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Sensitivity to chemotherapeutic and immunomodulating agents of two mouse lymphomas and of a macrophage tumor.

The effect of treatment with 15 chemotherapeutic and 10 immunomodulating agents on the growth of T-cell lymphoma EL-4, macrophage tumor J774, and B-cell lymphoma 70Z/2 of the mouse has been studied using the prolongation of median survival time of tumor-bearing hosts as an index of therapeutic effectiveness. The survival time of mice bearing 70Z/2 was prolonged more than 100% by single-agent therapy with actinomycin D, cyclophosphamide, 6-mercaptopurine, mitomycin C, and vinblastine; a similar response of J774 was produced by therapy with Adriamycin, cyclophosphamide, or 6-mercaptopurine. No chemotherapeutic agent prolonged the median survival time of mice bearing EL-4 by 100% or more. Of the immunomodulating agents, mycobacterial preparations (Bacillus Calmette-Guérin or interphase material), Corynebacterium parvum, and polyinosinic-polycytidylic acid moderately prolonged the survival time of mice bearing J774 or 70Z/2; the EL-4 lymphoma was refractory to all 10 immunomodulating agents.

Adrenal Cortex Hormones↗

Influence of agents with immunomodulating activity on phagocytosis and bactericidal function of human polymorphonuclear cells.

Six immunomodulators were tested for the influence on phagocytosis and intracellular bactericidal activity of human polymorphonuclear cells (PMN). Frentizole, lamprene, intal and levamisole but not dapsone enhanced phagocytosis in the presence of serum. Without serum, frentizole strongly enhanced phagocytosis, whereas lamprene, levamisole and dapsone had weaker enhancing activity. Rifampin suppressed phagocytosis of Staphylococcus aureus whether the serum was present or not. The influence on phagocytosis was time and dose dependent. All drugs but dapsone markedly enhanced intracellular bactericidal activity of PMN in a dose dependent fashion. Dapsone enhanced bactericidal activity without the serum and suppressed it in its presence. It may be concluded that immunomodulators are a heterogeneous group of substances and their influence on phagocytosis and cellular bactericidal activity varies. Enhancing activity of some immunomodulators implies that they may be used in conditions with impaired phagocytosis.

Adjuvants, Immunologic↗

Current status and perspectives of immunomodulators of microbial origin.

The chemical structure and characteristics, the antitumour activity, the antibacterial, antiviral, antifungal, antiparasitic activities, immunological properties and mode of action of immunomodulators of microbial origin, especially antitumour polysaccharide lentinan, have been discussed immunopharmacologically in comparison with pachymaran, schizophyllan, DiLuzio's yeast glucan, Coriolus preparation PS-K, Streptococcal preparation OK-432, Nocardia rubra cell wall skeleton N-CWS together with BCG and Corynebacterium parvum. Lentinan exerts its inhibitory action not only on allogeneic tumours but also on syngeneic and autologous tumours, and prevents chemical and viral carcinogenesis. The phase III randomized control study of lentinan in cancer patients with gastric and colo-rectal cancer showed the clinical efficacy of lentinan in prolonging the life span and improving host immune responses. Experimental and clinical application demonstrated the advantage of N-CWS over BCG-CWS, and a recent study on OK-432 showed similar results to those obtained with C. parvum. In future work on microbial immunomodulators, it will be essential to find a parameter of the host-tumour relationship which will indicate the protocol for application of immunomodulators, and to find a new-type of selective immunostimulant. For this purpose, exhaustive studies on lymphokines, monokines and lymphocyte tropic hormones are indispensable.

Adjuvants, Immunologic↗

The activation of tumoricidal properties in macrophages of endotoxin responder and nonresponder mice by liposome-encapsulated immunomodulators.

The purpose of these studies was to determine whether various immunomodulators such as lipopolysaccharide (LPS), lymphokines with macrophage activation factor (MAF), or muramyl dipeptide (MDP) could activate the tumoricidal properties in LPS-responsive C3H/HeN and LPS-unresponsive C3H/HeJ mice. In all studies we examined the interaction of the different immunomodulators in a free form or encapsulated within liposomes (multilamellar vesicles) with alveolar macrophages (AM) and/or peritoneal exudate macrophages (PEM). In vivo infection with viable Mycobacterium bovis, strain BCG, induced the development of highly activated macrophages from C3H/HeN mice, yet only marginally activated macrophages from C3H/HeJ mice. In vitro incubation with MAF or LPS rendered AM and PEM from C3H/HeN, but not C3H/HeJ, mice tumoricidal. The failure of C3H/HeJ macrophages to respond to LPS stimulation was due to an intracellular defect. C3H/HeJ macrophages bound fluorescein-conjugated LPS to the same extent as that found for C3H/HeN macrophages. Furthermore, LPS encapsulated in liposomes activated C3H/HeN but not C3H/HeJ AM and/or PEM. Macrophages from both strains could be rendered highly tumoricidal following interaction with free MDP or following endocytosis of liposomes containing MDP or MAF. These results indicate that the inability of C3H/HeJ macrophages to respond to LPS stimulation is specific and that the activation of macrophages by different immunomodulators could occur by different pathways.

Acetylmuramyl-Alanyl-Isoglutamine↗

Modulation of granulomatous hypersensitivity. IV. Immunoglobulin and antibody production by vigorous and immunomodulated liver granulomas of Schistosoma mansoni-infected mice.

The interlesional production of immunoglobulins and SEA-specific antibodies was examined in vitro in cultured hepatic granulomas isolated from Schistosoma mansoni-infected mice. Vigorous lesions of 8-wk and immunomodulated lesions of 20-wk infected mice were cultured in serum-free medium for 48 hr; the supernatant fluid was concentrated, dialyzed, and tested for immunoglobulins by immunodiffusion. Whereas cultures of vigorous granulomas contained only IgG1, those of immunomodulated lesions yielded IgG1, IgG2a, IgG2b, IgG3, and IgA immunoglobulins. Both types of lesions incorporated 14C-labeled leucine into IgM and IgG class immunoglobulins thus proving intralesional synthesis. The immunoglobulins also had specific anti-SEA activity proven by passive hemagglutination and in vivo PCA test. The kinetics of SEA-specific IgM and IgG antibody-forming granuloma lymphocytes was examined by the plaque assay after the dispersal of the lesions. At 8 wk of the infection the number of IgM antibody-producing lymphocytes was low and that of IgG was negligible. In subsequent weeks both IgM and IgG antibody-forming cells increased in numbers. The IgM producer cells peaked at 12 to 16 wk and by 32 wk they dropped to barely detectable levels. The IgG antibody-producing lymphocytes peaked in numbers in the immunomodulated lesions at 20 wk and also disappeared by 32 wk. The kinetics of the granuloma lymphocytes as well as the magnitude of their response differed from those of splenic cells. Intralesional antibody production may promote antigen sequestration, complex formation, and occasional tissue injury. The participation of locally produced antibodies in the modulation of the granulomatous inflammatory response remains to be established.

Animals↗

[The mechanism of the combined action of immunomodulators on phagocytic cells].

The study revealed that the injection of different immunomodulators (salmosan, levamisole, BCG, prodigiosan) or such irritants as meat-peptone broth led to the formation of heterogeneous macrophage populations, differing in their phagocytic function, oxidation metabolism, secretion of protein products. The additional injection of immunomodulators led neither to further increase in the influx of cells into the abdominal cavity, nor to further activation of the phagocytic function in all cases, irrespective of background and additional preparations used in the experiment. The response was determined by the first stimulus. Each of these macrophage populations was seemingly in a characteristic state of self maintenance during a certain period when it was insensitive to the second stimulus, i.e. the existence of a certain refractory period was revealed. The effect produced by the additional injection was registered only at the expiration of the refractory period. Therefore, the data on the presence of a certain refractory period and its duration for each immunomodulator should be established and taken into consideration in working out the schedule of their combined use.

Adjuvants, Immunologic↗

Effects of a novel topical immunomodulator, imiquimod, on keratinocyte cytokine gene expression.

A novel immunomodulator, imiquimod, has been shown to be an effective topical antiviral and antitumor agent in animal models. Imiquimod has been reported to induce interferon-alpha and other cytokines in animals and humans, but its precise role as an immunomodulator at skin sites has not been determined. We investigated its effect on cytokine gene expression in the human epidermal carcinoma cell line COLO-16 and human keratinocytes. COLO-16 cells were incubated with imiquimod (1 and 10 micrograms/ml) and human keratinocytes with 5 micrograms/ml for 6 or 24 h. Cytokine gene expression was analyzed by reverse-transcriptase PCR. In COLO-16 cells, imiquimod stimulated IL-6 mRNA levels 2.3- and 4.4-fold at 1 and 10 micrograms/ml after 6 h. IL-8 mRNA increased 4-fold at both 1 and 10 micrograms/ml. At 24 h, though IL-6 mRNA level at 1 micrograms/ml was further stimulated, enhanced expressions of IL-8 at 1 micrograms/ml and both IL-6 and IL-8 at 10 micrograms/ml were down-regulated. In human keratinocytes, 5 micrograms/ml of imiquimod stimulated IL-6 mRNA levels 1.4-fold at 6 h and 2.1-fold at 24 h, and IL-8 mRNA levels 1.7- and 2.0-fold at 6 and 24 h. IL-1 alpha mRNA levels in COLO-16 or keratinocytes were unchanged by either dose or incubation time. These results suggest that stimulation of IL-6 and IL-8 expression may be involved in the immunomodulating action of imiquimod.

Adjuvants, Immunologic↗

Effect of immunomodulators in the hu-PBL-SCID mouse model.

The effects of two immunomodulators were investigated in severe combined immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID mice). Both immunomodulators, maleic anhydride divinyl ether (MVE-2) and 4-imino-1,3-diazobicyclo-(3.1.0)-hexan-2- one (imexon), have been previously studied by us in retrovirus-infected mice. To determine the effects of these compounds as they may function in humans, 24 SCID mice were each reconstituted with 20 x 10(6) ficoll-purified lymphocytes from a single donor. Five weeks after reconstitution, the mice received 16 mg/kg/day of MVE-2 intraperitoneally (i.p.) on days 0, 7, and 14 or 110 mg/kg/day of imexon i.p. daily for 14 days. Spleens were removed and splenocytes labeled with monoclonal antibodies for T- and B-cell enumeration as determined by flow cytometry 24 h after final treatment. Imexon-treated mice demonstrated a slight increase in total T cells and T cell subsets compared to control mice. T helper/T suppressor cell ratios in imexon-treated mice were brought to a normal 3:2 ratio compared to placebo-treated mice. Human immunoglobulin levels were markedly increased in imexon-treated mice. MVE-2-treated hu-PBL-SCID mice had significantly reduced numbers of total T cells compared to controls. The T-cell population results using human cells in SCID mice were similar to the effects of these immunomodulators on murine cells in immunologically competent mice.

Adjuvants, Immunologic↗

[Food-acquisition and avoidance behaviors: the role of immunomodulators in their systemic organization].

The experimental data concerning some aspects of neuroimmunology were analysed. The problems of likeness between immune and nervous systems (origin, functions, common substances, etc.) and particularly the participation of immunomodulators in the mechanisms of neural memory are under discussion. It was shown that administration of immunomodulator neurotropin (NSP) results in more steady consolidation and retention of feeding and avoidance behavior, and some neurophysiological mechanisms of that phenomena were revealed. Among them were the reorganization of neuronal interspike patterns in cortex and hippocampus; increasing the levels of vegetative (heart rate, respiration) and behavior parameters of learning during conditioning. Whole this complex of changes was retrieved during intersignal periods. The results suggest that one of the mechanisms of immunomodulators action on the learning and memory is the activation of reverberation processes in brain.

Adjuvants, Immunologic↗

Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract.

Commercially available mistletoe extract standardized for the galactoside-specific lectin (ML-1; Eurixor) and a chromatographically ML-1-depleted preparation (same charge no. and composition of remaining components) were tested for their immunomodulating potency. In BALB/c-mice, regular subcutaneous administration of the optimal immunomodulating dosage (1 ng ML-1/kg body weight) could be shown to induce no influence on spleen weight, a non-significant increase of thymus weight, a significant increase of thymocyte, peritoneal macrophage, peripheral blood leukocyte, lymphocyte and monocyte and monocyte counts, and a significant decrease of peripheral blood granulocyte counts. Administration of analogue volumes (concentrations) of ML-1-depleted extract, however, did not induce any immunopotentiation. Accordingly, it may be assumed, that the galactoside-specific lectin (ML-1) represents the main immunomodulating component in commercially available mistletoe extracts.

Adjuvants, Immunologic↗

[Immunosuppressive and immunomodulator treatment of severe systemic lupus].

Immunosuppressor and immunomodulator therapies are widely used for the treatment of patients with severe systemic lupus erythematosus. In case of certain organ involvement (kidney, brain, heart), corticosteroids should be associated with immunosuppressors, especially cyclophosphamide. Cyclophosphamide, a powerful immunosuppressor, is generally given in an intravenous bolus rather than orally. Aziathioprine is proposed after cyclophosphamide or in less forms at onset. The therapeutic strategy in severe forms may require plasma exchange, carefully synchronized with the cyclophosphamide bolus. Depleted antibodies following plasma exchange induces a stimulation of B clones which produce antibodies sensitive to cyclophosphamide. Other immunomodulator treatments have also been used, for example cyclosporine or intravenous immunoglobulins. Cyclosporine has not been shown to be effective in severe lupus. Inversely, in certain conditions, cyclosporine can be used to limit other treatments although it does not have a significant effect on autoantibody levels. Intravenous immunoglobulins have been used at high dosages but only in selected cases due to undesirable side effects. Certain cases of renal failure induced by immunoglobulins have been described. Immunosuppressor or immunomodulator therapy is often required in systemic lupus erythematosus. Treatment modalities must however be carefully established in order to limit the predictable side effects while achieving maximal efficacy.

Adjuvants, Immunologic↗

[The individual selection of immunomodulating and vitamin preparations for miners who are frequently ill with ARVI].

Proper selection of immunomodulating and vitamin preparations in those miners often ill with ARVI promotes to a great extent both dispelling immunologic disbalance in the cellular link of immunity and normalization of the functional state. But this action is less effective in respect of specific and unspecific humoral factors of the immune system. Individual assessment of effectiveness of immunomodulating and vitamin preparations in vitro tests is regarded as a justified and promising tool enabling a relevant preparation endowed with stimulating effect to be selected and prescription of those substances sensibilizing the organism of the always ailing miners to be excluded, thus ensuring maximum immunomodulating effect.

Acute Disease↗

[Immunomodulating action of eubiotics].

The study was undertaken to study the immunomodulating action of 3 bacterial agents: bifidumbacterin, acylact, and biosporine used in various abnormalities accompanied by intestinal dysbacteriosis. Surveys were made of children permanently residing in the radionuclide-contaminated areas of the Bryansk Region, those from northern areas of the Russian Federation, those who suffered from atopic dermatitis; adult patients with severe systemic disease (chronic postinfection polyarthritis); chronic adult patients with spinal injury due to compression fractures of the spinal cord. The immunological parameters in all the above patient groups were shown to differ in the lower absolute or relative counts of most lymphocytic populations. The addition of bacterial drugs into their therapy promoted normalization of the intestinal microflora and led to improvement or complete normalization of immunological parameters. With this, bifidumbacterin and acylact were demonstrated to be potent, but mild immunomodulators as they significantly improved or normalized the status of the baseline suppressed immune system and virtually failed to affect normal immunological parameters. The earlier data obtained with biosporine provide evidence for that this bacterial agent has immunomodulating activity; however, it is necessary to comprehensively study its effects on the immune system in health and in disorders typical of various abnormalities.

Adjuvants, Immunologic↗

[Pancreatic islet transplantation: isolation techniques and in vitro immunomodulation].

OBJECTIVES: To develop pancreatic islet isolation and purification techniques in order to be able to test two human pancreatic islet immunomodulation techniques on an in vitro model of allograft islet rejection. METHODS: Islet isolation was performed according to Ricordi's method, which was slightly modified during the study. Purification was performed according to the Euroficoll discontinuous gradient method on a Cobe 2991 centrifuge. The results of immunomodulation techniques (depletion of cells expressing class II HLA molecules, and immunomasking of HLA class I molecules) were assessed in vitro by mixed lymphocyte-islet cocultures (MLIC). RESULTS: Seventeen pancreatic islets were isolated then purified. Technical improvements increased the yield from 2,247 +/- 1,984 to 4,567 +/- 990 islet-equivalents per gram. The mean purity was 70 +/- 19% (40-90%). Immunomodulation by depletion of class II HLA molecules regularly inhibited (84%) MLIC in contrast with masking of class I antigens, which induced only a moderate (44%) and inconstant (4 experimentations out of 6) inhibition. CONCLUSION: The modifications made to the islet isolation method improved its yield and now allow the possibility of clinical applications. The results of mixed lymphocyte-islet cocultures suggest that the suppression of nonendocrine cells expressing class II HLA molecules on their surface reduces the immunogenicity of pancreatic islet grafts.

Graft Rejection↗

[Prevention of acute respiratory infections in healthy young adults by using oral immunomodulators].

It is a general experience at army posts that right after the joining up period the number of airway infections suddenly increases. The upper and lower airway infections are especially facilitated by the confinement of military barracks, and the high number of smokers among soldiers. In the winter of 1995/96 at an army post of the Hungarian National Defense Forces authors treated 68 healthy, young recruits, aged between 18-23 preventively with an immunomodulant which contains lyophilized bacterial extracts, and placebo. The aim was to try this medicine on healthy adults to prevent or influence acute respiratory infections. In one third of the nine-month long follow-up period, a blind study was carried out, and two thirds of it were spent with a double blind one. The number of airway infections and off duty days was reduced by more than 40% in the group which was treated with the immunomodulant. In case of airway infection the complains and the signs were also milder in this group. Furthermore the medicine consumption decreased too. All of these indicate that the tried immunomodulant can be used in the primary prevention of airway infections among healthy adults even in a markedly infective environment.

Acute Disease↗

[The immunomodulating activity of a transfer-factor preparation transflavin, specific to tick-borne encephalitis virus].

Transflavin, a transfer-factor preparation specific to tick-borne encephalitis virus, was experimentally shown to possess immunomodulating action. The immunomodulating action of this preparation could be observed in a dose of 1 D (1 D being equivalent to 5 x 10(8) lymphocytes), which was manifested by an increase in the phagocytic activity of neutrophils and macrophages, a rise in the amount of T-lymphocytes, an increase in rosette formation, the number of antibody-forming cells, increased proliferation on T- and, to a lesser extent, B-cell mitogens, the restoration of the T-dependent expression of lymphocyte receptors, inhibited by trypsin. Transflavin in doses of 0, 1 and 10 D suppressed primary immune response. The probable mechanisms of the immunomodulating action of the Transflavin under study is discussed.

Adjuvants, Immunologic↗

Chemiluminescent analysis of the antioxidant and immunomodulation effects of several psychotropic drugs on peritoneal macrophages.

The present study describes the application of several chemiluminescent (CL) methods for evaluation of antioxidant and immunomodulation effects of psychotropic drugs upon phagocytes: KO2-induced luminal-dependent CL for detection of superoxide anion radicals in a pure chemical system; PMA- and A23187-induced CL of peritoneal macrophages for detection of free radicals in cell suspension; and CL, produced by the luciferase-catalyzed luciferin + ATP reaction, for evaluation of cell viability before and after drug application. These methods provide also a way to investigate the location of drug action. It was found that the psychotropic drugs in fluence the 'oxidative burst' of macrophages through two mechanisms: by expression of drug antioxidant properties and/or by a direct immunomodulation effect.

Amitriptyline↗

Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway.

Estrogen (E2)-induced immunomodulation involves dual effects on antigen-presenting cells (APC) and CD4(+)CD25(+) regulatory T cells (Treg) but not a direct effect on effector T cells. In this report, we further investigated the effects of E2 on APC and Treg function. We found that E2 treatment in vivo strongly reduced recovery of APC from the peritoneal cavity and inhibited induction of the inflammatory cytokines interleukin (IL)-12 and interferon-gamma but enhanced secretion of IL-10. Moreover, E2-conditioned bone marrow-derived dendritic cells (BM-DC) could both enhance Treg activity and directly inhibit responder T cells in the absence of Treg cells. We examined whether this E2-induced inhibitory activity of BM-DC might involve costimulation through the recently described PD-1 pathway. Both E2 and pregnancy markedly enhanced PD-1 expression in several types of APC, including macrophages, B cells, and especially dendritic cells (DC). Similarly to E2-induced enhancement of FoxP3 expression and experimental autoimmune encephalomyelitis protection, E2-induced enhancement of PD-1(+) cells was also mediated through estrogen receptor alpha (Esr1) in DC and macrophages but not in B cells. Based on antibody inhibition studies, PD-1 interaction with its ligands, PDL-1 and especially PDL-2, could mediate either positive or negative regulatory signaling in both mature and immature E2-conditioned DC, depending, respectively, on a relatively high (10:1) or low (1:1) ratio of T cells:BM-DC. These novel findings indicate that E2-induced immunomodulation is mediated in part through potentiation in BM-DC of the PD-1 costimulatory pathway.

Animals↗