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Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment.

It has been suggested that vitamin B12 (vit.B12) plays an important role in immune system regulation, but the details are still obscure. In order to examine the action of vit.B12 on cells of the human immune system, lymphocyte subpopulations and NK cell activity were evaluated in 11 patients with vit.B12 deficiency anaemia and in 13 control subjects. Decreases in the number of lymphocytes and CD8+ cells and in the proportion of CD4+ cells, an abnormally high CD4/CD8 ratio, and suppressed NK cell activity were noted in patients compared with control subjects. In all 11 patients and eight control subjects, these immune parameters were evaluated before and after methyl-B12 injection. The lymphocyte counts and number of CD8+ cells increased both in patients and in control subjects. The high CD4/CD8 ratio and suppressed NK cell activity were improved by methyl-B12 treatment. Augmentation of CD3-CD16+ cells occurred in patients after methyl-B12 treatment. In contrast, antibody-dependent cell-mediated cytotoxicity (ADCC) activity, lectin-stimulated lymphocyte blast formation, and serum levels of immunoglobulins were not changed by methyl-B12 treatment. These results indicate that vit.B12 might play an important role in cellular immunity, especially relativing to CD8+ cells and the NK cell system, which suggests effects on cytotoxic cells. We conclude that vit.B12 acts as an immunomodulator for cellular immunity.

Adjuvants, Immunologic↗

Immunomodulating effects of 3-thia fatty acids in activated peripheral blood mononuclear cells.

BACKGROUND: 3-thia fatty acids such as tetradecylthioacetic acid (TTA) are modified fatty acids that have been suggested to change the plasma profile from atherogenic to cardio protective. Because of its interaction with peroxisome proliferator activated receptor (PPAR) we hypothesized that TTA also could have immunomodulatory properties. Based on the suggested role of inflammation in atherogenesis, any immunomodulating effects of TTA would be of particular interest for the potential use of this fatty acid in atherosclerotic disorders. MATERIALS AND METHODS: We examined if TTA could modulate proliferation and the release of cytokines from peripheral mononuclear cells (PBMCs) taken from five healthy blood donors. RESULTS: Our main findings were: (i) TTA had several effects on cytokine release from activated PBMCs with a marked increase in interleukin (IL)-10 accompanied by a reduction in IL-2 possibly favouring anti-inflammatory net effects. (ii) These cytokine-modifying effects were found in both T cells and monocytes when cultured separately. (iii) Tetradecylthioacetic acid increased the cytokine stimulating effects of tumour necrosis factor alpha with a particularly enhancing effect on IL-10. (iv) Tetradecylthioacetic acid significantly suppressed PBMC proliferation, and this antiproliferative property did not involve enhanced apoptosis or necrosis. (v) These immunomodulatory effects of TTA were accompanied by a marked down-regulation of PPARoad mRNA expression, the most abundant PPAR subtype in PBMCs. CONCLUSIONS: Our findings show potent immunomodulatory effects of TTA in activated PBMCs, possibly involving PPAR-related mechanisms.

Adult↗

Effect of the synthetic immunomodulator, linomide, on experimental models of thyroiditis.

The drug Linomide is an immunomodulator showing marked down-regulation of several experimental autoimmune diseases. In this study, its effect on three different experimental models of thyroid disease and on spontaneous infiltration of salivary glands (sialoadenitis), was investigated. Although very effective at preventing thyroid infiltrates in mice immunized with mouse thyroglobulin and complete Freund's adjuvant and in spontaneous models of thyroiditis and sialoadenitis, it completely failed to modify experimental autoimmune thyroiditis (EAT) induced in mice immunized with mouse thyroglobulin and lipopolysaccharide. There was no significant shift in the observed isotypes of anti-mouse thyroglobulin antibodies and only anti-mouse thyroglobulin antibodies in the spontaneous model were completely down-modulated by the drug. One surprising fact to emerge was that Linomide-treated donor mice, although protected from thyroid lesions themselves, were still able to transfer EAT showing that they must have been effectively primed while being treated with Linomide. It is possible that the drug down modulated EAT by interfering with the trafficking of primed effector cells.

Adjuvants, Immunologic↗

Antibabesial effect of the immunomodulator AS101 in mice: role of increased production of nitric oxide.

The immunomodulator AS101 has been shown to induce cell proliferation and to increase the secretion of a variety of cytokines. In the present study we evaluated the effect of AS101 on the pathogenicity of B. rodhaini infected mice. In order to clarify its mechanism of action we studied the ability of AS101 to activate neutrophils and macrophages, both of which inhibit parasite growth. More specifically, we studied the ability of AS101 to induce secretion of nitric oxide (NO). We found that AS101 protects mice from babesiosis in a time and dose dependent manner. At 10 and 20 micrograms/injection, two weeks prior to parasites, AS101 significantly increased the number of neutrophils and more than doubled the survival rate of infected mice. Similarly, at these concentrations when injected one month, or at 20 micrograms, injected 24 h before parasites. AS101 mitigated the course of infection and reduced by half the peak of parasitaemia. At 0.1 microgram/ml AS101 induced the secretion of significantly higher levels of NO in vitro than control. This was abrogated by adding the NO synthase inhibitor. NG-monomethyl-L-arginine. In vivo the antiparasitic protection of AS101 was abrogated by another NO synthase inhibitor, aminoguanidine. We found that AS101, partly by elevating levels of NO, can significantly mitigate the course of infection and thus increase survival, and may therefore be proven as an effective antiparasitic drug.

Adjuvants, Immunologic↗

Immunomodulation by hydatid cyst fluid toxin (Echinococcus granulosus).

Since the experimental infection by hydatid cysts (Echinococcus granulosus) in mice causes immunomodulation of the host, the effects of hydatid fluid (HF) and fractions of HF were compared in vitro and in vivo. Fractions of HF were obtained using ammonium sulphate precipitation, chloroform/methanol extraction and thin-layer chromatography (TLC). HF proved to be toxic to murine peritoneal macrophages in vitro, and when macrophages were incubated with the different fractions of HF, most toxicity was found in a single TLC-purified fraction with an adjuvant-like effect on the production of specific antibodies against bovine albumin and human red blood cells in mice. Treatment of mice with the toxin caused a drop in the percentage of peripheral blood lymphocytes. Flow-cytometric analysis showed that T-cells from toxin-treated mice had lower membrane-CD3, CD4 and CD8 density, and higher percentages of CD8+ splenocytes and CD4+ thymocytes expressing CD25. The toxin caused a down-regulation of CD4 and CD8 expression on thymocytes in vitro, that was dependent on the presence of macrophages. The results may attribute to these toxins a role in the host-parasite relationship of hydatidosis.

Animals↗

Biological effects of the immunomodulator beta 1-3D polyglucose are strongly potentiated by conjugation to biodegradable microbeads.

It is demonstrated that the biological effects of the immunomodulator beta 1-3D polyglucose, when covalently linked to polymethacrylate or biodegradable albumin microbeads, are strongly potentiated. The potentiation is recorded as an increased protection effect of the conjugates in Escherichia coli sepsis in mice, and as increased IL-1 production by murine macrophages in vitro.

Adjuvants, Immunologic↗

Tolerance or rejection: A delicate balance as judged by exposure of heart-transplanted rats to the immunomodulator Linomide.

When applied in rodent transplant models most immunosuppressive drugs yield adequate graft protection for as long as the drug is given, and permanent graft survival is often induced. The immunomodulator, Linomide, previously shown to stimulate T cells and prevent apoptosis, usually reduces or abolishes both tolerance induction and the graft-protective effect of the immunosuppressive drug. By chance, we observed that Linomide alone exerted a modest but unequivocal graft-protective effect in the BN to WF strain combination. This finding was analysed by simple genetic mapping of rat strains. Untreated WF recipients kept BN grafts for a median of 8 days, whereas Linomide treatment prolonged graft survival to 12. 5 days (P = 0.0001). In control groups (DA to LEW, BN to LEW, DA to WF and WF to BN), median graft survival was 5.5-7 days irrespective of whether Linomide was given. However, the BN to F1 (LEW x WF) combination also manifested slightly longer graft survival in the presence of Linomide. F1 (BN x WF) to WF grafts survived a median of 15 days without Linomide and 46 days with Linomide treatment. Both in the presence and absence of Linomide, two of the control graft combinations [F1 (BN x DA) to WF and F1 (BN x WF) to BN] manifested 6-7-day graft survival. Taken together, our results suggest a delicate balance between unresponsiveness and rejection, while a single agent (Linomide) may either cause on its own long-term survival of allografts in one setting or rejection despite optimal immunosuppression in another setting.

Adjuvants, Immunologic↗

The role of somatostatin in schistosomiasis: a basis for immunomodulation in host-parasite interactions?

This review explores the possible modulatory role of the neuropeptide somatostatin in the outcome of Schistosoma-caused morbidity in man. Somatostatin could play an important role in Schistosoma mansoni-man interactions via its influence on intersystem signalling; therapeutically, via its direct effect on Schistosoma-caused morbidity (fibrosis, granuloma size, portal hypertension, variceal bleeding); and via immunomodulation of Schistosoma-induced inflammatory responses in the liver and intestines. In schistosomiasis-endemic regions two interesting patterns of infection emerge. First, the intensity of infection is higher in children than in adults; secondly, at any given time, only a fraction of Schistosoma-infected individuals develop Symmer's pipe-stem fibrosis. These morbidity patterns cannot be explained on the basis of acquired immunity alone. Somatostatin has an inhibitory effect on hormone, immune and physiological body functions like growth hormone secretion, Interferon (IFN) gamma production, collagen I and III formation and hepatic stellate cell activation. Levels of somatostatin secreted endogenously by man upon the onset of Schistosoma infection may be one factor regulating the activity of the above, and thereby fibrosis in the host. The neuropeptide hormone somatostatin may determine pre-disposition to Schistosoma-caused morbidity.

Adjuvants, Immunologic↗

Transfusion-related immunomodulation in Chinese children with thalassaemia.

BACKGROUND AND OBJECTIVES: Multiple transfusions can induce immunomodulation. This study was carried out to investigate the immunological status of 50 transfusion-dependent children with beta-thalassaemia, taking into account that lymphocyte characteristics are affected by sex, age and race. We paid particular attention to the influence of transfusion and serum ferritin on the lymphocyte subsets which may be affected by the exposure to foreign antigens. MATERIALS AND METHODS: By multicolour immunofluorescent analysis using flow cytometry, we determined lymphocyte characteristics with regard to major subsets (T lymphocytes, B lymphocytes and NK cells), activation (membrane IL-2 receptor CD25, HLA-D) and memory/naive T cells (CD45RO/CD45RA). Data from 51 age- and sex-balanced children served as controls. RESULTS: The normal Chinese children had higher NK levels than the beta-thalassaemia children. The levels of CD25 and HLA-D indicated a broad-based increase in activation status. Memory T cells were also increased when compared with their normal counterparts. We found additional and more marked alterations in the lymphocyte subsets of those who had received over 100 transfusions. While levels of NK cells were inversely correlated with the number of transfusions, CD25+ cells increased with transfusions. CONCLUSION: Many multitransfused beta-thalassaemia children have altered levels of lymphocyte subsets compared with normals. What remains to be investigated is the long-term consequence of possessing low NK and non-MHC-restricted T cells (CD3+CD56+CD16+) and a high activation status in terms of resistance of infections and development of malignancy.

Adjuvants, Immunologic↗

Optimization of vaccine responses in early life: the role of delivery systems and immunomodulators.

Infant immunization is a particularly important field with multiple challenges for vaccine research and development. There is, together with a high susceptibility to infections, a lower efficacy of most vaccinations in newborns and young infants, compared to those performed later in life. In the present review, the authors focus on problems arising from the attempt to vaccinate against pathogens very early in life, and on the role of selective adjuvants (i.e. antigen delivery systems or immunomodulators) that could be used to: (i) rapidly induce strong antibody responses of the appropriate isotypes; (ii) elicit sustained antibody responses extending beyond infancy; (iii) induce efficient Th1 and CTL responses in spite of the preferential Th2 polarization of early life responses; (iv) escape from maternal antibody mediated inhibition of vaccine responses; (v) show acceptable reactogenicity in early life; and (vi) allow incorporation of several vaccine antigens into a single formulation so as to reduce the number of required injections. How such objectives might be achieved by several of the vaccine formulations currently in development is illustrated by reviewing data from experimental models and clinical studies, when available.

Adjuvants, Immunologic↗

Laboratory acquired infection with recombinant vaccinia virus containing an immunomodulating construct.

Handling of Vaccinia virus represents a risk for laboratory-acquired infections, especially in individuals without completed vaccination. We report the case of a Vaccinia infection in a previously vaccinated researcher working with various genetically modified strains. We could confirm the infection by electron microscopy, positive cell culture, virus-specific PCR, sequence analysis, and viral neutralization test. The isolated virus carried a functionally inactivated cytohesin-1 gene of human origin, which had been shown to impair leukocyte adhesion by interacting with the LFA/ICAM-1 axis. The immunomodulating nature of the inserted construct might thus have added to the infectivity of the virus. We emphasize on the necessity of Vaccinia vaccination in laboratory staff working in the field.

Adjuvants, Immunologic↗

Immunomodulation by the autonomic nervous system: therapeutic approach for cancer, collagen diseases, and inflammatory bowel diseases.

The distribution of leukocytes is regulated by the autonomic nervous system in humans and animals. The number and function of granulocytes are stimulated by sympathetic nerves whereas those of lymphocytes are stimulated by parasympathetic nerves. This is because granulocytes bear adrenergic receptors, but lymphocytes bear cholinergic receptors on the surface. These regulations may be beneficial to protect the body of living beings. However, when the autonomic nervous system deviates too much to one direction, we fall victim to certain diseases. For example, severe physical or mental stress --> sympathetic nerve activation --> granulocytosis --> tissue damage, including collagen diseases, inflammatory bowel diseases, and cancer. If we introduce the concept of immunomodulation by the autonomic nervous system, a new approach for collagen diseases, inflammatory bowel diseases, and even cancer is raised. With this approach, we believe that these diseases are no longer incurable.

Animals↗

Nonspecific immunomodulation influences the course and location of Cryptosporidium parvum infection in neonatal BALB/c mice.

The influence of nonspecific immunomodulation with Thymomodulin (a calf thymic extract with immunomodulatory activity) and hydrocortisone on the course and location of Cryptosporidium parvum infection in neonatal BALB/c mice (infected with 10(6) or 10(5) oocysts on day 7 of life) was studied using scanning electron microscopy of the inner surface of different parts of intestine. Daily peroral treatment of suckling mice with 20 mg/kg/day of Thymomodulin for 5 days before inoculation resulted in an earlier peak and earlier termination of cryptosporidial infection when compared with control infected mice. On the other hand, peroral administration of 25 mg/kg of hydrocortisone every second day led to the persistence of cryptosporidial infection in the ileum of immunosuppressed mice until the end of observation (day 15 post infection), whereas only transient infection was observed in the intestine of control infected mice. The location of infection was also altered in hydrocortisone--treated mice--the severe infection was observed in more proximal parts of the intestine (anterior and middle jejunum), whereas no cryptosporidia were found in these parts of the intestine in nontreated infected mice.

Adjuvants, Immunologic↗

Immunomodulation therapy in colorectal carcinoma.

There has been much progress in the understanding of the relationship between the immune system and colorectal cancer. This has led to the use of immunomodulatory therapy in the adjuvant and palliative treatment of the condition. Although attempts at the use of non-specific immunomodulation with agents such as levamisole, cimetidine, alpha interferon and Bacillus Calmette-Guerin (BCG) have not produced significant clinical benefits when tested in randomized trials in both the adjuvant setting and for metastatic disease, promising results are being obtained with more specific therapy. Edrecolomab [corrected], a murine monoclonal antibody targeting the 17-1A antigen on malignant colorectal cells has produced a reduction in relapse and mortality rates when used as adjuvant treatment following surgery for Dukes' C colon cancer. Active specific therapy with autologous tumour vaccine administered with BCG has produced similar benefits in Dukes' B cancer. Both 3H1 anti-idiotypic antibody against carcinoembryonic antigen and 105AD7 antibody to gp72 glycoprotein have demonstrated in-vitro and in-vivo immune activation against tumour. Non-randomized studies postulate prolongation of survival using these antibodies in advanced disease. These agents are all currently being tested in randomized studies powered to detect meaningful survival differences and clinical benefit. Immune therapy offers the potential of low toxicity therapy in colorectal cancer and may have a role as an adjunct to conventional chemotherapy.

Adjuvants, Immunologic↗

Prevention of experimental myointimal hyperplasia by immunomodulation.

INTRODUCTION: we have tested the hypothesis that treatment with a mycobacterial preparation that modulates the antibody response, would diminish restenosis in a rat angioplasty model. MATERIALS/METHODS: male Sprague-Dawley rats were used. All immunisations were given subcutaneously. Group A (control) received normal saline on days 0, 21, and 42. Group B received SRL172 on days 0, 21, and 42. Group C received SRL172 on days 0, 21, and 42, and hsp65/Incomplete Freund's on days 21 and 42. Group D received hsp65/Freund's on days 21 and 42. Right common carotid arteries were balloon-injured on day 63 using a standard technique known to produce MIH and animals were sacrificed on day 77. For each carotid 6 microm cross sections were cut from paraffin blocks. Cross-sectional areas were measured by computerised planimetry. RESULTS: balloon injury resulted in MIH in all animals. Data represents mean+/-SEM for the percentage of area enclosed within the internal elastic lamina occupied by MIH (% MIH); which for groups A, B, C, and D was 85+/-11, 24+/-3, 27+/-7, and 17+/-3 respectively. All the treatment groups had significantly less MIH when compared to the control group but no statistically significant difference was found between any of the treatment groups. CONCLUSIONS: this is the first report that immunomodulation with mycobacterial material suitable for use in man, can reduce MIH. Since such modulation has low risk, this raises the prospect of an important new therapeutic modality to combat restenosis.

Adjuvants, Immunologic↗

Decreased interleukin-2 production in murine acute pancreatitis: potential for immunomodulation.

BACKGROUND & AIMS: The role of the cytokine interleukin 2 (IL-2) has long been recognized as central to normal immunologic function and defense against infection after burns and trauma, but little effort has been directed towards its role in acute pancreatitis (AP), which also has a high mortality related to sepsis. This study investigated the potential role of IL-2 in mice with diet-induced AP. METHODS: AP was induced in mice by 10 days of feeding a choline-deficient, ethionine-supplemented diet. T-helper (CD4) cells were estimated, and T-cell mitogen-stimulated splenocyte proliferation and IL-2 production in vitro were measured on days 3, 7, and 10. RESULTS: Significant reduction in IL-2 production was found on day 3 (32%; P < 0.05) and day 10 (48%; P < 0.005). Administration of intraperitoneal lipopolysaccharide on day 10 was associated with reduced IL-2 production (P < 0.025) 4 hours later and 90% mortality in animals with AP. In vivo therapy with recombinant IL-2 improved in vitro IL-2 secretion (P < 0.05) and reduced lipopolysaccharide-induced mortality (P = 0.036). CONCLUSIONS: Murine diet-induced AP is associated with impaired immune function and increased susceptibility to sepsis and may be a valuable tool in the investigation of immunomodulation in AP.

Acute Disease↗

Immunomodulating properties of the diterpene andalusol.

Andalusol [ent-13(16),14-labdadiene-6 alpha,8 alpha,18-triol], a labdane diterpene isolated from an anti-inflammatory extract of the medicinal plant Sideritis foetens Clem. was evaluated for immunomodulating properties. It exhibited a dose-dependent inhibitory effect on the hemolytic activity of the classical complement pathway and also inhibited lymphocyte proliferation induced by concanavalin A at non-cytotoxic concentrations (1-100 microM). No effect on the alternative pathway was observed. These results indicate that andalusol has immunosuppressive effects in vitro in addition to its anti-inflammatory activity.

Adjuvants, Immunologic↗

Effect of oral application of an immunomodulating plant extract on Influenza virus type A infection in mice.

The influence of the oral administration of an aqueous-ethanolic extract of a mixture of Thujae occidentalis herba, Baptisiae tinctoriae radix, Echinaceae purpureae radix and Echinaceae pallidae radix, on the course of Influenza A virus infection in Balb/c mice was investigated. The extract was administered to mice via the drinking water for 14 days starting 6 days before intranasal infection with Influenza A virus. The progress of infection was recorded during a time range of 21 days. Parameters for the evaluation of antiviral activity were survival rate and mean day to death. In a further set of experiments infected mice were sacrificed on defined days. Determination of consolidation score and virus titer were performed for each lung. The data show that the oral treatment with the extract induced a statistically significant increase in the survival rate, prolonged the mean survival time and reduced lung consolidation and virus titer. The experiments demonstrate that the plant immunomodulator given 6 days before exposure is a potent inhibitor of Influenza A virus pathology in vivo.

Administration, Oral↗