoattractants (brucella melitensis and brucella abortus) antigens improved significantly, without reaching normal values.We concluded that ascorbic acid supplementation might partially restore peripheral, monocyte function and help the monocyte-macrophage system to mount an effective immune response against chronicity of brucella infection.
TL;DR: During 90 days of elimination diet nineteen children with food allergy manifesting atopic dermatitis were treated with either 120 mg/day of thymomodulin or placebo in a double blind design, showing an increase in total and specific IgE serum levels, which decreased only in the group receiving the thymic derivative.
Abstract: During 90 days of elimination diet nineteen children with food allergy manifesting atopic dermatitis were treated with either 120 mg/day of thymomodulin (10 subjects) or placebo (9 subjects) in a double blind design. After this period an improvement in skin lesions was observed in both groups. Subsequently a food challenge was performed for two weeks: in the group treated with thymomodulin skin lesions did not modify while they worsened in the placebo group and the comparison was statistically significant (p less than 0.01). Before the beginning of the trial laboratory assessments evidenced an increase in total and specific IgE serum levels, which decreased by the end of the study only in the group receiving the thymic derivative (p less than 0.05).
TL;DR: The augmentation of resistance against Listeria monocytogenes after an intraperitoneal administration of shosaiko-to in mice was shown to depend on the time interval between the treatment and the infection.
Abstract: The augmentation of resistance against Listeria monocytogenes after an intraperitoneal (ip) administration of shosaiko-to in mice was shown to depend on the time interval between the treatment and the infection A maximal effect was expressed in mice treated 4 days before ip infection The time dependent resistance correlated to the accumulation of macrophages in the peritoneal cavity just before the infection, but not to bactericidal activity as judged by the fact that peritoneal macrophages from untreated mice and those from mice treated with shosaiko-to 4 days before showed a high bactericidal activity of the same degree Resistance to the infection in untreated mice may be attributable to newly accumulating macrophages with a low level of bactericidal activity, but not to resident macrophages with a high level of the activity After intravenous infection, on the other hand, a maximal effect was expressed in mice treated with shosaiko-to 2 days before The resistance correlated to accumulation of macrophages and bactericidal activity in the spleen just before the infection Participation of cytokines in an augmenting effect of shosaiko-to on protection against the infection was examined Shosaiko-to induced a transient elevation of serum CSF activity that was maximal at 3 hours after the administration in uninfected mice, though it did not augment the CSF activity induced by the infection The elevation of CSF activity may induce accumulation of macrophages with a high level of bactericidal activity in the spleen 2 days after administration of shosaiko-to and then in the peritoneal cavity 4 days after administration IFN-gamma and TNF-alpha did not participate in the effect because administration of anti-IFN-gamma or anti-TNF-alpha just before administration of shosaiko-to or just before infection did not abrogate the inhibitory effect of shosaiko-to on the bacterial growth in the early stage of infection Shosaiko-to also induced an increase of CFUm number in the spleen The effect may contribute to the augmentation of resistance in the late stage of infection by differentiating to mature macrophages
TL;DR: X-ray irradiation elevates the target sensitivity to NKCF, which may be involved in the increased NK sensitivity, and that the X-ray effect may be different from that of UV radiation or DNA synthesis inhibition.
Abstract: Irradiation with low-doses of X-rays of tumor cells elevated their susceptibility to lysis by natural killer (NK) cells in an accompanying paper. Cytotoxicity assays conducted at the single cell level revealed that X-ray irradiation of K562 cells did not affect the number of effector-target conjugates but increased the frequency of dead conjugated target cells. During interaction with K562 cells large granular lymphocytes released a soluble cytotoxic factor (NKCF) that killed the target cells. X-ray irradiation did not affect the NKCF stimulatory ability of K562 cells, while it elevated their sensitivity to the lytic effect of NKCF. In contrast to X-rays, exposure to ultraviolet (UV) radiation of K562 cells did not elevate their NK sensitivity but rather reduced it. Treatment with mitomycin C produced no effect on NK sensitivity. These results indicate that X-ray irradiation elevates the target sensitivity to NKCF, which may be involved in the increased NK sensitivity, and that the X-ray effect may be different from that of UV radiation or DNA synthesis inhibition.
TL;DR: Results reveal-beside efficacy of levamisole as immunoregulant in schistosome immunity--a possible role for the granuloma as a T-cell mediated response in maintenance of immunity.
Abstract: Mice infected for 45 days with 120 Schistosoma mansoni cercariae and treated with levamisole (25 mg/kg subcutaneously) have more efficient acquired immunity when challenged with 240 Schistosoma mansoni cercariae the same day of treatment (97.7% # 87.7% in infected challenged controls). In praziquantel-treated mice (500 mg/kg for 2 days orally), the reduction in the percent resistance (45.5%) was accompanied by a significant diminution in the size of granuloma, delayed foot pad swelling and granuloma proportionate T-helper cells number. Levamisole when given two weeks post praziquantel treatment and with the challenge infection increased the percent resistance to 79.2%. The increase in percent resistance recorded in mice receiving both praziquantel and levamisole was accompanied by restoration of granuloma size, delayed foot pad swelling and granuloma proportionate T-helper cells number to infected challenged untreated control values. Results reveal-beside efficacy of levamisole as immunoregulant i...
TL;DR: The PGE2 inhibition on immunoglobulin synthesis in PWM-stimulated cultures seems to be mediated by a complex effect on both the T cell subsets.
Abstract: It is shown that a short incubation of peripheral human lymphocytes with PGE2 is able to reduce the B cell differentiation induced by PWM. The target of PGE2 action appears to belong to T lymphocytes, since the treatment of non-T cells is uneffective in reducing the immune response. Both OKT4+ and OKT8+ subsets are sensitive to PGE2. Data concerning the role of endogenous as well as exogenous PGE2 either on unfractionated or fractionated OKT4+, OKT8+ and non-T lymphocytes are also discussed. The PGE2 -inhibition on immunoglobulin synthesis in PWM-stimulated cultures seems to be mediated by a complex effect on both the T cell subsets.
TL;DR: The ability of EL-4 thymoma cells to produce interleukin-2 (IL-2) following exposure to phorbol-12-myristate 13-acetate (PMA) and Concanavalin A (Con A) has been studied in vitro using medium containing either 10% or 1% fetal calf serum (FCS).
Abstract: The ability of EL-4 thymoma cells to produce interleukin-2 (IL-2) following exposure to phorbol-12-myristate 13-acetate (PMA) and Concanavalin A (Con A) has been studied in vitro using medium containing either 10% or 1% fetal calf serum (FCS). The potent stimulatory effect of PMA on IL-2 production by EL-4 cells has been confirmed by measuring 3H-thymidine incorporation by the IL-2-dependent T cell line, CTLL-2, in the presence of conditioned medium (CM) from stimulated cultures. EL-4 cells produced several times more IL-2 when cultured in medium containing 10% FCS than when only 1% FCS was present. Added together, PMA and Con A acted synergistically in some EL-4 cell cultures. The ability of E:-4 cells to produce IL-2 was maintained after further incubation without stimulants. CM with IL-2 activity from stimulated EL-4 cells could prove useful in immunotoxicity testing.
TL;DR: The objective of the present review is to compare and evaluate the cell injury process induced by effector lymphocytes with that caused by low temperature, which mimics most, if not all, the currently known criteria of immune effector cell mediated injury of target tumor cells.
Abstract: Various forms of cellular injury, whether induced by immune effector cells, aberrant metabolic processes, chemotherapeutic drugs or temperature shifts, result in common morphological changes consisting of the formation and shedding of membrane vesicles from the injured cell surfaces. This dynamic cell surface membrane behavior appears to be dependent on the disruption of cytoplasmic microtubules. Concommitant with the altered cell surface morphology certain physiological and biochemical events have been found to be associated with cell injury. These include changes in membrane permeability, elevated oxygen consumption rates and nuclear DNA fragmentation. However, it remains to be experimentally established which of these biological changes defines a state of irreparable cell injury.The objective of the present review is to compare and evaluate the cell injury process induced by effector lymphocytes with that caused by low temperature. The latter mimics most, if not all, the currently known criteri...
TL;DR: ISO can be a potential immunomodulator of suppressed immune function following thermal injury, particularly in patients whose lymphocyte responses to T cell mitogen Con-A are not completely suppressed.
Abstract: The effect of in vivo administration of Isoprinosine (ISO) on, i) the proliferation of splenic lymphocytes in response to the T-cell mitogen, concanavalin-A (Con-A) and, ii) the natural killer (NK) cell cytotoxicity was studied following a full skin thickness burn injury in a rat model. Administration of ISO (100 mg/kg body wt/day) twice daily, resulted in significant augmentation of the proliferative responses of lymphocytes compared to non-treated burned animals, at 7 days post injury. However, it did not effect the lymphoproliferation at 14 days post injury, the time period at which a complete suppression of lymphocyte proliferation was observed in burned non-treated animals. Also, the proliferation of lymphocytes from normal nonburned animals was not affected by treatment with ISO. ISO treatment of the burned animals resulted in a significant increase in the NK cytotoxicity compared to non-treated burned animals. As with Con-A responses, ISO administered to control nonburned animals did not ha...
TL;DR: The results confirm part of previously reported findings concerning the involvement of vitamin B- in immune processes and showed the direct relation between the concentration of deoxypyridoxine and the degree of DNA synthesis' inhibition with subsequent lymphocyte proliferation.
Abstract: We studied the effect of pyridoxine deficiency state on the responses of human lymphocytes to certain mitogenic factors. Deoxypyridoxine (DB6), a potent pyridoxine antagonist, considerably inhibited Bromodeoxyuridine (BrdU) incorporation into the newly synthesized DNA of lymphocytes cultured with Phytohemagglutinin (PHA) and Concanavalin A (Con A) in separate sets of experiments. The addition of deoxypyridoxine simultaneously with or few hours prior to initiation of cell cultures did not significantly alter the inhibitory action of deoxypyridoxine. Titration studies of deoxypyridoxine showed the direct relation between the concentration of deoxypyridoxine and the degree of DNA synthesis inhibition with subsequent lymphocyte proliferation. The results obtained with monoclonal antibody (anti-BrdU) studies were further confirmed with tritiated thymidine incorporation (3H Thymidine) studies. Addition of pyridoxine concurrently with the addition of DB6 or 8 hours later than initiation of lymphocyte inc...
TL;DR: Results indicate that 5-HT sensitive Ca++ dependent K+ channels are likely to be involved in the delivery of lytic signal(s) by immune effector lymphocytes and suggests that neuroendocrine products may modulate the functional activity of in vivo derived lymphocytes.
Abstract: Potassium channel activity has been implicated in the lytic function of cloned murine effector T lymphocytes (5) and human NK cells (12) as well as in the initiation of the injury process in tumor cells (23). In the present studies, the effects of various K+ channel blockers on the cytolytic function of in vivo derived alloimmune lymphocytes towards P815 tumor cells were evaluated. The classical K+ channel blocker 4-aminopyridine (4-AP), the naturally occurring monoamine serotonin (5-hydroxytryptamine, 5-HT) and its agonist, quipazine, as well as the Ca++ dependent K+ channel blocker quinidine were chosen for investigation based on their known ion channel gating properties. These agents, when present in the assay medium, inhibited in a dose dependent manner the lysis of P815 tumor cells as measured by specific 51Cr release. Preincubation of effector lymphocytes with the various K+ channel blockers resulted in greater inhibition of lysis than did the preincubation of target cells. The 5-HT agonist ...
TL;DR: In four ovarian cancer patients with malignant ascites, the priming administration of OK-432 can induce both intraperitoneal macrophages and peripheral blood monocytes into a primed state, and the triggering administration ofOK- 432 can increase the number of intra peritoneal Ok-432-primed macrophage and induce TNF release from these cells.
Abstract: In four ovarian cancer patients with malignant ascites, 10 KE of OK-432 was intraperitoneally administered four times every other day for priming, and 40 KE of OK-432 in a single dose by the same route on day 13 for triggering. The changes in peripheral blood monocytes and intraperitoneal macrophages and the production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMC) and ascitic lymphoid cells (ALC) were examined. In two of the four patients in whom TNF was induced in the ascites, the TNF production by PBMC and ALC was noted during priming, and after triggering, an increase in both the number of intraperitoneal macrophages and the TNF production by ALC was noted. In two other patients in whom TNF was not detected in the ascites, the ratio of intraperitoneal macrophages to ALC did not change throughout the whole period, and the TNF production by ALC was not augmented. These findings suggest that the priming administration of OK-432 can induce both intraperitoneal macropha...
TL;DR: The mechanism of human interleukin (IL)-1 beta-mediated cytolysis was studied in a human melanoma cell line, A375.6, and this model may be useful for delineating intracellular biochemical events integral to IL-1 action.
Abstract: The mechanism of human interleukin (IL)-1 β-mediated cytolysis was studied in a human melanoma cell line, A375.6. Purified recombinant human IL-1β produced 50% cytocidal activity at 50 pg/ml. A variety of compounds were tested for their ability to interfere with A375.6 lysis. Compounds were added simultaneously with IL-1β (100 pg/ml), and tumor cytolysis was measured after 72 hr of culture by release of 125I from DNA of A375.6 cells labeled with [125I]-dUrd. A variety of antiinflammatory/immunosuppressive agents (including auranofin, chloroquine, cyclosporin A, d-penicillamine) and several cyclo-oxygenase/lipoxygenase inhibitors (AA-861, BW755c, and indomethacin) lacked protective activity. Similarly, phospholipase inhibitors (mepacrine and 4-bromophenacyl bromide), putrescine, inhibitors of lysosomal activity (chloroquine and NH4CI), calcium channel blockers (nifedipine and verapamil), calmodulin inhibitors (W-7 and calmidazolium), and inhibitors of ADP ribosylation (nicotinamide and 3-aminobenza...
TL;DR: Treatment with corticosteroids and ATG produces long-term enhanced suppressor activity, a finding which suggests that treatment with combination ATG and Prednisone is a rational form of immunomodulation in conditions associated with decreased suppressor function.
Abstract: Corticosteroids and anti-thymocyte globulin (ATG) have been extensively used in the treatment of autoimmune diseases, aplastic anemia and organ graft rejection; nonetheless, the precise mechanisms of action of these agents are unknown. Studies of their long term immunoregulatory effects, particularly in humans, have been limited. We examined the long term effects of therapy with ATG given for 2-4 weeks and prednisone for 2 months in 4 patients with newly diagnosed insulin dependent diabetes (IDD). Three matched newly-diagnosed untreated IDD patients and 17 healthy volunteers served as controls. No differences in total lymphocyte count, percentage of B cells, percentage of total T cells (CD3), helper-inducer T cells (CD4) or cytotoxic-suppressor cells (CD8), lymphocyte blastogenesis assays, or pokeweed mitogen-induced IgG secretion in T & B cell co-cultures were detected before therapy. A transient lymphopenia following ATG administration was the only immunological defect found in the first month of therapy. At 2 months, however, patients treated with ATG and prednisone had diminished immunoregulatory T cell function demonstrated by production of only 28 +/- 3% IgG expected in T & B co-culture, compared to 205 +/- 35% for untreated IDD patients and 107 +/- 13% for normals (p less than 0.01). This diminished IgG production resulted from excessive suppressor function, since co-cultures of T cells from treated patients with T and B cells from normal volunteers suppressed the latter's IgG production by 76 +/- 9%. This enhanced suppressor activity persisted for 3-6 months following therapy. Other immunological functions were not statistically different from those present at the inception of the study. Thus, treatment with corticosteroids and ATG produces long-term enhanced suppressor activity, a finding which suggests that treatment with combination ATG and Prednisone is a rational form of immunomodulation in conditions associated with decreased suppressor function.
TL;DR: It is demonstrated that K+ ion channels are involved in the LAK cell cytolytic process and that compounds, including neuroendocrine products, which modulate K- ion channel function are capable of modulating the lytic activity of these effector cells.
Abstract: Cells of the immune system possess K+ ion channels which have been implicated in various cellular functions including activation, differentiation and cytolytic function. To define the role of K+ ion channels in the lytic function of lymphokine-activated killer (LAK) cells, we investigated the effects of K+ channel blockers on their cytolytic activity. Results show that when LAK cell mediated cytolysis of AKIL-20 tumor cexis was carried out in the presence of: a) the K+ channel blocker, 4-aminopyridine (4-AP); b) the monoamine, serotonin (5-hydroxytryptamine; 5-HT); c) the serotonin agonist, quipazine; d) or the Ca++ dependent K+ Channel blocker, quinidine, the cytolytic activity of the LAK cells was inhibited in a dose-dependent manner. Preincubation of LAK effector cells also inhibited lysis in a dose-dependent manner, whereas preincubation of the AKIL-20 tumor target cells produced no inhibitory effects. This study demonstrates that K+ ion channels are involved in the LAK cell cytolytic process ...
TL;DR: These two results supported the independence of the two receptors detected by the assay, and fortified chemiluminescence counting allowed us to obtain a more definite answer about the activation of each receptor.
Abstract: Luminol-enhanced chemiluminescence assay was used to detect the surface expression and the consequent activation of receptors (FcRI and FcRII) of murine macrophages (Mos). When murine IgG2a was used for the specific detection of FcRI and IgG2b for FcRII, a newly established procedure enabled us to detect the activation of each receptor with as few as 3×105 Mos. Briefly, TNP-SRBC coated with monoclonal IgG2a or IgG2b antibodies directed to TNP (sensitized SRBC) were used as reagent, in the presence of 1× 10−5M luminol, and the emission was measured with a liquid scintillation counter.When results obtained by chemiluminescence counting were compared to the results obtained by the rosette formation by adding the same SRBC reagent to peritoneal Mos obtained after ip injection of Listeria, fortified chemiluminescence counting allowed us to obtain a more definite answer about the activation of each receptor.Under the conditions established, the specific activation of FcRI was obtained by the addition of...
TL;DR: Results suggest that SV is unlikely to alter immune competence markedly as only DTH to SRBC and PFC numbers were found to be slightly altered and sodium valproate did not exert marked effects.
Abstract: Spleen and thymus weight, delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC), contact hypersensitivity to picryl chloride, anti-sheep red blood cell hemagglutinin titers and plaque-forming cells (PFC), resistance against experimental toxoplasmosis as well as serum total and intestinal specific IgA were investigated in Swiss mice given sodium valproate (250 mg/kg/day) orally for 21 consecutive days. Sodium valproate (SV) did not exert marked effects as only DTH to SRBC and PFC numbers were found to be slightly altered. These results suggest that SV is unlikely to alter immune competence markedly.
TL;DR: Exposure to both marijuana and placebo smoke for 28 days resulted in suppressed growth of secondary and tertiary implants, suggesting that noncannabinoid constituents of the smoke may contribute to the suppression of tumor growth.
Abstract: Fisher rats were treated for 28 or 60 days to multiple exposures to the smoke of marijuana or marijuana placebo cigarettes. Primary, secondary and in some instances tertiary tumor implants were performed. Murine sarcoma 180 tumor cells (7.5 x 10(7)) were implanted subcutaneously on day 1, 14 and 28 following initiation of smoke exposure (28 day studies) or on day 1, 14 after cessation of smoke exposure (60 day studies). Tumor areas were measured on alternate days beginning on the second or third day after implantation for 13 or 14 days. Exposure to both marijuana and placebo smoke for 28 days (6, 9 and 18 cigarettes per day) resulted in suppressed growth of secondary and tertiary implants. Administration of delta 9 tetrahydrocannabinol (50 mg/kg, i.p., 20 days) failed to suppress the growth of primary and secondary tumors. This suggests that noncannabinoid constituents of the smoke may contribute to the suppression of tumor growth. Exposure of rats to 9, but not 4 or 6, marijuana or placebo cigarettes per day for 60 days suppressed the growth of primary but not secondary tumors. Thus, the effects of smoke exposure appear to be lost by two weeks after cessation of treatment. The possible existence of a non-cannabinoid immunostimulant in the smoke is discussed.