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At least 685 records · Page 38Linked to original sources

PubMed2000

Polymeric drugs based on conjugates of synthetic and natural macromolecules. II. Anti-cancer activity of antibody or (Fab')(2)-targeted conjugates and combined therapy with immunomodulators.

We provide data on in vivo targeting of the Thy 1.2 (CDw90) cell surface receptor expressed on neoplastic T cells, mouse EL4 T cell lymphoma. The targeting antibody and the anticancer drug, doxorubicin (DOX) were conjugated to a water-soluble copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA) acting as a carrier responsible for controlled intracellular release of the conjugated drug. The in vivo therapeutic efficacy of HPMA copolymer-bound DOX targeted with anti-EL4 antibody, polyclonal anti-thymocyte globulin (ATG), monoclonal anti-Thy 1.2 antibody or its F(ab')(2) fragment was compared with the efficacy of DOX conjugated to HPMA copolymer containing nonspecific IgG or bovine serum albumin (BSA). Anti-EL4 antibody-targeted conjugate caused a significant retardation of tumor growth and an extension of the life span of treated mice. The effect was comparable with that of HPMA copolymer-bound DOX targeted with ATG, anti-Thy 1.2 antibody or its F(ab')(2) fragment. However, considerable antitumor effect was seen also in conjugates targeted instead of specific antibodies with syngeneic nonspecific IgG or BSA. Patients with advanced cancer are often immunocompromised due to dysfunction of their immune system induced by cancer and cytotoxic drugs. A significant decrease of unwanted side-effects of targeted drugs against a number of vital organs was already documented. In this study we have compared immunotoxic effects of free DOX with those of its antibody-targeted form on NK cells and cytolytic T lymphocytes (CTLs) isolated from C57BL/10 mice bearing EL4 T cell lymphoma. In the same model we have tested the combination therapy with immunomodulators (beta-glucan or AM-2) injected together with targeted daunomycin. We have observed a significant protective effect of targeted DOX against NK cells and CTLs. Moreover, the data revealed that combination therapy considerably enhances antitumor efficacy of the targeted anticancer drug.

Adjuvants, Immunologic↗

PubMed1993

Immunomodulating effect of ursodeoxycholic acid therapy in patients with primary biliary cirrhosis.

Peripheral blood lymphocytes of 22 patients with primary biliary cirrhosis under ursodeoxycholic acid therapy were examined for selected lymphocyte activation markers. The percentage of dipeptidyl peptidase IV positive Peripheral blood lymphocytes of primary biliary cirrhosis patients by using immune- and enzyme-histochemical staining was found to be low (5-12%), with healthy controls exhibiting a normal range of 18-27%. After pokeweed mitogen stimulation in vitro the interleukin-2 production by peripheral blood lymphocytes in primary biliary cirrhosis patients was significantly decreased (3.135 pg/ml mean value), compared to healthy subjects (61.167 pg/ml mean value). After 4-20 weeks ursodeoxycholic acid treatment the dipeptidyl peptidase IV expression and IL-2 production were normalised. These results provide evidence for the immunomodulating effect of ursodeoxycholic acid.

Adjuvants, Immunologic↗

PubMed2002

Immunomodulating activities of soluble synthetic polymer-bound drugs.

The introduction of a synthetic material into the body always affects different body systems, including the defense system. Synthetic polymers are usually thymus-independent antigens with only a limited ability to elicit antibody formation or to induce a cellular immune response against them. However, there are many other ways that they influence or can be used to influence the immune system of the host. Low-immunogenic water-soluble synthetic polymers sometimes exhibit significant immunomodulating activity, mainly concerning the activation/suppression of NK cells, LAK cells and macrophages. Some of them, such as poly(ethylene glycol) and poly[N-(2-hydroxypropyl)methacrylamide], can be used as effective protein carriers, as they are able to reduce the immunogenicity of conjugated proteins and/or to reduce non-specific uptake of liposome/nanoparticle-entrapped drugs and other therapeutic agents. Recently, the development of vaccine delivery systems prepared from biodegradable and biocompatible water-soluble synthetic polymers, microspheres, liposomes and/or nanoparticles has received considerable attention, as they can be tailored to meet the specific physical, chemical, and immunogenic requirements of a particular antigen and some of them can also act as adjuvants.

Adjuvants, Immunologic↗

PubMed2001

Immunomodulating activity of mycobacterial heat shock protein 65 in tumor cells.

In recent years, heat shock proteins have been shown to be effective in enhancing the immunogenicity of tumors. In this study, we examined the effect of mycobacterial hsp65 gene transfection in a non-immunogenic and aggressive tumor cell-line in order to understand the factors that could contribute to the increase in immunogenicity mediated by Hsp65. The transfected cells were found to have indeed lost their tumorigenenicity and increased their immunogenicity. Tumor-specific cytotoxic T cells were present only in mice immunized with the Hsp65-expressing cells. Furthermore, endogenous Hsp70 was significantly increased in irradiated Hsp65-expressing cells and recombinant Hsp65 protein was able to stimulate the mRNA expression of various T helper 1 (Th1) and pro-inflammatory cytokines in splenocyte cultures, as well as a modest expansion of CD4 T cells. These results provide further evidence of the immunomodulating properties of Hsp65, which could be exploited for the treatment of cancer.

Adjuvants, Immunologic↗

PubMed2000

Immunostimulating and protective effects of an oral polybacterial immunomodulator 'Dentavax' in a rabbit experimental model.

The immunostimulating and protective effects of an oral polybacterial immunomodulator, Dentavax (D), composed of killed cells from Klebsiella pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Candida albicans and Lactobacillus acidophilus and their lysates, have been investigated on an experimental rabbit model. In this model, mixed suspensions of the above bacterial wild strains have been injected in six sides of oral mucosa. A long-lasting inflammation with the development of infiltrates and confluating abscesses has been observed. The influence of orally given Dentavax on the course of the model infection as well as on the dynamics of the immune response has been studied. A two-fold decrease in the duration and severity of inflammatory reaction, confirmed by the histological findings, has been registered. In immunised animals, an activation of polymorphonuclear phagocytosis, together with stimulation of humoral systemic and mucosal immunity with synthesis of specific serum (predominantly, IgG) and coproantibodies (predominantly, S-IgA) determined by ELISA, has been found. The results obtained proved the strong immunostimulating and protective effects of the preparation D, which is meant for the prophylaxis and treatment of inflammatory periodontal diseases.

Adjuvants, Immunologic↗

PubMedDate not supplied

The immunomodulator OM-89 induces ACTH and glucocorticoid secretion in rats through an IL-1 dependent pathway.

The immunomodulator OM-89 (bacterial extract from E. coli), known to act on the immune system by modulating both humoral and cellular responses, significantly increases ACTH and glucocorticoids secretion in normal Wistar rats. A comparative administration of IL-1 displays a similar pattern of release. Moreover, OM-89-induced responses are blocked by IL-1ra, the soluble receptor antagonist of IL-1. The effect of OM-89 can thus be explained, at least in part, via IL-1 which directly enhances the secretion of both stress hormones. Finally, a comparative experiment between control and stressed rats (by immobilization) shows that the responses to OM-89 measured in this study (ACTH and corticosterone secretion) are stress-modulated.

Adjuvants, Immunologic↗

PubMedDate not supplied

Bacterial cell wall components as immunomodulators--II. The bacterial cell wall extract OM-85 BV as unspecific activator, immunogen and adjuvant in mice.

The bacterial extract Broncho-Vaxom used for the prevention and treatment of recurrent respiratory tract infections is an immunomodulator in vitro and in vivo, as determined in a murine model. The extract acts, on the one hand, as macrophage activator and polyclonal B-lymphocyte stimulant. On the other hand, after repeated intraperitoneal or oral immunizations, the extract is immunogenic, inducing serum IgG binding to the bacterial strains used for the preparation of the extract. On bacteria, the sera recognize the cell wall components porin, lipoprotein/lipopeptide and murein. The bacterial extract also exhibits adjuvant properties when applied in mixture with antigens, such as TNP-BSA or an influenza vaccine preparation. The unspecific and the immunospecific stimulatory effect of the extract as well as its adjuvant properties could be of importance for understanding its therapeutic effect.

Adjuvants, Immunologic↗

PubMedDate not supplied

Down-regulation of tumor necrosis factor-alpha, moderate reduction of interleukin-1beta, but not interleukin-6 or interleukin-10, by glucan immunomodulators curdlan sulfate and lentinan.

The effects of glucan-based immunomodulators curdlan sulfate (CRDS) and lentinan on cytokine production stimulated by lipopolysaccharide (LPS) in bacillus Calmette-Guerin (BCG)-primed mice were investigated. Pretreatment with CRDS or lentinan before LPS administration induced a striking inhibition of up to 89% of circulating tumor necrosis factor-alpha (TNF), a moderate reduction of 25% of interleukin (IL)-1beta, no significant differences in IL-6 or IL-10 levels, and a marked depression of chemiluminescence activity. Animals receiving CRDS prior to infection with alpha-hemolysin positive Escherichia coli inhibited measurable TNF production by 63%. The ability of CRDS and lentinan to significantly reduce the TNF production in vivo indicates the potential of glucans in possible therapeutic strategies that are based on down-regulation of TNF.

Adjuvants, Immunologic↗

PubMed1997

Immunomodulating activity of Chinese medicinal herbs and Oldenlandia diffusa in particular.

The effect of eight different Chinese medicinal herbs (CMHs) on lymphocytes was studied in vitro using murine spleen cells. Among the studied eight CMHs, Astragalus membranaceus and Oldenlandia diffusa markedly stimulated murine spleen cells to proliferate. The responder cells for CMHs were B cells, because the response was depleted by the treatment of spleen cells with anti-immunoglobulin (i.g.) antibody and complement and after purification by nylon wool column. This response was not due to contamination by lipopolysaccharide (LPS), because CMHs could stimulate C3H/HeJ spleen cells which are low responders to LPS. CMHs enhanced the production of Ig. CMHs also enhanced the induction of allo-antigen specific cytotoxic T lymphocytes. However, CMHs had no effect on natural killer cells. Furthermore, CMHs stimulated macrophages to produce interleukin-6 and tumor necrosis factor. The electroelution of the proteins from SDS-PAGE gel showed that the active components of Oldenlandia diffusa had an apparent molecular weight of 90-200 kD and were sensitive to pronase E and NaIO4 treatment, suggesting glycoproteins in nature. These results suggest that CMHs have immunomodulating activity in vitro and this activity could be used clinically for the modulation of immune responses.

Adjuvants, Immunologic↗

PubMed1999

Immunomodulating activity of seaweed extract on human lymphocytes in vitro.

Effect of eight kinds of seaweed extract (SWE) on human lymphocytes was studied in vitro. The extracts of Hizikiafusiformis and Meristotheca papulosa (green) markedly stimulated human lymphocytes to proliferate, whereas Eucheuma muricatum and Meristotheca papulosa (red) weakly stimulated proliferation. The responder cells are T cells, because T cells purified by sheep red blood cell (SRBC) rosette-formation were significantly stimulated with SWE, but B cells were not. These extracts enhanced the induction of cytotoxic T lymphocyte (CTL) activity, but failed to enhance natural killer (NK) cell activity. These extracts had a stimulatory effect on immunoglobulin (Ig) production by B cells and tumor necrosis factor (TNF) production by monocytes. The activity of Hizikia fusiformis associated with polysaccharides which were extracted with ethanol and purified by ion-exchange and gel filtration chromatography, whose molecular weight was about 100 kDa. These results suggest that SWE has an immunomodulating activity on human lymphocytes and this ability might be useful for clinical application to treat several diseases such as tumors.

Adjuvants, Immunologic↗

PubMed1999

Protective effects of RU 41740, a bacterial immunomodulator, against experimental infections: induction of cytokine and immunoglobulin release in mice after oral administration.

RU 41740 (Biostim) is an immunomodulator extracted from Klebsiella pneumoniae (strain O1:K2). In humans, it is able to reduce the number and duration of infectious exacerbations of chronic bronchitis. Using a mouse model of experimental infection, we found that oral RU 41740 administration strongly protected against gram-negative infections by preventing lethal septicemia, and, to a lesser extent, protected against the gram-positive intracellular pathogen L. monocytogenes. Oral administration of RU 41740 leads to the mobilization of newly dividing T and B cells in the thoracic duct lymph, reflecting the ability of the drug to induce an immune response in gut-associated lymphoid tissue. In cells isolated from mesenteric lymph nodes and spleen, RU 41740 leads to preferential release of the proinflammatory cytokines interleukin (IL)-12 and/or interferon (IFN)-gamma, as well as IL-10, a cytokine involved in inhibiting the synthesis of these latter cytokines. RU 41740 also increases the serum total immunoglobulin (Ig)M concentration and elicits IgM and IgG antibodies against the drug. Infection of mice with Klebsiella pneumoniae has similar functional consequences. Pretreatment of infected mice with RU 41740 leads to a fall in the high levels of proinflammatory cytokines (which could be detrimental), and to an increase in IgG antibodies (which are protective).

Adjuvants, Immunologic↗

PubMed1985

Immunomodulation of hematopoietic tumors.

Immunotherapy has been used in a variety of hematopoietic and solid tumors. Because patients with leukemia and lymphoma are immunosuppressed, immunomodulation with chemotherapy may be beneficial. Chemoimmunotherapy of canine lymphoma is discussed.

Animals↗

PubMed1984

Morphology and function of liver after intravenous and intraportal injections of the immunomodulating agent Propionibacterium granulosum.

An immunomodulator, cell walls from Propionibacterium granulosum strain KP-45 (PG), has been applied in rabbits to test its influence on morphology and function of liver cells. For investigation of distribution in internal organs, the PG preparation was 51Cr-labelled and injected i.v. into mice. Functional liver tests were performed in rabbits injected intravenously or intraportally with PG. Morphologic studies (light and electron microscopy) of liver sections were performed in mice and rats injected intravenously with PG, 1-60 d prior to liver examination. Intravenous or intraportal application of PG did not cause detectable clinical symptoms during the whole observation period (1-60 d). During the first 3-7 d, elevation of serum globulins and transaminases (SGOT, SGPT) were noted with reappearance of normal values after 14-20 d. 131I-labelled Bengal Rose injected into PG-treated rabbits was trapped mostly in the spleen, and to a smaller extent in liver, where radioactivity was significantly lower than in saline-injected control animals. 51Cr-labelled PG injected i.v. into mice were after 60-90 min localized preferentially in lungs and liver, where the radioactivity was much higher than in the spleen. Morphological studies revealed that 6 h following i.v. injection of PG, there appeared partial clearing of the hepatocyte cytoplasm and lowering of their basophilic content with enhancement of pinocytic activity of the hepatocytes. This was accompanied by enlargement of RES cells in liver with enhanced intracellular digestion, higher number of lysosomes and appearance of phagocytic vacuoles.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗

PubMed2001

Deoxynivalenol-induced immunomodulation of human lymphocyte proliferation and cytokine production.

Mycotoxins are a structurally diverse group of secondary metabolites produced by different genera of fungi, and include deoxynivalenol (DON), T-2 toxin, aflatoxin B1 (AFB1) and fumonisin B1 (FB1). Despite widespread human exposure and potent immunomodulation in animals, their effects on the human immune system remain to be defined. In this study, the effect of these toxins on human lymphocyte proliferation was evaluated using the MTT assay. Additionally, the effect of DON on cytokine profiles was measured. A 50% inhibition in cell proliferation was observed with a DON concentration of 216 ng/ml. T-2 toxin was more potent with 50% inhibition between 1 and 5 ng/ml. Negligible effects were observed with AFB1 and FB1, and a mixture of DON with either FB1 or AFB1 did not show any synergistic effects in this assay. Short-term treatment of PHA-stimulated lymphocytes with DON (100, 200 and 400 ng/ml) modulated the kinetics of IL-2, IL-4 and IL-6 production. IL-2 levels were up to 12-fold higher (P<0.05) in comparison to control levels at toxin concentrations of 200 and 400 ng/ml 72 h after treatment. IL-4 levels were only slightly elevated and IL-6 levels were slightly inhibited by these DON concentrations. The kinetics of cytokine production was followed for an extended period of 8-9 days at DON concentrations of 200 and 400 ng/ml. At the lower DON concentration (200 ng/ml), IL-2 levels were elevated 17-25-fold with a concomitant mild elevation in IFN-gamma. Consistent with earlier experiments, IL-6 levels were slightly suppressed by DON at this concentration. At 400 ng/ml, IL-2 levels were again significantly (P<0.05) elevated until 6 days post-treatment, while the effects on IL-4 and IL-6 were less marked. These data suggest DON has potent effects on human lymphocyte cytokine production which merit investigation in exposed human populations.

Cell Culture Techniques↗

PubMed2003

Immunomodulation by cocaine and ketamine in postnatal rats.

The abuse of cocaine (COC) in combination with ketamine (KET) among pregnant women was shown to be high. Transplacental exposure is not the only route by which a newborn may be exposed to these agents, but they can also distribute into breast milk. Chronic COC exposure is associated with immunological modulation in human and animal models. The effect of sub-chronic exposure to COC and KET alone and in combination on the developing immune system was assessed in neonatal male Sprague-Dawley (SD) rats. To simulate the route of exposure during lactation, newborn male rats were treated orally with saline, COC alone (20 mg/kg), KET alone (50 mg/kg), or KET (50 mg/kg) followed 15 min later by COC (20 mg/kg) from days 1 to 21 of life. Pups were sacrificed 30 min following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, while spleen/body weight ratio and IgM antibody response to sheep red blood cells (SRBCs) were increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin 10 (IL-10) concentration; however, it did not affect serum interferon gamma (IFN-gamma) concentration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when co-administered with COC, the immunomodulatory effects of COC were prevented. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. Lack of significant change of plasma and tissue concentrations of norcocaine (NC) suggested no role for COC metabolism in COC-induced immunomodulation. However, the results of this study indicate that COC-induced immunomodulatory reactions and their prevention by KET most likely occurred through neuroendocrinal mechanisms.

Adjuvants, Immunologic↗

PubMed1998

Immunomodulation induced by intrauterine transfusions.

Intrauterine transfusion (IUT) therapy offers a unique model to study the immunological consequences of fetal exposure to donor alloantigens. IUT can result in immediate and short effects. Directly after IUT a relative leukocytosis was observed, which was evenly distributed among the different leukocyte subsets. After the course of IUT treatment a memory response against donor antigens was generated. This was also reflected by an increase in CD3/CD45RO+ T-cells and modulation of T cell receptor Vbeta (TCRBV) repertoire. However, a long term clinical follow-up study on IUT patients who received this treatment in the 1960's revealed no evidence of serious side effects. Furthermore, persistence of donor leukocytes and in vitro immunomodulation could not be observed.

Blood Transfusion, Intrauterine↗

PubMed1998

Structural elucidation and conformational properties of the immunomodulator linomide.

Linomide is a new synthetic immunomodulator which exerts prominent anti-autoimmune effects in various experimental models. Recently, it was tested in clinical trials to patients suffering from multiple sclerosis and showed to inhibit the activity of the disease. Therefore, due to its pharmacological importance, we attempted elucidate its structure using one-dimensional and two-dimensional nuclear magnetic resonance (NMR) techniques and study its conformational properties using a combination of two-dimensional NMR spectroscopy and molecular modeling. The conformational analysis of linomide was based on the measurement of interproton nuclear Overhauser enhancement (NOE) values obtained from a two-dimensional NMR spectrum and a number of molecular modeling techniques used to calculate the low energy conformers of this compound. This information will serve as an aid to synthetic chemists whom their research activity is focused on developing linomide analogs with better biological profiles.

Adjuvants, Immunologic↗

PubMed2001

New immunomodulating drugs in autoimmune blistering diseases.

The autoimmune blistering diseases are a fascinating group of diseases characterized by the presence of blisters involving the skin and mucous membranes. Understanding of the diagnosis, pathophysiology, and advances in treatment of these diseases has grown enormously in recent years. In this article, the author discusses the major clinical and immunopathologic findings in bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, linea IgA bullous disease, and pemphigus. The article focuses on the therapeutic management of patients with autoimmune blistering diseases, including the appropriate treatment of patients, with particular emphasis on the use of immunomodulating and immunosuppresive agents.

Adjuvants, Immunologic↗