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PubMed1993

Ascorbigen and other indole-derived compounds from Brassica vegetables and their analogs as anticarcinogenic and immunomodulating agents.

Searches for the natural compounds that determine the anticarcinogenic properties of a cruciferous-vegetable diet, revealed the products of alkaloid glucobrassicin biotransformations; among these, ascorbigen, an indole-containing derivative of L-ascorbic acid, was found to be the most abundant. Study of chemical properties of ascorbigen showed that it is capable of different transformations in acidic (including gastric juice) and slightly alkaline (including blood) media. The stable and unstable products of ascorbigen transformation determine the biological properties of the compound. The most important product of ascorbigen transformation in gastric juice is 5,11-dihydroindolo[3,2-b]-carbazole, with a binding affinity to the Ah receptor only 3.7 x 10(-2) lower than that of tetrachlorodibenzodioxin. This compound may be responsible for modifying P450 enzyme activities. Ascorbigen and its analogs are available synthetically. Their biological evaluation showed that some of the compounds of these series are immunomodulators. The most active is N-methylascorbigen, which demonstrates therapeutic effects (inhibition of tumor growth, protection of animals from bacterial and viral infections). The immunomodulatory activity of natural ascorbigen may be an additional factor of importance for the anticarcinogenic properties of a cruciferous-vegetable diet.

Adjuvants, Immunologic↗

PubMed1994

Immunorestorative effect of glucan immunomodulator on guinea pigs with experimental ascariosis.

The immunorestorative effect of glucan immunomodulator, combined with porcine immunoglobulin and zinc (GI) on T- and B-lymphocytes and peritoneal macrophage phagocytic ability was studied in guinea pigs with experimental ascariosis (Ascaris suum) after a cyclophosphamide (CY)-evoked immunosuppression. During the migration phase of A. suum infection GI exerted a significant restorative effect on the CY-reduced percentage occurrence of T- and B-cell populations in the mesenteric, mediastinal and hepatic lymph nodes and spleen of A. suum hosts. On the contrary, it did not influence the CY-suppressed phagocytic activity and index of phagocytic activity of the peritoneal macrophages. The protective effect of the GI evaluated by the reduction in the number of migrating ascarid larvae in the lungs of guinea pigs after immunosuppression with CY and administration of GI was 14.46% higher, compared with the suppressed and infected group without administration of GI.

Adjuvants, Immunologic↗

PubMed1981

Immunomodulation in mice by Bacillus megaterium and its dependence on culture conditions.

Mice pretreated with Bacillus megaterium ATCC 33085 grown on TSA medium developed a significant increase in primary antibody response to SRBC. Conversely, pretreatment with a spore suspension harvested from nutrient Agar medium decreased this antibody response. A suspension of organisms grown on a defined, phosphorus-deficient medium (P-Medium) had no effect. Otherwise, only the spore suspension was able to enhance the contact sensitivity to dinitrofluorobenzene. Peritoneal leucocyte numbers were increased by inoculation with both TSA-cultured bacteria and the spore suspension, but not by P-Medium-cultured bacteria. Administration of both the spore suspension and P-Medium-cultured bacteria decreased the in vitro phagocytosis by peritoneal adherent cells. These immunomodulator properties are discussed in relation to characteristics of the strain tested.

Animals↗

PubMed1989

Immunomodulating properties of the N-(1-deoxy-D-fructos-lyl) derivative of amphotericin B in mice.

Immunomodulating properties of the N-(1-deoxy-D-fructos-lyl) derivative of Amphotericin B (N-Fru-AmB) was investigated in vitro on T and B mouse lymphocytes and compared to that of the original AmB molecule. Results indicate that N-Fru-AmB is a potent polyclonal B cell activator capable of inducing B lymphocytes to proliferate and to differentiate into Ig secreting cells in absence of any additional signal. N-Fru-AmB is also mitogenic for a fraction of peripheral T lymphocytes. Together, the results suggest a potential interest of such derivatives in the treatment of mycosal infections in immunodeficient patients.

Adjuvants, Immunologic↗

PubMed1991

Splenic immunomodulation with swimming-induced stress in rats.

In order to determine the effects of swimming-induced stress, young male Wistar rats swam for a single session of 2 h duration, or for one 2-h session a day for five consecutive days. The absolute number of splenic mononuclear cells and the in vitro proliferation of mitogen-stimulated (PHA) T lymphocytes were studied. A single swimming session did not significantly diminish the number of splenic mononuclear cells, but it did significantly reduce splenic T-lymphocyte proliferation. This effect on T-lymphocyte proliferation was significantly blocked, in part, by subcutaneous injection of naltrexone before a swimming session. It was not significantly blocked by pre-exercise oral administration of aminoglutethimide. Repeated swimming sessions induced no significant changes in immune parameters. In conclusion, these data suggest that immunosuppression seen with a single swimming-induced stress period may partly be due to endogenous opioids, and that repetition of the swimming session reduced swimming-induced immunomodulation.

Aminoglutethimide↗

PubMed1989

Arenavirus infection in the guinea pig model: antiviral therapy with recombinant interferon-alpha, the immunomodulator CL246,738 and ribavirin.

Human arenaviral infections have a high mortality, and are dangerous to work with in the laboratory. There is a need for good antiviral agents to treat these infections. Pichinde virus infection of the inbred strain 13 guinea pig is a relatively safe, good animal model for human arenavirus infections. Mortality is consistently 100% between days 12 and 25 (mean 14.8) days after infection. When infected animals were treated with recombinant human interferon alpha A, or with CL246,783, an immunomodulator known to induce interferon, no beneficial effect was noted. When animals received ribavirin, 25 mg/kg/day for the first 14 days of infection, the course of infection was prolonged, with death occurring a mean of 22.5 days after infection. If ribavirin was administered for 28 days, mortality was reduced to 25%, with those animals dying a mean of 21.0 days after infection. These results confirm the studies that indicate that ribavirin is a useful agent for treating arenaviral infections. However, treatment with this agent must be prolonged. They also demonstrate the potential usefulness of Pichinde virus infection in strain 13 guinea pigs as an animal model of human disease.

Acridines↗

PubMed1994

Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A.

Peptides from 10 to 22 amino acids containing sequences encompassed by Staphylococcus aureus protein A were synthesized. Some of these peptides, when present in cultures of lymphomononuclear cells from healthy donors or from cancer patients (melanoma, breast carcinoma, non-Hodgkin lymphoma and renal cell carcinoma) promoted: (i) changes in the phenotype of the lymphomononuclear population, (ii) stimulation of monocytes (release of IL-1 and TNF-alpha), and (iii) an increase in cytotoxicity against K562, Daudi and HT-29 cells. Isolated monocytes responded also to those peptides with a release of IL-1 and TNF alpha and an increase of cytotoxicity against HT-29 cells. It was found that the active peptides had the following structural pattern: a length of at least 15 amino-acid residues with a proline at position 6, valine, leucine, isoleucine, glycine, alanine or lysine at position 2, and glutamic or aspartic acid at position 11. Replacement of Pro at position 6 with any other residue turned the peptide inactive. Replacement of residues at positions 2 and 11 with amino-acid residues other than those required for activity resulted in compounds with a marked decrease in the immunomodulating properties described, or lacking these properties altogether.

Amino Acid Sequence↗

PubMed1995

Serum gangliosides as endogenous immunomodulators.

Gangliosides suppress various immune activities in vitro and in vivo. Their level is significantly elevated in tumors and atherosclerotic aorta tissue, as well as in the sera of patients with tumors or atherosclerosis. Here, Lev Bergelson suggests that ganglioside-induced immunomodulation might be involved in atherogenesis and carcinogenesis, and describes a hypothesis that cites gangliosides as a factor interfering with the clearance of low-density lipoproteins (LDLs) and promoting the formation of atherosclerotic plaques.

Animals↗

PubMed1990

Lack of favorable effect of immunomodulators on outbred syngeneic rodent islet transplantation.

We studied the effect of two immunomodulators, lobenzarit disodium and OK-432, on outbred syngeneic islet transplantation. Six hundred fresh islets taken from two male Wistar rats were transplanted intraportally into other male Wistar rats that had been made diabetic with streptozotocin. Lobenzarit was given to 12 recipients and OK-432 to seven recipients intraperitoneally for 1 month, while nine controls received only intraperitoneal saline. Both drug-treated groups could not maintain lower fasting plasma glucose levels or higher fasting body weights at each time as compared with controls. The islet survival time in lobenzarit-treated (23.5 +/- 8.0 days) and OK-432-treated (25.3 +/- 13.4 days) groups was not longer than that (21.6 +/- 9.4 days) of the control group. All the pancreatic insulin contents of the seven surviving controls, ten surviving lobenzarit and five surviving OK-432 recipients were less than 0.8% of the mean insulin content obtained from 12 normal male rats. The hepatic insulin content of both drug-treated groups was not higher than that of the control group. These results suggest that lobenzarit disodium and OK-432 cannot protect outbred syngeneic islet grafts.

Adjuvants, Immunologic↗

PubMed1995

Eicosanoid production by parasites: from pathogenesis to immunomodulation?

In this review, Adam Belley and Kris Chadee discuss eicosanoid production by various parasites and propose roles they may play in pathogenesis and immunomodulation. The commonality between parasites is prostaglandin production and, therefore, special attention is given to the cyclooxygenase pathway, highlighting the enzymes and functions of prostaglandins.

Journal Article↗

PubMed1982

Properties and specificity of binding sites for the immunomodulator bestatin on the surface of mammalian cells.

The binding of the immunomodulator bestatin, an inhibitor of cell surface bound leucine aminopeptidase and aminopeptidase B, to mammalian cells of varying origin has been studied. The specific binding of [3H] bestatin was a rapid and saturable process exhibiting one affinity, characterized by an association constant of 0.8 x 10(5) M-1, as determined in the L5178y mouse lymphoma system. Optimal binding was observed at 37 degrees C. L-leucine and L-leucine-beta-naphthylamide prevented the binding, suggesting that the complex was formed between leucine aminopeptidase and bestatin. The protein nature of the bestatin-"receptor" was suggested by its susceptibility to trypsin. Under the conditions used here intracellular translocation of bestatin appeared to be negligible. A maximum of about 2.2 x 10(6) bestatin molecules could bind to L5178y mouse lymphoma cells. Under identical conditions by far the highest amount of bestatin was bound to macrophages from mice. Lower levels were measured with T-lymphocytes; very low binding capacity was observed with B-lymphocytes. Experiments with synchronized L5178y cells revealed a cell cycle dependent change of binding capacity for bestatin; the highest level was observed during the transition from S-to G2 phase and the lowest during G1- and early S phase. These data lend further support to the assumption that the immuno-potentiating activity of bestatin is due to a stimulation of T-lymphocyte proliferation probably mediated through the activation of macrophages.

Adjuvants, Immunologic↗

PubMed1983

Enkephalins as immunomodulators.

The protective effects of methionine enkephalin as well as leucine enkephalin were studied in BDF1 mice inoculated with 1 X 10(4) and 1 X 10(2) cells of L1210 murine leukemia. Significant increases in number of survivors were observed in mice treated with enkephalins. Methionine enkephalin in the presence of PHA was found to stimulate lymphocyte blastogenesis at concentrations of 1 mg/ml to 10(-8) mg/ml. In the case of leucine enkephalin, concentrations of 1 mg/ml to 10(-10) mg/ml stimulated blastogenesis. Stimulation of blastogenesis was seen at PHA dilutions of 1:100, 1:250, 1:750, with both methionine enkephalin and leucine enkephalin. The results are discussed in terms of immunomodulation. It is proposed that endogenous enkephalins play a neuroendocrine role between the central nervous system and the immune system and are direct immunostimulants.

Animals↗

PubMed1983

Adriamycin induced immunomodulation: dependence upon time of administration.

The immunomodulating capabilities of the anti-neoplastic agent, Adriamycin, were investigated. The day of Adriamycin administration to mice was varied from -15 to -1, day 0 being when mice were either immunized or sacrificed and their spleen cells sensitized in culture. Humoral and cellular immune responses against allogeneic or xenogeneic cellular antigens in mice and in culture, as well as phagocytic and ADCC activities were evaluated using spleen cell populations. The cellular responses and phagocytic activities were affected in a cyclical manner with time after Adriamycin's administration. Peaks of increased activity were seen subsequent to day -5 and day -11, administration and low activities following day -1, -3 and day -7, -9 administration. The humoral responses were not affected in a biphasic manner but single peaks of increased activity were seen which corresponded to the times of low cellular cytolytic and phagocytic activities. The ADCC was independent of time of Adriamycin administration. The significance of these findings to the design of therapeutic protocols is discussed.

Animals↗

PubMed1985

A new immunomodulator, LF 1695--I. In vitro effects on the T lymphocyte lineage in man.

A new immunomodulator, LF 1695, was analyzed in vitro for its capacity to induce T cell markers (HTLA and OKT3, 4 and 8 antigens), to enhance the mitogen-induced lymphocyte proliferation, and to increase the Con A-induced suppressor activity. The inductive activity was compared with that of thymic hormone (thymosin fraction V). LF 1695 was capable of significantly augmenting the percentages of HTLA+ cells (10-15%) and of OKT 3+,T4+, or T8+ cells (13-28%) in human bone marrow prothymocytes. Maximum induction was observed at the concentration of 0.5 microgram/ml. In addition, LF 1695 significantly augmented the proliferation of human peripheral blood lymphocytes stimulated by mitogens (Concanavalin A, phytohemagglutinin, pokeweed mitogen and phorbol myristate acetate). LF 1695 also increased the Con A-induced suppressor activity of human lymphocytes. These data indicate that LF 1695 is active both on T cell precursors and on more mature T cells.

Adjuvants, Immunologic↗

PubMed1986

In vivo immunomodulating activity of PK 1195, a structurally unrelated ligand for "peripheral" benzodiazepine binding sites--I. Potentiation in mice of the humoral response to sheep red blood cells.

PK 11195, an isoquinoline carboxamide compound with the highest affinity for the peripheral type benzodiazepine binding site has been shown to enhance the humoral response of mice to sheep red blood cells, a T cell dependent antigen. The compound was active when administered i.p. 1 day following immunization. The active doses ranged from 10 ng to 1 mg/kg. Such an immunomodulating activity might be related to the presence of peripheral type benzodiazepine binding sites, previously detected on the macrophage.

Adjuvants, Immunologic↗

PubMed1986

Immunomodulation exerted by cyclophosphamide is not interfered by N-acetyl cysteine.

Metabolism of cyclophosphamide (Cy) by liver enzymes results in cytostatic products and acrolein, which exerts urotoxicity. Experiments were designed to determine which metabolites are responsible for Cy-induced immunomodulation. For this purpose, mice were treated simultaneously with Cy and N-acetyl-cysteine (NAC), a thiol compound which reacts with acrolein, and different immunological functions were assayed. Results show that NAC did not interfere with Cy effects on antibody-dependent cellular cytotoxicity (ADCC), NK activity, delayed-type hypersensitivity (DTH) or antibody production, indicating that modulation of these functions by Cy is mediated by its cytostatic metabolites.

Acetylcysteine↗

PubMed1986

Immunopharmacological profile of HWA 486, a novel isoxazol derivative--II. In vivo immunomodulating effects differ from those of cyclophosphamide, prednisolone, or cyclosporin A.

We have shown in earlier studies that the isoxazol derivative, HWA 486, prevents the onset of the adjuvant disease in Lewis rats. The diminished arthritic reaction was correlated with an improved response of lymphocytes to T- and B-cell mitogens, indicating that HWA 486 may have immunomodulating activity. We have further elucidated the activity of this substance in mice and compared it to that of cyclophosphamide (Cy), prednisolone (Pr) and cyclosporin A (CsA). After five days of oral treatment the HWA 486 pattern of response differed from each of the three immunosuppressive agents. Both Cy and Pr inhibited the formation of plaque forming cells (PFC) to sheep red blood cells (SRBC), antibody production to SRBC, mitogen induced lymphocyte proliferation, and the PMA stimulated chemiluminescence of peritoneal lavage cells (PL-cells). CsA and HWA 486 were also inhibitory in the formation of PFC and antibodies to SRBC, yet neither substance affected the LPS induced blastogenesis. HWA 486 differs, though, from CsA in that the T-cell mitogens (Con A and PHA) were able to induce proliferation in lymphocytes obtained from animals treated with this compound. Also, the PMA-induced chemiluminescence from PL-cells was enhanced. The data indicates that HWA 486 has inhibitory activity on T-dependent B-cells, yet does not affect T-independent B-cells, and may not influence T-cell responsiveness. These findings may explain the disease modifying activity of HWA 486 in adjuvant-induced arthritic rats.

Animals↗

PubMed1987

Alleviation of depressed immunity caused by restraint-stress, by the immunomodulator, lobenzarit disodium (disodium 4-chloro-2,2'-iminodibenzoate).

The immunomodulating effect of lobenzarit disodium (CCA, disodium 4-chloro-2,2'-iminodibenzoate), was examined in restraint-stressed mice which exhibited immunodeficient conditions mainly based on dysfunction of helper T cells. Primary direct plaque-forming cell (PFC) responses to T cell-dependent antigens such as sheep red blood cell (SRBC) and dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH) were severely diminished by restraint-stress, whereas responses to T cell-independent antigens such as DNP-Ficoll (DNP-Fic) and trinitrophenyl-lipopolysaccharide (TNP-LPS) were little reduced and sometimes were even increased. CCA, orally administered to mice at a dose of 50 mg/kg body weight, significantly restored anti-SRBC PFC response. Restraint-stress also markedly decreased the proliferative response of splenic lymphocytes to concanavalin A (Con A), while it slightly augmented the response to lipopolysaccharide (LPS). CCA increased the response to Con A and suppressed the response to LPS. The number of T and B lymphocytes in the spleen were, however, reduced to the same degree by the stress and there was no striking difference in the susceptibility of these two subpopulations of splenic lymphocytes as analysed with fluorescein-activated cell sorter. CCA increased both T and B lymphocytes, but Lyt-1+ (helper/inducer T) cells recovered even more. It is noteworthy that in all these experiments CCA restored the weight of the thymus which is considered to be one of the organs most sensitive to stress. These results indicate that CCA promotes proliferation and differentiation of T cells, especially helper T cells, and restores immune functions depressed by restraint-stress.

Animals↗