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PubMedDate not supplied

Effect of an inactivated Parapoxvirus based immunomodulator (Baypamun) on post weaning diarrhoea syndrome and wasting pig syndrome of piglets.

Post weaning diarrhoea syndrome (PWDS) and wasting pig syndrome (WPS) are two entities of the pig industry induced by stress factors occurring at the early weaning and further complicated by opportunistic pathogens. In the present paper we examine--through one pilot and one final trial--whether prevention of these two syndromes can be achieved in the field by immunomodulation of the pig e.g., by improving its non-specific immunological response. In both trials two groups of early weaned piglets were submitted to the treatments. In the pilot trial the first group received no treatment and served as controls and the animals of the second group were injected twice with an inactivated Parapoxvirus based immunomodulator (Baypamun, Bayer, Germany). In the final trial the first group of piglets received no treatment and served as a control group. The animals of the second group were injected twice with a freeze-dried immunomodulator (Baypamun). Piglets were compared with regard to the severity of PWS, mortality, growth performance parameters, and for the presence of pathogens in their faeces. The results have shown that Baypamun treated piglets performed significantly better than negative control piglets in all the parameters examined. It was concluded that stimulation of the non-specific immunity of piglets may be helpful in preventing the appearance of PWDS and WPS in the field.

Adjuvants, Immunologic↗

PubMed2003

Comparisons of PAH-induced immunomodulation in three bivalve molluscs.

There is growing evidence that contaminants may be partly responsible for the observed increase in disease in marine organisms by adversely affecting their immunity. Bivalve molluscs are common sentinels used in invertebrate immunotoxicology, however, to date, studies have been restricted to a few resilient species. This present study is a comparative investigation into the effects of the polycyclic aromatic hydrocarbon, phenanthrene, on the immunocompetence of three bivalve species. The commonly-studied marine mussel, Mytilus edulis, was compared with two species that have never been studied with respect to immunomodulation, namely, the edible cockle, Cerastoderma edule and the razor shell, Ensis siliqua. Animals were exposed to a range of phenanthrene concentrations (50, 100, 200 or 400 microg l(-1)) and haemocyte immune parameters, including haemocyte counts, phagocytosis, superoxide generation, lysosomal enzymes and lectin-binding, were monitored. Aims were not only to extend existing knowledge of bivalve immunotoxicology, but also to establish whether contaminant-induced immunomodulation in the sentinel species, M. edulis, is comparable to that observed in other bivalves. Results showed that the immune response of the three species was differentially affected by phenanthrene exposure, with immunomodulation in M. edulis not reflecting the immunological changes observed in the other two species. This suggests M. edulis may not be a suitable sentinel bivalve, and that other species, such as C. edule, may more accurately reflect the general immunological response of this group of marine animals.

Animals↗

PubMed2000

Immunomodulators in infectious diseases: panoply of possibilites.

Infections which caused ravages in the past centuries are again resurgent and newly emerging pathogens capable of human diseases continue to surface. Multidrug antibiotic resistance has turned into a major medical problem. Judicious concepts for combating infections in the 21st century have acquired a new poignancy. Immunomodulators of natural, synthetic, and recombinant origin can stimulate host defense mechanisms for the prophylaxis and treatment of diverse viral, bacterial, parasitic and fungal diseases. Some immunomodulator preparations are already licensed for use in patients and numerous others are being extensively investigated in preclinical and clinical studies. Immunomodulators offer a novel adjunct to established antimicrobial therapies.

Adjuvants, Immunologic↗

PubMed1999

Time-dependent effects of stressor application on metastasis of tumor cells in the lung and its regulation by an immunomodulator in mice.

The effects of the timing of stressor application on transplanted tumor cells and its possible regulation by an immunomodulator was investigated. Male C57 BL/6N mice were subjected to rotational stressor for 7 days relative to tumor cell inoculation: stressor after inoculation of Lewis lung cancer cells, stressor during inoculation and stressor before inoculation. Stressor application and tumor cell inoculation induced transient decreases in body weight, particularly in mice stressed after inoculation. The mice exposed to the stressor during inoculation or before inoculation showed significant increases in the number of metastatic foci relative to control mice. Early administration of an immunomodulator, PSK, significantly attenuated the increase of metastatic foci in stressed mice. The weights of thymus gland and spleen at 14 days after inoculation were similar in the three stressor groups and the control group. Application of the stressor reduced NK cell activity of the normal mice as well as tumor bearing mice. The lowest pre-inoculation NK cell activity was observed in mice stressed for 7 days beginning on the day of inoculation. The NK cell activity decreased in the tumor bearing mice which were stressed at the time of tumor inoculation. Decreased NK cell activity was reversed at day 14 after tumor inoculation. The mice exposed to the stressor after inoculation showed lowest level of NK cell activity relative to mice exposed to the stressor before or during inoculation. The treatment of mice with PSK reduced these changes significantly. The present results suggest that the rotational stress reduces splenic NK cell activity, which may influence the magnitude of tumor metastasis, depending on the time of tumor cell injection. Further, administration of an immunomodulator may counteract the reduction of the NK cell activity.

Adjuvants, Immunologic↗

PubMed2001

Cutaneous T-cell lymphoma. New immunomodulators.

During the most recent decades, much knowledge has been gained concerning the immunologic and pathologic mechanisms of CTCL. The development of immunomodulators aimed at correcting aberrations in immunology and cellular growth and differentiation reflects this increased understanding. This review of the currently available immune-response modifying drugs shows that recombinant forms of natural cytokines and retinoids can be developed with tolerable toxicity profiles and substantial efficacy. Although milestone drugs such as bexarotene have been approved by the FDA- for treatment of CTCL, other agents such as IL-12 may also have a place in treatment of the disease. Even though unapproved, IFN-alpha may be the most active single immunomodulating agent against CTCL. It seems that further delineation of CTCL cytokine profile changes and immunologic aberrations are key in developing effective immunomodulators that are able to reverse these alterations.

Adjuvants, Immunologic↗

PubMed1996

Neuropathy of metachromatic leukodystrophy: improvement with immunomodulation.

A 4-year-old child with metachromatic leukodystrophy was initially diagnosed with chronic immune demyelinating polyneuropathy and treated with immunosuppressive therapy. Physical examination revealed diffuse, distal > proximal weakness and areflexia. Electro-diagnostic studies revealed nerve conduction velocities that were slowed to variable degrees in different nerves. In the 18 months after institution of immunomodulating therapy, she had functionally significant improvement and a quantitative increase in her strength. Treatment was discontinued at age 6 years when the patient developed urinary incontinence, followed by loss of motor and cognitive skills. We conclude that immunomodulation early in the course of metachromatic leukodystrophy presenting as a neuropathy may result in temporary functional improvement. Whether the immunomodulation altered the disease progression or had direct effects on the function of the dysmyelinated axons is not known.

Azathioprine↗

PubMed2003

Immunomodulation by Yersinia enterocolitica: comparison of live and heat-killed bacteria.

This study compared the immunomodulating properties of viable and killed Yersinia enterocolitica O9 in BALB/c mice. At 10 days after infection by the intragastric route, ex vivo assays showed a suppression of spleen cell proliferation in response to Salmonella lipopolysaccharide, concanavalin A and heat-killed yersiniae. Mice infected with Y. enterocolitica O9 for 10 days resisted the challenge with a lethal dose of Listeria monocytogenes. In contrast, intravenous administration of heat-killed yersiniae did not modify the ability of spleen cells to proliferate in response to lipopolysaccharide or concanavalin A, and proliferation in response to killed yersiniae was significantly increased. By 3 days after administration of a single dose of heat-killed yersiniae, the resistance of mice to L. monocytogenes challenge was significantly increased. Our findings show profound differences in immunomodulation by viable and heat-killed yersiniae, but suggest that killed yersiniae retain interesting immunomodulating properties.

Animals↗

PubMed2005

Immunomodulating capacity of kefir.

Kefir is a fermented milk produced by the action of lactic acid bacteria, yeasts and acetic acid bacteria, trapped in a complex matrix of polysaccharides and proteins. Beyond its inherent high nutritional value as a source of proteins and calcium, kefir has a long tradition of being regarded as good for health in countries where it is a staple in the diet. However, published human or animal feeding trials to substantiate this view are not numerous. The aim of this work was to determine the immunomodulating capacity of kefir on the intestinal mucosal immune response in mice and to demonstrate the importance of dose and cell viability on this response. BALB/c mice were fed with commercial kefir ad libitum (diluted 1/10, 1/50, 1/100 or 1/200) or pasteurized kefir (diluted 1/6, 1/10, 1/50, 1/100) for 2, 5 or 7 consecutive days. At the end of each feeding period, the bacterial translocation assay was performed in the liver. Small intestine structure was studied by haematoxilin-eosin staining and light microscopy. The number of IgA+ and IgG+ cells was also determined. For the functional doses chosen, cytokines (IL-2, IL-4, IL-6, IL-10, IL-12, TNF-alpha and IFN-gamma) were determined. Kefir and pasteurized kefir were able to modulate the mucosal immune system in a dose-dependent manner. Kefir was administred 10-times more diluted than pasteurized kefir, but it induced an immunomodulation of similar magnitude, indicating the importance of cell viabilty. The results suggest that a Th1 response was controlled by Th2 cytokines induced by kefir feeding. Pasteurized kefir would induce both Th2 and Th1 responses. This is the first study in vivo regarding the mechanisms involved in the immunomodulating capacity of the oral administration of kefir containing viable or heat-inactivated bacteria at different doses.

Animals↗

PubMed1998

The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network.

Interactions between infiltrating T cells and keratinocytes via the secretion of the TH1 cytokines interleukin (IL) 2 and interferon gamma (INF-gamma), the keratinocyte growth factor transforming growth factor alpha (TGF-alpha) and the cytokines IL-6 and IL-8 are thought to be the predominant mechanisms inducing skin lesions in psoriatic patients. Systemic treatment of psoriasis with fumaric acid derivatives (FAEs) has been reported to be effective in the treatment of psoriasis, but the mode of action is still unknown. To clarify this phenomenon, keratinocytes from psoriatic patients as well as from healthy volunteers were mono- and cocultured with HUT 78 T cells with/without the addition of FAEs; the cytokine concentrations were then measured in the culture supernatants. Furthermore, mRNA expression was determined in epidermal growth factor (EGF) -activated keratinocytes as well as in phytohaemagglutinin (PHA)-activated HUT 78 T cells. Only dimethylfumarate (DMF) diminished IL-6 and TGF-alpha secretion in the psoriatic cocultures. However, it did not have this effect on cocultures from control subjects or on monocultures. DMF suppresses EGF-induced TGF-alpha mRNA induction in psoriatic keratinocytes. DMF inhibited INF-gamma secretion in all cultures but stimulated the IL-10 secretion. This immunomodulation away from the TH1 cytokine IFN-gamma to the TH2 cytokine IL-10 was confirmed in HUT 78 T cells by Northern blot analysis. An increased number of eosinophils is a known side-effect in patients treated with this drug, suggesting a clinical relevance of this immunomodulation in vivo. This immunomodulation and the suppression of cytokines from the psoriatic cytokine network could be responsible for the beneficial effect of DMF in the treatment of a hyperproliferative and TH1 cytokine-mediated skin disease.

Adult↗

PubMed2001

Enhanced maturation and functional capacity of monocyte-derived immature dendritic cells by the synthetic immunomodulator Murabutide.

Murabutide is a safe synthetic immunomodulator derived from muramyl dipeptide, the smallest bioactive unit of bacterial peptidoglycan. Although it is well known that muramyl peptides modulate the functions of monocytes/macrophages, their activity on dendritic cells is poorly documented. We thus investigated the effects of Murabutide on immunophenotype, endocytosis, T-cell stimulatory capacity, and cytokine secretion of human monocyte-derived immature dendritic cells (iDCs). We found that Murabutide triggers immunophenotypic changes as upon treatment, iDCs up-regulate the surface expression of the major histocompatibility complex type II molecule human leucocyte antigen-DR, the co-stimulatory molecules CD80, CD86 and CD40 and the differentiation marker CD83, and down-regulate the expression of the mannose receptor. These phenotypic changes are also mirrored by changes in their biological activity. Subsequent to treatment with the synthetic immunomodulator, DC have a decreased endocytic capacity but exhibit enhanced stimulatory capacity for both allogeneic and autologous T cells. In addition, Murabutide-stimulated iDCs have a greater cytostatic activity toward the tumour cell line THP-1. Furthermore, in the presence of Murabutide, DCs transiently increased the release of macrophage inhibitory protein-1 beta, tumour necrosis factor-alpha and interleukin-10, whereas the enhanced production of macrophage-colony stimulating factor was sustained over the 3-day period analysed. In addition, Murabutide triggers the phosphorylation of the three classes of mitogen-activated protein kinases in iDCs. Altogether our results demonstrate that Murabutide triggers the maturation and activation of monocyte-derived iDCs. As this immunomodulator is approved for administration in humans, it could be a useful adjunct to boost the efficacy of DC-based vaccines designed against tumours or virus-infected cells.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2004

Relationship between interaction sites in the gut, hydrophobicity, mucosal immunomodulating capacities and cell wall protein profiles in indigenous and exogenous bacteria.

AIMS: To investigate whether there is a relationship between interaction sites in the gut, hydrophobicity, mucosal immunomodulating capacities and cell wall protein profiles in lactobacilli, bifidobacteria and enterococci. METHODS AND RESULTS: Hydrophobicity, cell wall protein profiles and sites of interaction in the gut (by using fluorescein isothiocyanate-labelled bacteria) were determined for Lactobacillus casei, L. acidophilus, L. fermentum, Bifidobacterium bifidum, B. animalis and Enterococcus faecalis. We also determined the number of immunoglobulin (Ig)A+, tumour necrosis factor (TNF)alpha+, interleukin (IL)-6+ and IL-10+ cells after oral administration of the above bacteria to BALB/c mice. All strains assessed were found to interact with the sites of induction of the immune response in the gut. No correlation with hydrophobicity was observed. When some strains at certain doses were administered to mice, bacterial translocation to liver was observed. The oral administration of indigenous (104 cells day(-1)) and exogenous (107 cells day(-1)) bifidobacteria and lactobacilli for 5 consecutive days activated the systemic and intestinal mucosal immune response in a strain-specific way, independently whether the strain was indigenous or exogenous in relation to the host. The differences in the immunopotentiating capacity of the various strains might be related to the differences in their cell wall protein profiles. CONCLUSIONS: Indigenous bacteria activated the mucosal immune response at a dose significantly smaller than the one required for probiotic exogenous bacteria. However, probiotic exogenous bacteria can be used at high concentrations in fermented dairy products with a great impact on the immune system, favouring its immunomodulation. SIGNIFICANCE AND IMPACT OF THE STUDY: The immunomodulation capacity of probiotic bacteria is strain specific and independent of the specificity of the host. The ability of certain strains to down-regulate the production and release of IL-6 by IL-10 may have potential implications in their use in cases in which cytokine deregulation or excessive production at the mucosal level can be the cause of tissue damage.

Animals↗

PubMed2001

Safety of the new macrolide immunomodulators.

With the wide acceptance of cyclosporine in the treatment of skin disease, there has been an effort to find new immunomodulating agents with superior safety profiles for use in dermatology. Among the most promising of the classes are the new macrolide immunomodulators, including tacrolimus and pimecrolimus. Of these, only tocrolimus has had widespread use for nondermatologic indications, primarily solid organ transplantation. Both of these agents have been studied for inflammatory diseases of the skin. In this article, we review the systemic and topical toxicities of these macrolide immunomodulators.

Humans↗

PubMed2005

Immunomodulator tuftsin increases the susceptibility of Cryptococcus neoformans to liposomal amphotericin B in immunocompetent BALB/c mice.

The co-administration of immunomodulators and antibiotics has been proved very successful for treatment of opportunistic infectious diseases. In the present study, we evaluated the combination of liposomal amphotericin B (lip-Amp B) and immunomodulator tuftsin to cure Cryptococcus neoformans infection in BALB/c mice. Mice infected with C. neoformans were treated with Amp B deoxycholate and tuftsin free or tuftsin-loaded Amp B liposomes. The results of the present study demonstrated higher efficacy of tuftsin-loaded Amp B liposomes against experimental murine cryptococcosis, in terms of enhanced survival rate and reduced fungal burden in organs (lungs and brain) of the treated mice. Interestingly, pre-treatment of mice with liposomal tuftsin before challenging them with the C. neoformans infection resulted in 100% survival of the treated animals followed by treatment with lip-Amp B. Immunomodulator-based therapy seems likely to be more beneficial for treatment of fungal infectious diseases.

Amphotericin B↗

PubMed2002

Perinatal immunomodulation.

The fetus and the neonate are particularly vulnerable to injury caused directly by immunologic mechanisms or inflicted by infectious agents that take advantage of their relatively immature and inexperienced immune system. With increasing survival of high-risk neonates in the surfactant era, prevention/treatment of sepsis and chronic lung disease (CLD) has emerged as an area of priority in neonatal research. Considering the role of inflammatory mediators in the pathogenesis of sepsis and CLD, the clinical application of immunomodulator therapy to neonatology is perhaps more important at present than ever. Advances in molecular biology and immunology have led to development of newer immune modulator therapies that are directed towards specific cells or cytokines rather than resulting in a general suppression of the immune response. Failure of promising, newer immunomodulator therapies in sepsis trials in adults has, however, clearly documented the difficulties in diagnosing/correcting the imbalance between pro- and anti-inflammatory responses. As in the case of sepsis, development of a single magic bullet for prevention/management of a multi-factorial illness like CLD may be difficult, as prevention of prematurity - the single most important high-risk factor for CLD - is an unachievable goal at present. As new frontiers are being explored, older, well-established therapies like antenatal anti-D immunoglobulin prophylaxis continue to emphasize the tremendous potential of immunomodulator therapy in neonatology/perinatology. The current immunomodulators/immunotherapeutic agents with established/potential clinical applications in the perinatal period are reviewed.

Adjuvants, Immunologic↗

PubMed1996

Enhancement in vivo of the antiinflammatory and antitumor activities of type I interferon by association with the synthetic immunomodulator murabutide.

The therapeutic efficacy of type I interferon (IFN) has been reported to vary considerably in different indications. The use of the cytokine as adjuvant therapy has been suggested to enhance its efficacy and reduce the toxicity frequently associated with long-term and high-dose administration. In this study, we have assessed the activity of type I IFN in the protection against and treatment of acute hepatitis induced in mice by the administration of concanavalin-A (ConA). At the same time, we have evaluated the efficacy of the synthetic immunomodulator murabutide when administered alone or in combination with type I IFN to protect against ConA hepatitis and in the treatment of tumors in MethA sarcoma-bearing mice. Our results demonstrate a prophylactic effect as well therapeutic effects of type I IFN and of murabutide in the inflammation-mediated model of liver damage. The use of combination therapy presented enhanced efficacy in inhibiting the ConA-induced elevation of plasma transaminases. Both compounds were found to suppress IFN-gamma mRNA accumulation in the livers of ConA treated mice. This activity is discussed with respect to the mechanism of action of the two immunomodulators. In addition, the combination of murabutide with type I IFN exhibited synergistic antitumor activity that was clearly seen in the significant regression of MethA tumors and resulted in almost 50 percent tumor-free mice. The potential clinical application of combination therapies using a cytokine and a safe immunomodulator is analyzed in terms of enhancing the cytokine efficacy and extending its use to new indications.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1996

Effect of a novel topical immunomodulator, S-28463, on keratinocyte cytokine gene expression and production.

A new immunomodulating agent, imiquimod, has been reported to have antiviral and antitumor activities in animal models. S-28463 (4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-1H-imidazo[4, 5-c]quinoline-1-ethanol), an analog of imiquimod, has more potent antiviral activity in animals than imiquimod. It has also been shown to be more potent at inducing cytokines in human blood in vitro. However, its precise role as an immunomodulator in the skin has not been determined. We investigated the effect of S-28463 on human keratinocyte (KC) production of interferon-alpha (IFN-alpha) and other proinflammatory cytokines, including interleukin (IL)-1alpha, IL-8, and tumor necrosis factor-alpha (TNF-alpha). Human KC were incubated with S-28463 at two concentrations (1 microgram/ml and 10 micrograms/ml) for 6 h. Cytokine gene expression was analyzed by reverse-transcriptase PCR. In human KC, S-28463 stimulated significant increases in IFN-alpha mRNA at both concentrations. IL-1alpha mRNA increased 1.4-fold at 10 micrograms/ml. IL-8 mRNA was upregulated 2.5-fold at 10 micrograms/ml. Twenty-four hours after treatment, IL-1 alpha, IL-8, and TNF-alpha protein were increased, but IFN-alpha was below the level of detection. These results suggest that in the skin, S-28463-induced-IL-1 alpha, IL-8, and TNF-alpha production may be involved in the immunomodulating action of S-28463.

Adjuvants, Immunologic↗

PubMed1997

Seed-specific immunomodulation of abscisic acid activity induces a developmental switch.

A single-chain Fv antibody (scFv) gene, which has previously been used to immunomodulate abscisic acid (ABA) activity in transgenic tobacco to create a 'wilty' phenotype, was put under control of the seed-specific USP promoter from Vicia faba and used to transform tobacco. Transformants were phenotypically similar to wild-type plants apart from their seeds. Anti-ABA scFv embryo development differed markedly from wild-type embryo development. Seeds which accumulated similar levels of a scFv that binds to oxazolone, a hapten absent from plants, developed like wild-type embryos. Anti-ABA scFv embryos developed green cotyledons containing chloroplasts and accumulated photosynthetic pigments but produced less seed storage protein and oil bodies. Anti-ABA scFv seeds germinated precociously if removed from seed capsules during development but were incapable of germination after drying. Total ABA levels were higher than in wild-type seeds but calculated free ABA levels were near-zero until 21 days after pollination. We show for the first time seed-specific immunomodulation and the resulting switch from the seed maturation programme to a germination programme. We conclude that the immunomodulation of hormones can alter the development programme of target organs, allowing the study of the directly blocked endogenous molecules and manipulation of the system concerned.

Abscisic Acid↗

PubMed1989

The role of immunomodulators in the treatment of patients with AIDS.

In the last several years, the biologic modification of the immune system has become one of the therapeutic alternatives in medicine. The use of interferon alpha has resulted in both antineoplastic and antiviral effects in patients with AIDS-associated Kaposi's sarcoma. Trials currently underway will determine whether or not this drug, either alone or in combination with zidovudine, is of overall value to patients with early stages of HIV-1 infection. Hematopoietic growth factors, GM-CSF and erythropoietin in particular, offer new hope that the bone marrow suppressing toxicities of certain therapeutic agents such as zidovudine and ganciclovir can be ameliorated, thus allowing the more aggressive use of these important medications. Although a variety of non-biologic immunomodulators have been evaluated in patients with HIV-1 infection, none thus far has shown the clear clinical advantage that has been demonstrated for zidovudine and a variety of clinical trials continue in this area. The area of immunologic reconstitution, although promising in concept, has been disappointing in practice, even in combination with zidovudine. Recent approaches to immunomodulation have included active immunotherapy involving immunization of HIV-1 infected individuals with either inactivated virus or recombinant HIV-1 proteins. Continued investigation of the role of immunomodulation in the therapy of patients with HIV-1 infection should be of value, not only in developing better therapies for patients with HIV-infection, but also in helping develop a better understanding of the nature of the immunologic defects seen in the context of this infection.

Acquired Immunodeficiency Syndrome↗