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PubMed2004

Ameliorating effects of the immunomodulator 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole in an experimental model of colitis in the rat.

The therapeutic efficacy of the immunomodulator 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (ST1959) in colonic inflammation was assessed in rats. One hour following colonic instillation of ethanolic 2,4,6-trinitrobenzene sulphonic acid (TNBS), intracolonic administration of 0.4 mg/kg ST1959 was started and continued once daily for 1 or 2 weeks. Daily administration of ST1959 for 1 week significantly reduced macroscopic and histological damage, myeloperoxidase activity, and colonic tissue levels of tumour necrosis factor-alpha and interferon-gamma. ST1959 did not affect interleukin-12 levels but significantly enhanced the production of interleukin-10 (sixfold increase). Two weeks of ST1959 treatment reduced the thickness of the colonic wall and myeloperoxidase activity to the same extent, and the histologic appearance of the mucosa was largely restored. The ameliorating effects seem to be ascribable to an impairment of both neutrophil infiltration/activation and tumour necrosis factor-alpha and interferon-gamma production, possibly consequent to the observed increase in the colonic tissue levels of the potent anti-inflammatory cytokine interleukin-10. Similar results were observed with the reference drug 5-aminosalycilic acid.

Animals↗

PubMed2006

Effect of the immunomodulator leflunomide on the induction of endometriosis in an experimental rat model.

The effect of immunomodulator leflunomide on the development of an experimental endometriosis model was assessed by surgically transplanting autologous fragments of endometrial tissue onto the inner surface of the abdominal wall and arterial cascades of the small intestines. Leflunomide was found to affect the development of endometriosis negatively and seemed to interfere with the growth and maintenance of the uterine explant in this experimental rat model.

Animals↗

PubMed2004

Immunomodulation by a dual altered peptide ligand of autoreactive responses to the acetylcholine receptor of peripheral blood lymphocytes of patients with myasthenia gravis.

Myasthenia gravis (MG) is a T cell-dependent, antibody-mediated autoimmune disease. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogs of two myasthenogenic peptides was demonstrated to downregulate in vitro and in vivo murine MG associated autoreactive responses. Furthermore, treatment with the dual APL ameliorated the clinical manifestations of an established experimental autoimmune MG in mice. This study was undertaken in order to investigate the ability of the dual APL to immunomodulate MG-associated responses of peripheral blood lymphocytes (PBL) of patients with MG to the native autoantigen acetylcholine receptor (AChR). PBL of 22 of 27 patients with MG tested responded by proliferation to torpedo AChR. The proliferative responses of PBL of 21 of 22 responders were significantly inhibited by the dual APL. The inhibition was specific because a control peptide did not inhibit these proliferative responses. The dual APL also downregulated the levels of the secreted pathogenic cytokine IFN-gamma in supernatants of stimulated PBL of 80% of the tested patients. The latter inhibitions correlated with an upregulated production of the immunosuppressive cytokine, tumor growth factor beta. Thus, the results of our study demonstrate that the dual APL is capable of downregulating in vitro autoreactive responses of patients with MG and suggest that this peptide is a potential candidate for a novel specific treatment of patients with MG.

Adult↗

PubMed2005

The course of infections and pathology in immunomodulated NOD/LtSz-SCID mice inoculated with Plasmodium falciparum laboratory lines and clinical isolates.

Human chimeras are potentially invaluable models for hemoprotozoan parasites such as Plasmodium falciparum. The work presented assesses the susceptibility of immunomodulated NOD/LtSz-SCID mice to genetically distinct P. falciparum parasites. To this end, mice grafted with human erythrocytes were inoculated with two P. falciparum laboratory lines, 3D7 and Dd2 and four clinical isolates, ISCIII-230, ISCIII-231, ISCIII-381 and ISCIII-399. The results showed that, without a previous period of parasite adaptation, 100% of the inoculated mice developed an infection, generally self-limited, though some mice died. The parasitemias ranged from 0.05 to 8% and lasted an average of 19 days (15-26 days) depending on the line or isolate studied. Sexual forms of different maturity, stage II-IV and mature gametocytes were observed in the peripheral blood of mice in 22, 50, 25, 72 and 80% of the mice infected with Dd2, ISCIII-399, ISCIII-230, ISCIII-231 and ISCIII-381 isolates, respectively. The study of the clinical symptoms, the haematological parameters and the histopathological changes in the infected mice showed that most of the malaria features were present in the infected mice except that the sequestration of infected erythrocytes was absent or at most a minor phenomenon, as also indicated by the presence of mature forms of the parasites in the peripheral blood. This study shows that the human chimeras allow the complete asexual and sexual erythrocytic cycle of different P. falciparum lines and clinical isolates to be observed in vivo. It opens a new way to investigate any parasite population in terms of infectivity, transmission, and drug resistance.

Animals↗

PubMed2004

Immunomodulating effects of cefodizime on Klebsiella pneumoniae-stimulated neutrophils.

To explore the immunoregulating effects of cefodizime on neutrophils and its mechanisms, we detected the expression of some cytokines secreted by neutrophils after heat-killed Klebsiella pneumoniae induced inflammation. We analyzed the changes of signal transduction in this process by detecting the mRNA expression of toll like receptor 4 (TLR4) and the inhibitor factor of kappaBalpha (I-kappaBalpha) expressed by neutrophils. The activity of nuclear factor kappaB (NF-kappaB) in neutrophils was also assayed by electrophoretic mobility shift assay (EMSA). We found cefodizime increased neutrophil production of TNF-alpha, IL-1beta in the early stage of inflammation, which was in agreement with the enhanced mRNA expression of TLR4 and DNA-binding activity of NF-kappaB. Taken together, the immunomodulating effects of cefodizime on cytokine production of K. pneumoniae stimulated neutrophils is possibly due to its regulation of TLR4 mRNA expression and DNA binding activities of NF-kappaB through the LPS-TLR4-NF-kappaB pathway.

Animals↗

PubMed2006

Immunomodulating capacity of commercial fish protein hydrolysate for diet supplementation.

Dietary proteins harbour bioactive peptides that can be released by a fermentation process. Fish proteins are a valuable and little-exploited source of potentially active biopeptides. The aim of this research was to evaluate the effects of a commercially available fermented fish protein concentrate (Seacure) (FPC) derived from a fermentation process, on the mucosal immune response in a murine model. BALB/c mice received the FPC or the non-fermented powder at different concentrations (0.20, 0.25 or 0.30mg/ml) for 2, 5 or 7 consecutive days. At the end of each feeding period, histological studies of the gut were carried out and the phagocytic activity of peritoneal macrophages, the number of IgA+ cells in the small intestine lamina propria and bronchial tissue and the number of IL-4+, IL-6+, IL-10+, IFNgamma+ and TNFalpha+ cells in the small intestine lamina propria were determined. Different accumulative doses of FPC did not induce any inflammatory immune response and the normal morphology of the small intestine was not affected. Phagocytic activity of peritoneal macrophages was enhanced following FPC administration at 0.3mg/ml for 7 consecutive days. The number of IgA+ cells increased in the small intestine lamina propria but not in the bronchial tissue. IL-4, IL-6 and IL-10 were all significantly increased in the lamina propria of the small intestine of animals that received FPC. At the same time, some pro-inflammatory cytokines such as IFNgamma and TNFalpha also increased, but the intestinal homoeostasis was maintained and no tissue damage was observed. We conclude that FPC is an immunomodulating food with a demonstrated capacity to enhance non-specific host defense mechanisms.

Administration, Oral↗

PubMed2004

ES-62, a filarial nematode-derived immunomodulator with anti-inflammatory potential.

Arthropod-transmitted filarial nematodes can survive for in excess of a decade via modulation of the vertebrate host immune system. Although human infection can result in very severe pathology, most infected individuals show remarkably little evidence of this. Analysis of the anti-nematode response indicates that apparently pathology-free individuals have an anti-inflammatory immunological phenotype and it has been suggested that this favours maintenance of host good health. It is considered that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus investigated the properties of a filarial nematode glycoprotein secreted in some abundance, ES-62. This molecule shows a plethora of immunomodulatory activities that can be classified as anti-inflammatory. It has been observed in a number of studies that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are transmitted to humans. Furthermore, it has been speculated that these two observations are linked although molecular explanations for such an association have not been forthcoming. Although the aetiology of RA remains unknown a majority of data are consistent with it being mediated via excess pro-inflammatory cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might be able to counter the pathology associated with diseases like RA. Indeed, we found that exposure to ES-62 prevented initiation of collagen-induced arthritis (CIA) in a murine model and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects correlated with inhibition of TNF-alpha production and inhibition of collagen-specific TH-1 responses. The nematode product was also able to suppress pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus constitutes a pathogen-derived immunomodulator with significant therapeutic potential.

Animals↗

PubMed2004

Characterization and immunomodulating activities of polysaccharide from Lentinus edodes.

The polysaccharide L-II was isolated and purified from the fruiting body of Lentinus edodes, which consisted of d-glucopyranose and had the molecular weight of 2.03 x 10(5) Da. We evaluated the effects of the polysaccharide L-II on the cellular immune response of Sarcoma 180-bearing mice. Mice were treated with three doses of the polysaccharide L-II (1, 5, and 10 mg/kg body weight) for 10 days. Tumor weight, relative spleen and thymus weight, delayed-type hypersensitivity (DTH) response, phagocytosis of macrophage, splenocytes proliferation were studied. Concentration of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) in mice serum were measured in control and polysaccharide groups. At the dose of 1, 5 and 10 mg/kg, a significant increase (p<0.05) in relative spleen and thymus weight, DTH, phagocytosis of macrophage was observed, as well as a significant decrease in tumor formation. The concentration of TNF-alpha, IFN-gamma in serum increased significantly in the polysaccharide groups compared with the model control group, but IL-2 not. Moreover, the polysaccharide L-II could increase NO production and catalase activity in macrophages. Results of these studies demonstrated the antitumor activity of the polysaccharide L-II on mice-transplanted sarcoma 180 was mediated by immunomodulation in inducing T-cells and macrophage-dependent immune system responses.

Animals↗

PubMed2005

Botanical polysaccharides: macrophage immunomodulation and therapeutic potential.

Botanical polysaccharides exhibit a number of beneficial therapeutic properties, and it is thought that the mechanisms involved in these effects are due to the modulation of innate immunity and, more specifically, macrophage function. In this review, we summarize our current state of understanding of the macrophage modulatory effects of botanical polysaccharides isolated from a wide array of different species of flora, including higher plants, mushrooms, lichens and algae. Overall, the primary effect of botanical polysaccharides is to enhance and/or activate macrophage immune responses, leading to immunomodulation, anti-tumor activity, wound-healing and other therapeutic effects. Furthermore, botanical and microbial polysaccharides bind to common surface receptors and induce similar immunomodulatory responses in macrophages, suggesting that evolutionarily conserved polysaccharide structural features are shared between these organisms. Thus, the evaluation of botanical polysaccharides provides a unique opportunity for the discovery of novel therapeutic agents and adjuvants that exhibit beneficial immunomodulatory properties.

Adjuvants, Immunologic↗

PubMed2006

Cellular and humoral systemic and mucosal immune responses stimulated in volunteers by an oral polybacterial immunomodulator "Dentavax".

The oral polybacterial immunomodulator Dentavax (D), composed of killed cells from Klebsiella pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Candida albicans and Lactobacillus acidophilus and their lysates was created for immunoprophylaxis and therapy of oral mucosa and parodont inflammations. The stimulating effect of the preparation was evaluated in twelve volunteers immunized for 10 consecutive days. On days 7, 14, 21, 28 and 49 after the last immunization peripheral blood (PB) lymphocyte subsets, T lymphocyte activation and PB phagocytic activity, were studied by flow cytometry. PB lymphocyte proliferative responses to PHA, rIL-2, LPS and D were evaluated radiometrically. The production of TNF-alpha in supernatants of in vitro stimulated lymphocytes and specific IgA, IgM and IgG antibodies in serum and saliva was determined by ELISA. Ultrastructural morphologic changes in T and B lymphocyte populations were also investigated. Although no significant changes in the levels of basic lymphocyte subsets were detected, the early/late (CD57+/CD57-) CD8 T effectors ratio was increased at the end of the studied period, as were the percentage of PHA-responding (CD69+) T cells and PB phagocytizing cells. The most prominent lymphoprolipherative responses were measured upon costimulation with LPS+D and PHA+D on day 21. Electron-microscopic studies demonstrated a significant effect of D on both T and B cell activity. TNF-alpha concentration increased progressively from day 7 till the end of the investigation. Maximal concentrations were observed after stimulation with D and LPS. An increased level of specific salivary and serum antibodies against the components of D was found, with highest levels between days 7 and 21. Specific secretory IgA predominated in saliva as compared to IgM and IgG. Our results demonstrate the stimulating effect of Dentavax on PB lymphocyte functional activity and the specific humoral systemic and mucosal immunity.

Administration, Oral↗

PubMed2006

Anti-tumor and immunomodulating effects of Pleurotus ostreatus mycelia-derived proteoglycans.

Pleurotus ostreatus is one of the widely cultivated edible mushrooms. Water-soluble proteoglycan fractions from P. ostreatus mycelia were purified by alcohol-precipitation, ion exchange and followed by gel permeation (Sephadex G-100) chromatography. Three neutral fractions were found, which had polysaccharide to protein ratios 14.2, 26.4 and 18.3, respectively. These fractions were tested for in vitro and in vivo immunomodulatory and anticancer effects on Sarcoma-180-bearing mouse model. In vivo injection of proteoglycans to Sarcoma-180-bearing mice decreased the number of tumor cells and cell cycle analysis showed that most of the cells were found to be arrested in pre-G(0)/G(1) phase of cell cycle. All of the three proteoglycans elevated mouse natural killer (NK) cell cytotoxicity and stimulated macrophages to produce nitric oxide. The Fourier transform infra red (FTIR) spectra suggested the presence of beta-glycosidic bond in all the fractions. Fraction I strongly interacted with glucose/mannose-specific lectin Concanavalin A (ConA), indicating the presence of large number of terminal sugar with glucose/mannose. Thus, the three neutral proteoglycans derived from the mushroom (P. ostreatus) mycelia could be used as immunomodulators and anti cancer agents.

Animals↗

PubMed2006

Immunomodulating effects of lichen-derived polysaccharides on monocyte-derived dendritic cells.

Many naturally occurring polysaccharides from fungi and lichens have been found to have immunomodulating activity. However, the majority of these studies have focused on their effects on the innate arm of the immune system. Although dendritic cells (DCs) belong to the innate immune system, they play an important role as a bridge between the innate and the adaptive immune response. In this study, the effects of 11 chromatographically purified and well-characterised lichen polysaccharides (of different structural types) on the maturation of DCs were tested by analysing the secretion of IL-12p40 and IL-10 by human monocyte-derived dendritic cells in vitro. Four of the polysaccharides upregulated IL-10 secretion by the dendritic cells, as compared with unstimulated cells, the beta-glucans lichenan and Ths-2 and the heteroglycans Pc-4 and thamnolan. IL-12p40 secretion was significantly upregulated by the beta-glucan lichenan and the heteroglycans Pc-2, Pc-4, thamnolan and Ths-4, while the mature dendritic cells stimulated with the heteroglycan Pc-1 secreted significantly less IL-12p40 than the unstimulated cells. Proportional index (PI) was used to determine the relationship between the IL-12p40 and IL-10 secretion. The PI of all the beta-glucans, i.e. lichenan, pustulan and Ths-2, and the heteroglycan thamnolan was significantly lower than the PI observed for the unstimulated cells, which was mainly due to increased IL-10 secretion. Therefore, these polysaccharides could be considered suitable candidates in tolerance and anti-inflammatory studies, as IL-10 is one of the major cytokines involved in tolerance and anti-inflammatory responses.

Anti-Inflammatory Agents↗

PubMed2007

Topical therapy of atopic dermatitis: controversies from Hippocrates to topical immunomodulators.

Although atopic dermatitis can be treated efficiently, there is still much controversy about the risk/benefit ratio of both topical corticosteroids and topical immunomodulators. Conflicting data may be found about the usefulness of bathing, diet regulation, and other therapeutic interventions. These controversies result in part from the persistence of Hippocratic doctrines in modern medical thinking. Humoralist and diathetic doctrines, as they pertain to eczema, are reviewed. The paradoxical worsening of oozing and the deadly hazards of hospitalization before the era of antibiotics are brought to mind. We hope that this historical review will improve the understanding of current controversies and help dermatologists to manage patients with atopic dermatitis and other chronic skin diseases.

Dermatitis, Atopic↗

PubMed2004

Isolation, partial characterisation and immunomodulating activities of polysaccharides from Vernonia kotschyana Sch. Bip. ex Walp.

The roots from Vernonia kotschyana Sch. Bip. ex Walp. (Baccharoides adoensis var. kotschyana (Sch. Bip. ex Walp.) M.A. Isawumi, G.El-Ghazaly & B. Nordenstam) (Asteraceae) are used in Malian folk medicine for the treatment of gastritis, gastro duodenal ulcers, as an aid to ameliorate digestion and as a wound healing remedy. Since a common feature among these conditions is related to immune responses, immunomodulating activities of fractions isolated from both the 50 degrees C and the 100 degrees C water extracts from Vernonia kotschyana were investigated in this study. The active principles were identified as acidic polysaccharide fractions, containing pectic arabinogalactan type II structures, which showed both complement fixing ability and T-cell independent induction of B-cell proliferation in vitro. Some activity was also observed on macrophages. The present study may provide additional support for the popular use of this plant to improve intestinal health.

Animals↗

PubMed2005

Medicinal use of Cochlospermum tinctorium in Mali Anti-ulcer-, radical scavenging- and immunomodulating activities of polymers in the aqueous extract of the roots.

Cochlospermum tinctorium A. Rich. (Cochlospermaceae) is a widely used medicinal plant in the West African country, Mali. An ethnopharmacological survey was conducted and 106 traditional practitioners interviewed. The roots were the part of the plant reported to be the most frequently used for medicinal purposes. The main indications were to treat jaundice (41), gastro intestinal diseases or ailments (28), malaria (12), schistosomiasis (10) and dysurea (6). A high-molecular weight water extract (25, 50 and 100 mg/kg, body weight) significantly inhibited HCl/ethanol-induced gastric lesions in mice. The extract showed DPPH-radical scavenging- and immunomodulating activities in vitro. The main components of the extract were identified as polysaccharides (59.3%) and polyphenols (9.3%). The polysaccharides were purified and characterised as highly complex pectic arabinogalactans type II. As parts of the polyphenol compounds gallotannins and ferulic acids were identified. This study shows that the polysaccharides are partly responsible for the bioactivities observed in vitro. Both polysaccharides and polyphenols may be responsible for the anti-ulcer activities observed.

Adjuvants, Immunologic↗

PubMed2004

Antibody-mediated remyelination operates through mechanism independent of immunomodulation.

A set of antibodies capable of binding glial cells promotes remyelination in models of multiple sclerosis (MS). Within this set, the mouse antibody, SCH94.03, was immunomodulatory implying that immune system mobilization might be integral to remyelination. We evaluated whether the human remyelination-promoting antibody rHIgM22 influences acquired immunity. The antibody did not bind to immune cells, or influence humoral immune responses, antigen presentation, T cell proliferation or cytokine production. Treatment with rHIgM22 had no effect on demyelination or virus infection in two disease models. These results demonstrate that the remyelination-promoting activity of antibody rHIgM22 is not dependent on immunomodulation.

Adjuvants, Immunologic↗

PubMed2006

Immunomodulation of TGF-beta 1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy.

Irreversible connective tissue proliferation in muscle is a pathological hallmark of Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease due to lack of the sarcolemmal protein dystrophin. Focal release of transforming growth factor-beta1 (TGF-beta1) is involved in fibrosis development. Murine muscular dystrophy (mdx) is genetically homologous to DMD and histopathological alterations comparable to those in DMD muscles occur in diaphragm of older mdx mice. To investigate the early development of fibrosis and TGF-beta1 involvement, we assessed diaphragms in 6-36-week-old mdx and C57/BL6 (control) mice for fibrosis, and used real-time PCR and ELISA to determine TGF-beta1 expression. Significantly greater fibrosis and TGF-beta1 expression were found in mdx from the 6th week. Mice treated with neutralizing antibody against TGF-beta1 had lower levels of TGF-beta1 protein, reduced fibrosis, unchanged muscles fiber degeneration/regeneration, but increased inflammatory cells (CD4+lymphocytes). These data demonstrate early and progressive fibrosis in mdx diaphragm accompanied by TGF-beta1 upregulation. Reduction of TGF-beta1 appears promising as a therapeutic approach to muscle fibrosis, but further studies are required to evaluate long term effects of TGF-beta1 immunomodulation on the immune system.

Animals↗

PubMed2006

Leflunomide--an immunomodulator--induces regression of endometrial explants in a rat model of endometriosis.

OBJECTIVE: To test if leflunomide, an immunomodulator, could impede the growth of an ectopic uterine tissue. METHODS: Endometriosis was surgically induced in 26 rats by transplanting an autologous fragment of endometrial tissue onto the inner surface of the abdominal wall. Four weeks later two rats were killed. The volume and weight of the implants were measured. The remaining rats were randomly grouped, and in group 1 no medication was given. To the rats in group 2, 35 mg/kg/d of leflunomide was administered orally. Four weeks later, rats were killed and ectopic uterine tissues were reevaluated morphologically and histologically. A scoring system was used to evaluate preservation of epithelia. RESULTS: Two rats in the control group died 5 weeks after surgery. There was a significant difference in post-treatment spherical volumes (139.1 +/- 92.8 versus 33.5 +/- 12.5 mm3) and explant weights (156.3 +/- 105.6 versus 38.6 +/- 12.6 mg) between the control and leflunomide-treated groups. The epithelia were found to be preserved significantly better in the control group when compared with the leflunomide-treated group (median 2.5 [interquartile range, 1.25] versus median 1.00 [interquartile range, 1.5]). CONCLUSION: Leflunomide appeared to cause regression of experimental endometriosis in rats.

Animals↗