Showing papers in "Immunopharmacology and Immunotoxicology in 1987"
TL;DR: Yogurt feeding potentiates the host's cell-mediated immune response by increasing the percentage of B lymphocytes and the PHA and LPS-induced proliferative responses of PP cell suspensions.
Abstract: The first line of defense against pathogens that enter the host by the oral route involves the Peyer's Patches (PP). For centuries many populations of the mediterranean basin have empirically administered soured milk (yogurt. to prevent and treat diarrhoea and entero-colitis. Recent reports have offered evidence in favour of a possible influence of yogurt on the host's immunocompetence.Scope of the present study was to evaluate the influence of a diet supplemented with yogurt on the PP from BALB/c mice.The results reported here suggest that yogurt feeding potentiates the host's cell-mediated immune response by increasing the percentage of B lymphocytes and the PHA and LPS-induced proliferative responses of PP cell suspensions.
55 citations
TL;DR: Evidence indicates that the inhibitory effects of terfenadine on mediator release from mast cells are in some way related to its antiallergic effects, and that an elevated cAMP content may be effective to enhancemediator release inhibition.
Abstract: Terfenadine dose-dependently inhibited rat homologous PCA (2.5-10 mg/kg, p.o.) and experimentally-induced asthma in guinea pigs (0.5-5 mg/kg, p.o.). Similarly, metabolites I and II dose-dependently inhibited experimentally-induced asthma but their respective potencies were approximately 1/2 and 1/15th that of terfenadine. These results suggest that the metabolites contribute to the antiallergic effects of terfenadine. In ex vivo, terfenadine (5-20 mg/kg, p.o.) also inhibited the release of both antigen-induced histamine and SRS-A from sensitized guinea pig lung samples and that of histamine from rat peritoneal mast cells. Terfenadine dose-dependently increased the cAMP content in rat mast cells and in the lungs; in the latter, the augmented cAMP is associated with an increase in adenylate cyclase activity, but not with the inhibition of phosphodiesterase activity. The above evidence indicates that the inhibitory effects of terfenadine on mediator release from mast cells are in some way related to its antiallergic effects, and that an elevated cAMP content may be effective to enhance mediator release inhibition.
43 citations
TL;DR: It is demonstrated that rIL-1 injection increases the number of CFC that survive in irradiated mice and may be a consequence of the stimulation of C FC into cell cycle prior to irradiation.
Abstract: Data in this report compare the number of colony-forming cells (CFC) in bone marrow from irradiated and pre-irradiated C57Bl/6J mice injected with saline or recombinant interleukin-1-alpha (rIL-1). Eight to 12 days after sublethal or lethal irradiation, there were more CFU-E (colony-forming units-erythroid), BFU-E (burst-forming units erythroid), GM-CFC (granulocyte-macrophage colony-forming cells), and day 8 CFU-S (colony-forming units-spleen) in bone marrow from rIL-1 injected mice than from saline injected mice. Prior to irradiation, there was no increase in number of CFC in bone marrow from rIL-1 injected mice. However, as determined by sensitivity to hydroxyurea, rIL-1 injection stimulated GM-CFC into cell cycle. These results demonstrate that rIL-1 injection increases the number of CFC that survive in irradiated mice and may be a consequence of the stimulation of CFC into cell cycle prior to irradiation.
39 citations
TL;DR: An immunosuppressive protein isolated from Trichosanthes kirilowii root tubers inhibited ConA-induced transformation in lymphocytes isolated from spleens of CBA mice and was also potent in inducing mid-term abortion in mice.
Abstract: An immunosuppressive protein was isolated from Trichosanthes kirilowii root tubers by a procedure involving acetone fractionation and ion exchange chromatography on CM-Sepharose. Homogeneity of the protein was demonstrated in immunoelectrophoresis, SDS-polyacrylamide gel electrophoresis, gel filtration, high performance liquid chromatography and a single NH2-terminal sequence. The protein had a molecular weight of 26,000, aspartic acid as the NH2-terminal amino acid and no cysteine or carbohydrates in its molecule. It inhibited ConA-induced transformation in lymphocytes isolated from spleens of CBA mice. The protein was also potent in inducing mid-term abortion in mice.
35 citations
TL;DR: It is demonstrated that ProT α can fully restore the deficient T-cell proliferative responses in auto- and allo-MLR in patients with SLE.
Abstract: Systemic lupus erythematosus (SLE) is characterized by a variety of profound T-cell abnormalities among which are decreased autologous and allogeneic mixed lymphocyte reactions (auto-MLR and allo-MLR, respectively). In a group of 10 patients with SLE, the mean auto-MLR and allo-MLR responses, tested by tritiated thymidine incorporation, were significantly decreased. If optimal doses of highly purified prothymosin alpha (ProT alpha) were present during the auto- of allo-MLR, the T-cell proliferative responses of SLE patients were increased to normal levels. ProT alpha had more pronounced enhancing effect in patients than in normal individuals. Among patients, ProT alpha was more effective in those who had active disease and low proliferative responses. These results demonstrate that ProT alpha can fully restore the deficient T-cell proliferative responses in auto- and allo-MLR in patients with SLE. ProT alpha, or a certain peptidic fragment of it, could prove potentially useful in the treatment of SLE.
28 citations
TL;DR: Male swiss albino mice transplanted with 1 x 10(6) viable fibrosarcoma tumor cells were treated with Protein A right from the day of transplantation for 4 weeks, twice weekly, resulting in lesser tumor incidence, significant inhibition of tumor growth and enhanced percent survival in treated animals as compared to untreated controls.
Abstract: Male swiss albino mice transplanted with 1 x 10(6) viable fibrosarcoma tumor cells were treated with Protein A (60 micrograms/kg) right from the day of transplantation for 4 weeks, twice weekly. The therapy resulted in lesser tumor incidence, significant inhibition of tumor growth and enhanced percent survival in treated animals as compared to untreated controls. Treated animals also showed gains in body weight, an increase in peripheral blood leucocyte count, significant increase in macrophage function and number. Stimulation of macrophage number and macrophage function by Protein A may be related to its antitumor.
28 citations
TL;DR: Results indicate that dopamine produces selective T cell defects probably mediated by a direct peripheral action of the drug on subsets of T lymphocytes.
Abstract: Dopamine administration in BALM mice dcpressed the overall delayed-type hypersensitivity reaction to sheep red blood cells, Che mixed-lymphocyte culture responses, the generation of cytotoxic T cells, and the number of spleen T cell populations. Conversely, dopamine enhanced concanavalin A stimulation of spleen cells, and had no effect on stimulation by PHA, on total spleen and thymus cell number, and on distribution of thymus I,y-tI+ or I,y-t2+ cell subsets. These results indicate that dopamine produces selective T cell defccts probably mediated by a direct peripheral action of the drug on subsets ofT lymphocytes.
27 citations
TL;DR: As lead, nickel and selenium appear to exert complex and possibly opposite effects on antibody response and phagocytosis, it remains to establish which immunotoxic consequences if any, an acute or chronic exposure to these heavy metals is likely to have in man.
Abstract: Previous studies have shown that heavy metals may exert marked immunomodulatory effects, at least in rodents, despite some discrepancies. However, the mechanism of their influence on the immune system is still unclear. As host resistance assays against experimental infections are generally considered as the most relevant criteria when predicting the immunotoxicity of drugs and chemicals, the effects of lead acetate, nickel chloride and sodium selenite on the resistance toward experimental Klebsiella pneumoniae infection was investigated in mice, with particular emphasis on the interference of the time of toxic exposure with the infectious challenge. Interestingly, one single intraperitoneal dose of 24 mg/kg lead or 4 mg/kg nickel enhanced the resistance of mice against Klebsiella pneumoniae when administered 24 hours before the infectious challenge, whereas host resistance proved to be impaired when the same dose was injected 5 hours after the infectious challenge. A 3-day pretreatment with 8 or 1...
21 citations
TL;DR: Survival of mice after intraperitoneal (ip) or intravenous infection with Pseudomonas aeruginosa was augmented in the mice that had been pretreated ip with a Chinese traditional herbal medicine, xiao-chai-hu-tang, and shosaiko-to could augment nonspecific resistance to a variety of bacteria to which antibody plays an effective role.
Abstract: Survival of mice after intraperitoneal (ip) or intraveneous (iv) infection with Pseudomonas aeruginosa was augmented in the mice that had been pretreated ip with a Chinese traditional herbal medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to) 6 hours or 4 days previously. 1) The pretreatment with shosaiko-to 6 hours previously induced an accumulation of polymorphonuclear leukocytes (PMN) in the peritoneal cavity, and its protective effect against ip infection was not impaired by treatment with carrageenan, a macrophage blocking agent. These results suggested that the protective effects of shosaiko-to against P. aeruginosa infection depended mainly on PMN in mice preteated at this timing. 2) The pretreatment with shosaiko-to 4 days previously induced an accumulation of macrophages showing an augmented phagocytosis of P. aeruginosa in vitro in the presence of immune serum, and its protective effect against P. aeruginosa was impaired by treatment with carrageenan. In addition, the pretreatment w...
21 citations
TL;DR: From studies, it can be derived that PA induced tumor regression may be due to potentiation of macrophage induced antitumor activity.
Abstract: Swiss albino male mice were given Protein A (PA) treatment ip (0, 1.0, 6.0 or 12.0 micrograms per mouse) twice weekly for two weeks. Alterations in white blood cell counts, peritoneal cell number, peritoneal macrophage and mast cell number were found. Macrophage induced phagocytosis of sheep red blood cells was also found enhanced in PA group. The maximum effect was found in 1.0 microgram of PA dose group of mice. From our studies it can be derived that PA induced tumor regression may be due to potentiation of macrophage induced antitumor activity.
19 citations
TL;DR: Findings suggest that the inhibitory effect of KB-2413 on the release of chemical mediators contributes to the anti-allergic activity of this compound.
Abstract: The effect of KB-2413 on IgE-mediated histamine and LTC4, release from leukocytes obtained from asthmatic patients who were sensitive to mites, and from human lung tissues passively sensitized with IgE myeloma serum was studied. KB-2413 inhibited the IgE-mediated chemical mediator release concentration dependently at a range of 10-4 to 3±10-3 M. KB-2413 did not enhance histamine release at a higher concentration unlike ketotifen. These findings suggest that the inhibitory effect of KB-2413 on the release of chemical mediators contributes to the anti-allergic activity of this compound.
TL;DR: In this paper, Xiao-chai-hu-tang (Japanese name: shosaiko-to) injection was found to induce the accumulation of B lymphocytes in peritoneal cavity and spleen.
Abstract: We found that an intraperitoneal (ip) injection of a traditional Chinese herbal medicine, xiao-chai-hu-tang (Japanese name: shosaiko-to), induced accumulation of B lymphocytes (sIgM+) in the peritoneal cavity and spleen. 1) Cell surface marker analysis by a fluorescence-activated cell sorter (FACS) demonstrated that the accumulated B cells on day 4 or 7 after shosaiko-to administration (early phase) were composed mainly of sIgM+IgD- cells and suggested that these B cells maturated into sIgM+IgD+ cells on days 10 or 14 (late phase). Relative decrease of IgM+IgD+ cells at early phase was more profound in peritoneal cells (PC) than in spleen cells. 2) With respect to spleen lymphocytes, antibody responses to a thymus-independent (TI) antigen of type 2 (trinitrophenylated Ficoll) and a thymus-dependent (TD) antigen (sheep erythrocyte) were enhanced at late phase but not at early phase. In contrast, responses to trinitrophenylated lipopolysaccharide (TNP-LPS) as a TI-1 antigen and LPS as a B cell mitogen or a polyclonal B cell activator were enhanced markedly at early phase but declined at late phase. 3) With respect to peritoneal lymphocytes, responses to LPS were suppressed at early phase but recovered at late phase. Enhanced responses to TI and TD antigen at late phase in spleen lymphocytes and suppressed response to LPS at early phase in peritoneal lymphocytes may be explained by increases of IgM+IgD+ mature B cells and IgM+IgD- immature B cells, respectively, at those times. Enhanced responses to TI-1 or LPS in spleen lymphocytes at early phase may be explained by elevated sensitivity of IgM+IgD+ cells which reside in the spleen before shosaiko-to administration and receive the direct stimulation by shosaiko-to, or by acquired responsiveness of IgM+IgD- cells which migrate after stimulation with shosaiko-to.
TL;DR: The inhibitory effect of BZ on neutrophil functions seemed to be associated with a Ca++-involving mechanism, and a new physiological property for substances presenting an affinity for peripheral type BZ binding sites is supposed.
Abstract: Diazepam (DZP) inhibited in vitro in a concentration-dependent manner superoxide anion generation and chemiluminescence from human neutrophils stimulated by the formylated oligopeptide FMLP and by the calcium ionophore A23187. The dose-dependent inhibitory effect of DZP on A23187-dependent superoxide generation in the presence of Ca++ 0.6 mM was highly antagonized by increasing extracellular Ca++ concentration to 1.5 mM and to 2.0 mM. Ro 5-4864, a specific ligand for peripheral type benzodiazepine (BZ) binding site, inhibited superoxide generation induced by FMLP, while clonazepam (CNZ), which is selective for brain sites, did not possess any activity. Ro 15-1788, a central type BZ receptor antagonist, did not show any antagonistic activity on DZP-dependent inhibition. A new physiological property for substances presenting an affinity for peripheral type BZ binding sites is supposed. The inhibitory effect of BZ on neutrophil functions seemed to be associated with a Ca++-involving mechanism.
TL;DR: Thymomodulin is a biologically active compound which regulates the maturation of human and murine pre T lymphocytes, as well as modulate the functions of apparently mature human and animal B and T lymphocyte functions.
Abstract: Thymomodulin (Ellem Industria Farmaceutica spa, Milan, Italy) is a calf thymus acid lysate with immunomodulating activities. It is composed of several peptides with a molecular weight range of 1-10kD. Extensive studies in animal systems showed that Thymomodulin exhibited no, or very little toxicity even when used at high doses. Studies done in vitro and in vivo demonstrated that Thymomodulin is a biologically active compound which regulates the maturation of human and murine pre T lymphocytes, as well as modulate the functions of apparently mature human and animal B and T lymphocytes. It was observed that Thymomodulin can promote myelopoiesis as demonstrated by an increase of granulocyte-macrophage colonies in agar. Although additional studies to examine its target cell lineage are required, it appears that Thymomodulin exhibits specificity toward T cells. Therefore, enhancement of other cell lineage functions by Thymomodulin may be indirect, and mainly due to its effect on T cells. Of major importance is to note that Thymomodulin is prepared in a manner which allows it to maintain its biological activity when administered orally.
TL;DR: A significant stimulating effect on NK cell activity was also produced by AM3 treatments, which could be a consequence of a marked IFN induction and/or a modifying effect in prostaglandin synthesis.
Abstract: The "in vivo" effect of Immunoferon (AM3) on the production of interferon (IFN) and natural killer (NK) activity in young and old mice was studied. Although AM3 is not an IFN inducer by itself, enhancements in the serum IFN levels were produced when drug was associated to Newcastle disease virus or bacterial lipopolysaccharides as IFN inducers. This effect appeared to be dependent on the time lapsed between the inducer agent and drug. In addition, a significant stimulating effect on NK cell activity was also produced by AM3 treatments. This effect could be a consequence of a marked IFN induction and/or a modifying effect in prostaglandin synthesis.
TL;DR: The finding that human monocytes exposed to as low as 2% halothane anesthesia for 4 hours displayed a dramatic down-regulation of hydrogen peroxide (H2O2) release may help explain the enhanced susceptibility of post-operative patients to infections.
Abstract: In an effort to determine the impact of halothane anesthesia on certain human cell-mediated immune functions, normal, purified human monocytes and lymphocytes were exposed to halothane in vitro at varying concentrations for up to 8 hours. Subsequently, these human effector cells were analyzed for their ability to function in several cell-mediated immunologic assays. Natural killer cell activity against K-562 was unaffected by halothane in most of the donors tested. Similarly, the ability of purified monocytes to inhibit MBL-2 tumor cell growth was unchanged. Halothane appeared to decrease the proliferative response of lymphocytes to phytohemagglutinin (PHA) in approximately 50% of the normal donors tested. In contrast, the ability of monocytes to lyse antibody-coated red cell targets (ADCC) was unaffected by even maximal exposure to halothane. Of interest was the finding that human monocytes exposed to as low as 2% halothane anesthesia for 4 hours displayed a dramatic down-regulation of hydrogen p...
TL;DR: This model was used to assess the effects of marijuana smoke, marijuana placebo smoke and delta 9-tetrahydrocannabinol (delta 9-THC) on the local immune response to bacterial infection and suggested that the reduction in NI was unrelated to the pychomimetic component delta 9THC.
Abstract: Dermonecrosis was induced in ICR mice by subcutaneous implantation of Staphylococcus aureus absorbed onto sterile cotton pellets. This model was used to assess the effects of marijuana smoke, marijuana placebo smoke and delta 9-tetrahydrocannabinol (delta 9-THC) on the local immune response to bacterial infection. Mice were exposed to 40 or 80 "puffs" of marijuana smoke, marijuana placebo smoke or air daily for 4 consecutive days. The estimated dose of delta 9THC per day generated from 40 or 80 puffs of marijuana smoke was 3.2 and 6.4 mg/kg, respectively. A group of sentinel (Shelf) control mice were included in each experiment. The necrotic index (NI) of mice exposed to 40 or 80 puffs of marijuana smoke were 67% and 44% of control, respectively. Air exposed mice showed a necrotic index comparable to the shelf control group. In chronically (60 days) exposed mice (80 puffs per day) the necrotic index was about 12% of control, while air-exposed mice were about 40% of control. Placebo marijuana smoke exposed mice had a NI comparable to that of marijuana smoke exposed mice which suggested that the reduction in NI was unrelated to the pychomimetic component delta 9THC. To further explore which of the constituents of marijuana were responsible for the decreased NI, the ethanol extract from marijuana leaves was partioned between water (cannabinoid free) and chloroform (cannabinoid rich). Injection of the cannabinoid free fraction produced comparable decrease in the NI as observed with whole marijuana smoke, while the cannabinoid rich fraction produced no effect. delta 9THC at a dose of 10 mg/kg per day did not alter the NI.
TL;DR: Enhanced glucose utilization was observed in continuous cultures of macrophages in medium containing 4mM Quadrol, [N,N, N',N',Tetrakis(2-hydroxypropyl)ethylenediamine]; this enhancement was both time and concentration dependent.
Abstract: Enhanced glucose utilization was observed in continuous cultures of macrophages in medium containing 4mM Quadrol, [N, N, N', N', Tetrakis(2-hydroxypropyl)ethylenediamine]. This enhancement was both time and concentration dependent. Radiolabeled 4mM Quadrol, after incubation with macrophages for 60 minutes, was shown to be associated with the cells at a level of 4 nmoles/106 cells. This association increased linearly with time, reaching a maximum at 60 minutes with no observable difference after 24 hours. Trypsin-EDTA treatment of these macrophages for 15 minutes reduced the amount of Quadrol associated with cells by about 50%, Quadrol, unlike Ca Ionophore A23187, did not induce influx of 45Ca into the cells within the incubation period of 60 minutes. Quadrol methacrylate and Poly(Quadrol methacrylate) stimulated macrophages to exhibit increased phagocytosis of polystyrene beads. This stimulation was comparable to that observed for Quadrol.
TL;DR: Results suggest that TP-5 is not the smallest active fragment of thymopoietins, since peptides (TP-3 and TP-4) exhibit similar or higher T-cell membrane activation on E-receptor.
Abstract: The effects of seventeen synthetic analogs of thymopentin (TP-5) have been studied in the active and azathioprine-inhibited E-rosette tests. Thymopentin was gradually shortened from the C terminus to peptides and single amino acids. Thymopoietin 32-34 (Arg-Lys-Asp-RGH-0205-TP-3) (II) and thymopoietin 32-35 (Arg-Lys-Asp-Val-RGH-0206-TP-4) (I) were the most active peptides. Dipeptide Arg-Lys produced significant stimulatory effect on azathioprine (ED75) inhibited E-receptor. Treatment of azathioprine (ED75)-inhibited E-rosette forming cells (ERFC) with arginine or especially lysine increased the number of ERFC. Some of TP-4 analogs decreased further the number of ERFC decreased by azathioprine ED30. These "suppressive" peptides as well as TP-3 caused a partial arrest of K 562 cell proliferation up to 96 hours. Results suggest that TP-5 is not the smallest active fragment of thymopoietins, since peptides (TP-3 and TP-4) exhibit similar or higher T-cell membrane activation on E-receptor. Arginine, lysine, and acidic aspartyl residue seem to be a necessary basic structure to produce a cumulative chemical signal on the activity of T-lymphocytes.
TL;DR: It is indicated that murine CFU-GEMM contain the relevant aldehyde dehydrogenase activity, and the relevantAldehyde dehydration activity is retained upon differentiation to progenitors committed to the megakaryocytoid lineage, but lost upon differentiationTo progenitor cells to the granulocy toid/monocytoids and erythroid lineages.
Abstract: The ex vivo sensitivity of murine multipotent (CFU-GEMM) and committed (CFU-Mk, CFU-GM, BFU-E and CFU-E) hematopoietic progenitor cells to mafosfamide was quantified with and without concurrent exposure to cyanamide, an inhibitor of aldehyde dehydrogenase activity. In the absence of cyanamide, CFU-GEMM, CFU-Mk and CFU-GM were approximately equisensitive to mafosfamide while the erythroid progenitors were more sensitive to the drug. Cyanamide potentiated the cytotoxicity of mafosfamide toward CFU-GEMM and CFU-Mk, but not toward CFU-GM, BFU-E and CFU-E. Cellular aldehyde dehydrogenases are known to catalyze the oxidation of 4-hydroxycyclophos-phamide/aldophosphamide, the major intermediate in cyclophosphamide and mafosfamide activation, to the relatively nontoxic acid, carboxyphosphamide. Thus, our findings indicate that 1) murine CFU-GEMM contain the relevant aldehyde dehydrogenase activity, and 2) the relevant aldehyde dehydrogenase activity is retained upon differentiation to progenitors committe...
TL;DR: Results suggest that DYN might play a role in neuroendocrine regulation of the lymphocyte blastogenic process in PHA-induced lymphocyte proliferation.
Abstract: The effect of the opioid peptide dynorphin (DYN) on PHA-induced lymphocyte proliferation has been evaluated in the present study.A significant increase in PHA-induced lymphocyte activation was observed when DYN was added to cultures 48 hr after the mitogenic stimulation. This effect occurred at suboptimal (3.12 and 6.25 ug/ml) PHA concentrations and at DYN doses ranging from 10-9 to 10-12 M. Conversely, DYN did not affect the lymphocyte blastogenic process either when added before, or simultaneously or after intense PHA (12.5 ug/ml) stimulation.Naloxone preincubation did not modify the above described effects.Results suggest that DYN might play a role in neuroendocrine regulation of the lymphocyte blastogenic process.
TL;DR: Delta-9-THC inhibits immune responsiveness of B6C3F1 mice to homotypic challenge with HSV2, and this inhibition may be resultant of drug action on both effector immunocytes and target HSV 2 antigen-bearing cells.
Abstract: The present investigation was undertaken to determine the effect of in vivo Delta-9-tetrahydrocannabinol (Delta-9-THC) treatment on immune responsiveness to secondary exposure to herpes simplex virus type 2 (HSV2) antigens in vitro. A splenocyte proliferative assay, employing HSV2-infected mouse embryo fibroblasts as target cells, was used to measure immune responsiveness. Administration of 50 mg/kg or 100 mg/kg Delta-9-THC to B6C3F1 mice in concert with HSV2 infection resulted in suppression of the proliferative response to HSV2 cell-surface antigens expressed on virus-infected mouse embryo fibroblasts. Similarly, in vitro treatment of HSV2-infected cells with Delta-9-THC (10(-7) M to 10(-5) M) resulted in a dose-dependent suppression of proliferative responsiveness of splenocytes of non-drug-treated HSV2-sensitized mice. These results suggest that Delta-9-THC inhibits immune responsiveness of B6C3F1 mice to homotypic challenge with HSV2. This inhibition may be resultant of drug action on both effector immunocytes and target HSV2 antigen-bearing cells.
TL;DR: Mice maintained on tocopherol-deficient diets for 8 weeks post-weaning and those on regular diets exhibited increased IgG titers during peak response when injected with vitamin E, which partially alleviated the radiation-depression of the primary immune response induced by the smaller SRBC injection.
Abstract: Serum haemagglutination (HA) titers have been determined for irradiated and non-irradiated mice responding to injection of two different concentrations of sheep red blood cells (SRBC) 24 to 48 hours after irradiation and immediate intraperitoneal injection of 2.5 mg DL alpha-tocopherol, the emulsifying vehicle, or saline. Mice maintained on tocopherol-deficient diets for 8 weeks post-weaning and those on regular diets exhibited increased IgG titers during peak response when injected with vitamin E. This partially alleviated the radiation-depression of the primary immune response induced by the smaller SRBC injection. This stimulatory effect was most significant in mice maintained on vitamin E-deficient diets. The HA titers of irradiated and non-irradiated mice maintained on normal rations were determined following a 10-fold increase in the SRBC inoculation. Antibody titer was greater following injection of the higher concentration of SRBC but post-irradiation injection of tocopherol immediately or 24 hours after irradiation did not enhance immune response. At the higher SRBC concentration maximum observed HA titers decreased with increasing dose of radiation; however, tocopherol had no significant dose-reducing effect. Tocopherol toxicity as manifested by depressed HA titers was observed occasionally in non-irradiated mice challenged with the higher concentration of SRBC.
TL;DR: The antineoplastic drugs Vincristine and Vinblastine were tested for their effects on Concanavalin A induced Interleukin-2 (IL-2) release by rat splenocytes and both drugs were found to inhibit IL-2 release in vitro.
Abstract: The antineoplastic drugs Vincristine (VCR) and Vinblastine (VBL) were tested for their effects on Concanavalin A induced Interleukin-2 (IL-2) release by rat splenocytes. Both drugs were found to inhibit IL-2 release in vitro. This effect was noted at doses of 10 ng/ml and 100 ng/ml in case of VBL and at doses of 1 ng/ml, 10 ng/ml and 100 ng/ml with VCR. The in vivo effect of these drugs was studied by injection into rats three days before culture of splenocytes. This also resulted in inhibition of IL-2 release. The effect was manifested with VCR at doses of 0.1 mg/kg bw and 0.5 mg/kg bw and with VBL at 2 mg/kg bw. These drugs were also tested for their effect on Interleukin-1 (IL-1) release by lipopolysaccharide (LPS) stimulated rat peritoneal exudate cells (PEC's) in vitro. No modulation of the production of IL-1 was seen.
TL;DR: The oligopeptides TP-3, TP-4, and TP-5 are recommended for clinical trial in case of malignant tumors and immunodeficiency and decreased the immunosuppressive activity of Cyclophosphamid immunotoxicity.
Abstract: The oligopeptides Arg-Lys-Asp (TP-3), Arg-Lys-Asp-Val (TP-4), and Arg-Lys-Asp-Val-Tyr (TP-5) considered as the active short fragments of thymopoietin were administered (lo mg/kg) to C57B1 mice 24 hours before the intravenous inoculation of Lewis lung tumor (LLT) cells. A substantial decrease in lung metastasis number was observed as a result of treatment with all of the three oligopeptides. TP-3, TP-4, and TP-5 treatment decreased the immunosuppressive activity of Cyclophosphamid (240 mg/kg) given 96 hours before the inoculation of LLT cells. After thymectomy, performed eight days before the LLT inoculation, only TP-3 treatment resulted in the decrease of Cyclophosphamid immunotoxicity. A stimulating effect of TP-3 on T helper cell activity is assumed. The oligopeptides TP-3, TP-4, and TP-5 are recommended for clinical trial in case of malignant tumors and immunodeficiency.
TL;DR: It is demonstrated that a single dose cyclophosphamide can have profound effects on the gut immune system and that the drug has a similar effect when given either orally or parenterally.
Abstract: The gut associated lymphoid tissue plays an important role in intestinal defenses, food allergy, oral tolerance, and certain intestinal diseases. This study describes the effect of either oral or parenteral cyclophosphamide on IgA and IgG production in the gut. Mice were treated with cyclophosphamide either IV or PO, and Peyer's patch cell cultures were established to evaluate mitogen induced production of IgA and IgG. To evaluate the effect of cyclophosphamide on the plasma cell rich lamina propria, segments of jejunum were cultured and overnight secretion of IgG and IgA were measured. We found, the secretion of IgA or IgG by jejunal fragments was not influenced by cyclophosphamide (IV or PO). Mitogen induced secretion of IgA and IgG by Peyer's patch cells was markedly decreased 24 hrs after drug administration, with significant recovery by day 7. Cell mixing experiments revealed that a single dose cyclophosphamide reduced the capacity of Peyer's patch B cells to secrete IgA or IgG when co cultured with normal T cells. This study demonstrates that a single dose cyclophosphamide can have profound effects on the gut immune system and that the drug has a similar effect when given either orally or parenterally.
TL;DR: While Sch 24937 exhibits the type of immunopharmacological profile that is likely to yield a good therapeutic effect in the treatment of immune-mediated chronic inflammatory diseases, hepatotoxicity associated with the compound precludes its development for the treatmentof non-life threatening human autoimmune conditions.
Abstract: Sch 24937 (6-bromo-5-chloro-2-1[(methylsulfonyl) acetyl] 3-(2-pyridyl indole) was previously shown to be an immunosuppressant with potent inhibitory effects on B lymphocyte mediated immune responses (6). The present investigation was primarily designed to compare the immunopharmacological profile of Sch 24937 with that of cyclosporin A (CSA) a well-known immunosuppressive drug that has selective effects on T-lymphocyte-mediated immune responses. The results show that while the immunosuppressive activity of CSA in vitro is superior to that of Sch 24937, in general the latter agent is a more potent inhibitor of immune responses in vivo. The activity of Sch 24937 in rat models of adjuvant arthritis and experimental allergic encephalomyelitis is also described. While Sch 24937 exhibits the type of immunopharmacological profile that is likely to yield a good therapeutic effect in the treatment of immune-mediated chronic inflammatory diseases, hepatotoxicity associated with the compound precludes its de...
TL;DR: Pregnant mice were administered 2'-deoxycoformycin (2dCF), a potent inhibitor of adenosine deaminase activity, by intraperitoneal injection on day 7 or 15 of gestation or from day 8-12 or 14-18 of gestation, to suggest that there may be age-related differences in the sensitivity of certain cell populations to the effects of 2dCF.
Abstract: Pregnant mice were administered 2'-deoxycoformycin (2dCF), a potent inhibitor of adenosine deaminase activity, by intraperitoneal injection on day 7 or 15 of gestation or from day 8-12 or 14-18 of gestation. A total dose of 0.5 or 2.0 μg 2dCF/g of maternal body weight was given to the dams. In a seperate study, pups born to nontreated dams were given 5 intraperitoneal injections totaling 0.5, 2.0 or 4.0 μg 2dCF/g beginning at 4 weeks of age. Administered doses of 2dCF were at levels known to profoundly suppress adenosine deaminase levels in adult mice. Pups born to dams injected with 2dCF from day 14-18 all died within 48 h of birth whereas other injection schedules had no effect on birth rate or survival of pups. In utero 2dCF exposure had little effect on immune function in offspring. On the other hand, body, spleen and thymus weight, and splenic cellularity were decreased in weanling mice 24 h after the last injection of 4 μg/g 2dCF. Proliferative responses of splenocytes to T cell mitogens and...
TL;DR: Drug treatment had a limited impact on the in vivo resistance of mice to microbial infection, which was only affected by a drug injection of 18 mg/kg, a dose well within the confidence limits of the mean lethal dose of the drug.
Abstract: The new synthetic tripeptide p-F-Phe-m-bis-(2-chloro-ethyl) amino-Phe-Met-etoxy HCI, PTT.119, was studied for its effects on the host immune system. Doses of PTT.119 ranging from 3 to 18 mg/kg were administered i.p. to recipient mice which, at different times after drug treatment, were tested for allograft response, competence in producing lymphocytes active in lethal graft- versus-host disease, delayed-type hypersensitivity, mitogen responsiveness, humoral antibody production and natural resistance against microbial infections. At therapeutically active dosages, PTT.119 appeared to selectively inhibit functions mediated by B lymphocytes, leaving the majority of those involving T-cell subsets largely unaffected, even at the highest doses employed. Moreover, drug treatment had also a limited impact on the in vivo resistance of mice to microbial infection, which was only affected by a drug injection of 18 mg/kg, a dose well within the confidence limits of the mean lethal dose of the drug.
TL;DR: The results presented here indicate that thymosin beta 4 may be used as an immunoregulatory molecule in patients with immunodeficiencies.
Abstract: Thymosin fraction 5 polypeptides beta 4 and alpha 1 were tested for their ability to affect certain immunological parameters of human peripheral blood lymphocytes (PBL). PBL were cultured with various concentrations of the peptides for 24 hours. Thymosin beta 4 was found to induce a significant decrease in the expression of the Fc alpha receptors of PBL, as well as in their ability to express antibody dependent cellular cytotoxic (ADCC) activity. In addition, this peptide had the ability to increase the percentage of T4 lymphocytes in normal and immunosuppressed donors and to decrease the percentage of T8 positive cells in normal donors. Finally, beta 4 peptide caused a small increase in the capacity of peripheral blood lymphocytes to form sheep red blood cell (SRBC) rosettes (ER). In parallel experiments thymosin alpha 1 was found inactive. The results presented here indicate that thymosin beta 4 may be used as an immunoregulatory molecule in patients with immunodeficiencies.