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PubMed2002

Modulation of antigen-specific immune responses by the oral administration of a traditional medicine, bo-yang-hwan-o-tang.

Bo-yang-hwan-o-tang (BHT) has long been used to treat cancer in traditional Korean medicine and is believed to have immune-modulating activity. This study investigated the effect of BHT on the induction of antigen-specific immune responses using hen egg-white lysozyme (HEL) as a model antigen system. Oral administration of BHT enhanced both HEL-specific humoral and lymphocyte proliferative responses in HEL low-responder mice. Feeding BHT to the mice increased INF-gamma levels, but did not change IL-4 levels. Interestingly, however, the oral BHT feeding significantly increased HEL-specific antibodies of the IgG1, IgG2b, and IgG3 subtypes, which are associated with the direct stimulation of B cells. This indicates that BHT treatment enhances anti-HEL-specific humoral immune responses via the direct stimulation of B lymphocytes rather than by selective priming of specific subtypes of the helper T-cell population. This conclusion was supported by in vitro experiments, in which the presence of BHT significantly augmented B-cell mitogen-mediated proliferation of mouse splenocytes. This augmentation was closely associated with a glycoprotein with a molecular weight of around 100 kDa. The results suggest that BHT modulates antigen-specific immune responses, and might be used as a therapeutic agent for patients who need enhanced immune function.

Adjuvants, Immunologic↗

PubMed1986

Perspective on molecular immunology and modulation of immune responses.

Despite enormous advances made in recent years, there remain fundamental and fascinating unanswered questions in immunology. They would include the mechanism of tolerance, the biological significance of the major histocompatibility complex (MHC) restriction, generation of diversity in T cells, control of V region and isotype selection in B cells, how immune response genes work and how important their function is in man, among others. With the advent of monoclonal antibodies and recombinant DNA technologies, together with greater understanding of immunological interactions within the network and of the intracellular networks between membrane-associated receptors and cell function, a variety of immunological strategies are available for modulating immune responses in man. Some nonspecific strategies include immunomodulatory lymphokines, receptor modulation, and development of agonists and antagonists for important receptors. In addition, there is great potential for immunologically specific strategies for intervention, including the use of idiotypes and anti-idiotypes and genetic engineering of antibodies. Ultimately, there is the possibility of predicting antigenic epitopes likely to engage the cellular and humoral arms of the immune response on the basis of protein or DNA sequences. The potential of exploring these developments for new diagnostic tests and vaccines is emphasized here, as is the unpredictable importance of seemingly nonrelevant fundamental science in producing many of the tools for intervention, now and in the future.

Allergy and Immunology↗

PubMed2000

The scientific basis of immunonutrition.

Substrates with immune-modulating actions have been identified among both macro- and micronutrients. Currently, the modes of action of individual immune-modulating substrates, and their effects on clinical outcomes, are being examined. At present, some enteral formulas are available for the clinical setting which are enriched with selected immune-modulating nutrients. The purpose of the present paper is to review the scientific rationale of enteral immunonutrition. The major aspects considered are mucosal barrier structure and function, cellular defence function and local or systemic inflammatory response. It is notable that in critical illness the mucosal barrier and cellular defence are impaired and a reinforcement with enteral immunonutrition is desirable, while local or systemic inflammatory response should be down regulated by nutritional interventions. The results available from clinical trials are conflicting. Meta-analyses of recent trials show improvements such as reduced risk of infection, fewer days on a ventilator, and reduced length of intensive care unit and hospital stay. Thus, a grade A recommendation was proclaimed for the clinical use of enteral immune-modulating diets. Improvement in outcome was only seen when critical amounts of the immune-modulating formula were tolerated in patients classified as being malnourished. However, in other patients with severe sepsis, shock and organ failure, no benefit or even disadvantages from immunonutrition were reported. In such severe conditions we hypothesize that systemic inflammation might be undesirably intensified by arginine and unsaturated fatty acids, directly affecting cellular defence and inflammatory response. We therefore recommend that in patients suffering from systemic inflammatory response syndrome great caution should be exercised when immune-enhancing substrates are involved which may aggravate systemic inflammation.

Adjuvants, Immunologic↗

PubMed2001

Adjunctive immune therapy for fungal infections.

Fungal infections in immunocompromised patients can pose difficult problems in clinical management, because the available antifungal chemotherapy is often unable to eradicate the infection in these people. Hence, the use of immune modulating therapy to augment impaired host immune responses--and thus enhance the efficacy of antifungal drugs--is a reasonable approach to improve the prognosis of fungal infections. Advances in biotechnology have produced a variety of biological response modifiers with the potential to serve as adjunctive immune therapy for the treatment of fungal infections, including cytokines, monoclonal antibodies, and cell growth factors. In recent years, immune-modulating therapies have been studied in an effort to define their potential use for the treatment of fungal infections. Much of the available information on the use of this approach is encouraging and invites further investigation--with the caveats that the information is mostly anecdotal and that immune-modulating therapy occasionally has produced adverse effects.

Adjuvants, Immunologic↗

PubMed1995

Catecholamine influences and sympathetic neural modulation of immune responsiveness.

Primary and secondary lymphoid organs are innervated extensively by noradrenergic sympathetic nerve fibers. Lymphocytes, macrophages, and other cells of the immune system bear functional adrenoreceptors. Norepinephrine fulfills criteria for neurotransmission with cells of the immune system as targets. In vitro, adrenergic agonists can modulate all aspects of an immune response (initiative, proliferative, and effector phases), altering such functions as cytokine production, lymphocyte proliferation, and antibody secretion. In vivo, chemical sympathectomy suppresses cell-mediated (T helper-1) responses, and may enhance antibody (T helper-2) responses. Noradrenergic innervation of spleen and lymph nodes is diminished progressively during aging, a time when cell-mediated immune function also is suppressed. In animal models of autoimmune disease, sympathetic innervation is reduced prior to onset of disease symptoms, and chemical sympathectomy can exacerbate disease severity. These findings illustrate the importance of the sympathetic nervous system in modulating immune function under normal and disease states.

Animals↗

PubMedDate not supplied

Immune system modulation in the highly sensitized transplant candidate.

Heart transplantation can be a lifesaving option for patients with end-stage heart failure. However, implanting recipients with an organ or tissue from a donor presents immunologic challenges. Sensitized recipients are at risk for hyperacute rejection because of the presence of preformed antibodies. Immune modulation with cyclophosphamide, plasmapheresis, and intravenous gamma globulin are methods used to desensitize transplant candidates with preformed anti-HLA antibodies to achieve successful transplantation.

Acute Disease↗

PubMed2000

Lignin-carbohydrate complexes: intestinal immune system modulating ingredients in kampo (Japanese herbal) medicine, juzen-taiho-to.

An extract preparation (TJ-48) of a Japanese herbal (Kampo) medicine, Juzen-Taiho-To has been found to show an enhancing activity on proliferation of bone marrow cells mediated by Peyer's patch cells (intestinal immune system modulating activity) (1). When TJ-48 was fractionated by MeOH- and water-extractions, EtOH precipitation and dialysis, water-soluble dialyzable (F-3) and polysaccharide fractions (F-5) both showed a significant intestinal immune system modulating activity in vitro; other fractions had no activity. Oral administration of F-3 (150 mg/kg) also showed the intestinal immune system modulating activity in C3H/HeJ mice. Two active substances were purified by gel filtration from F-3. Chemical analysis indicated that the active substances comprised lignin as well as a carbohydrate consisting mainly of arabinose, galactose, glucose and galacturonic acid. Activity was significantly reduced not only by NalO4 oxidation but also by NaClO2 treatment. Standard lignin showed no activity. Carbohydrate and lignin in the active substances were co-eluted by hydrophobic-interaction chromatography on phenyl-Sepharose, and the stimulating effect and lignin content of the substances did not change even after the hydrophobic-interaction chromatography. These results suggest that lignin-carbohydrate complexes are involved in intestinal immune system modulation by TJ-48.

Animals↗

PubMed2004

Modulation of immune responses with transcutaneously deliverable adjuvants.

Transcutaneous immunisation is a novel vaccination strategy based on the application of antigen together with an adjuvant onto hydrated bare skin. This simple and non-invasive immunisation procedure elicits systemic and mucosal immune responses and therefore, it provides a viable and cost-effective strategy for disease prevention. For the induction of antigen-specific immune responses the use of adjuvants is critical. They potentiate and modulate the type of immune responses by stimulating the production of cytokines that drive the differentiation of T cells towards the Th1 or Th2-phenotype. These cells mediate protection against different infectious diseases and therefore, their selective induction is important for successful vaccination. In this review we give a brief overview of transcutaneously deliverable adjuvants and we discuss how they modulate immune responses to topically applied antigens.

Adjuvants, Immunologic↗

PubMed1996

Pharmacological aspects and therapeutic applications of lysozymes.

The therapeutic effectiveness of lysozyme (large scale manufactured hen egg-white lysozyme) is actually based on its ability to control the growth of susceptible bacteria and to modulate host immunity against infections and depressions of immune responses. If the former is based on the first evidence of the biological activity of this enzyme, the second is a relatively recent acquisition of extreme importance for the possibilities offered in terms of the regulation of the functioning of the host's immune system. Antibotic activity and immune stimulating effects are also used together, as in the case of the treatment of gastrointestinal infections, including those originated by therapeutical treatments. Based on these biological properties, in addition to the wide range of therapeutic activities for which lysozyme was exploited in the past, at present the most promising data concern the prevention of bacterial cariogenesis and treatment of cancer patients to improve the effectiveness of anticancer drugs or to allow the host to recover from the immune suppression caused by anticancer treatments. However, lysozyme does not yet hold a clear place as an immune modulating agent, in spite of the fact that it has been shown to stimulate immunity with no difference between experimental animals and human beings. The hope is therefore that doctors will understand its potential and that they will take advantage of the existence of this simple and useful molecule.

Adjuvants, Immunologic↗

PubMed2002

Molecular mechanisms for protein kinase A-mediated modulation of immune function.

Protein kinase A (PKA) is a serine/threonine kinase that regulates a number of cellular processes important for immune activation and control. Modulation of signal transduction by PKA is a complex and diverse process, and differential isozyme expression, holoenzyme composition and subcellular localization contribute specificity to the PKA signalling pathway. In lymphocytes, phosphorylation by PKA has been demonstrated to regulate antigen receptor-induced signalling both by altering protein-protein interactions and by changing the enzymatic activity of target proteins. PKA substrates involved in immune activation include transcription factors, members of the MAP kinase pathway and phospholipases. The ability of PKA type I to regulate activation of signalling components important for formation of the immunological synapse, demonstrates that the cAMP signalling pathway can directly modulate proximal events in lymphocyte activation. Furthermore, the recent discovery that PKA regulates Src kinases through modulation of Csk, supports the notion that PKA is involved in the fine-tuning of immune receptor signalling in lipid rafts.

CSK Tyrosine-Protein Kinase↗

PubMed2006

Co-delivery of plasmid-encoded cytokines modulates the immune response to a DNA vaccine delivered by in vivo electroporation.

In this study, in vivo electroporation of a DNA vaccine adjuvanted with plasmids encoding different cytokines was investigated in large animals. Sheep were injected intramuscularly with a DNA vaccine encoding an antigen of Haemonchus contortus (pNPA) and plasmids encoding different cytokines followed by in vivo electroporation. Plasmids (pCI) carrying the genes of different cytokines including ovine IL-4(pCI-IL4), IL-10(pCI-IL10), GM-CSF(pCI-GMCSF), and MCP-1alpha(pCI-MCP1alpha), and pCI-IL4+pCI-GMCSF were co-delivered with pNPA. The results showed that co-delivery of pCI-GMCSF or pCI-IL4+pCI-GMCSF significantly enhanced both antibody responses and T cell proliferation responses to the antigen after two DNA immunisations compared to co-delivery of pCI. In contrast, antibody responses of the sheep that received pCI-IL10 were decreased significantly. Other cytokine expressing plasmids did not significantly alter the measured immune responses. Furthermore, co-delivery of pCI-GMCSF increased IgG2 response more than IgG1 responses, suggesting a Th1 bias. However, the increase in IgG2 over IgG1 was less apparent when co-delivery of pCI-IL4 with pCI-GMCSF. Interestingly, the co-delivery of pCI-IL4 alone did not increase the IgG1 titre, suggesting that both pCI-GMCSF and pCI-IL4 are required for optimal IgG1 production. Thus, co-delivery of plasmid-encoded cytokine genes with in vivo electroporation has the ability to effectively modulate immune responses to a DNA vaccine in a large animal.

Animals↗

PubMedDate not supplied

[On the problem of prophylaxis of late effects induced by internal irradiation using immunomodulators].

Using the experimental modeling of late effects induced by intake of radionuclides (131I, 238,239Pu, 90Sr) the attempt to investigate the possibility of protection using immune modulators was made. Co-polymer of 2-methil-5-vinilprilidin and N-vinilpirrholidon (sovidon), G immunoglobulin and interferon, Fc fragment of immunoglobulin and S. parathyphi B. Breslau vaccine were used as immune modulators. The positive prophyletie influence of immune modulators was found for average life span, radiation action, immune status, of rates of occurrence and developments of breast tumors induced by 131I, 239Pu and 90Sr. At the same time the increase in osteosarcoma cumulative rate induced by immune modulators in case of body intake of 238Pu and 90Sr was registered.

Adjuvants, Immunologic↗

PubMed2003

Host background factors contributing to hepatitis C virus clearance.

This review is an attempt to characterize the host in the earliest events of hepatitis C virus (HCV) infection before the on-set of adaptive immune response. Host meets the replicating HCV with innate immune response in the form of proinflammatory cytokine production, activation of natural killer (NK), NKT and dendritic cells. The potency of innate response is shaped by a wide panel of genetically predetermined constants and acquired variables. Higher rates of HCV clearance associate with white ethnicity and certain HLA haplotypes. Lower clearance rates correlate with genetic immune deficiencies/disorders. Recent findings link infection outcome with variation in the genes for the low-density lipoprotein and complement type 1 receptors. Important though insufficiently characterized is the role of polymorphisms in the genes responsible for induction of antiviral immunity. The outcome of HCV entry and of subsequent acute infection (if that occurs) is pre-determined by the immune competence of the host at the moment of infection. Higher rate of HCV clearance is observed for pediatric patients and young adults. Bad prognostic markers would be post-transplantation immune suppression, transfusion-related immune modulation, alcohol-induced immune imbalance and intoxication. Among host variables is the immune modulation induced by parasitic and viral co-infections. Some of the variables are transient and hard to define in retrospective. These host characteristics set up the potency, kinetics, and profile (Th1/Th2) of subsequent adaptive immune response. Better understanding of the host correlates of viral clearance would be a step towards prophylaxis of infection and an efficient anti-HCV vaccine.

Age Factors↗

PubMed2002

Inducing oral immune regulation of hepatitis B virus envelope proteins suppresses the growth of hepatocellular carcinoma in mice.

BACKGROUND: Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) expresses hepatitis B surface antigen (HBsAg) on its cell surface, and this may serve as a tumor-associated antigen. It was shown previously that adoptive transfer of immunity against HBsAg facilitates the suppression of experimental human HCC-expressing HBsAg in athymic mice. The authors recently showed that it was possible to augment the anti-HBV immune response through induction of oral immune regulation for HBV-associated antigens. The objective of this study was to evaluate the effect of oral immune regulation for HBV antigens on the growth of HBsAg-expressing HCC. METHODS: Recipient athymic Balb/c mice were irradiated sublethally and injected with 10(7) human hepatoma cells followed by the adoptive transfer of 2 x 10(6) splenocytes from donor mice. Four groups of donor Balb/c mice were studied: Two groups were immune modulated through oral administration of HBV antigens (HBsAg, PreS1, and Pre S2) or bovine serum albumin (BSA). Two control groups were immunized for HBsAg and fed HBV antigens or BSA. Recipient mice were followed for tumor volume and serum alpha-fetoprotein (aFP) levels. The humoral immune response was determined by measuring serum HBs antibodies. HBV specific T-cell immune modulation was assessed in vitro by HBV specific T-cell proliferation and interferon gamma (IFNgamma) ELISPOT assays as well as cytokine expression by reverse transcriptase-polymerse chain reaction assays. RESULTS: The adoptive transfer of orally immune modulated HBV splenocytes induced complete tumor suppression in recipient mice compared with control mice transplanted with nonimmune modulated cells (BSA), which showed significant tumor growth (serum aFP levels were 3.5 ng/mL and 2320.0 ng/mL, respectively). Control mice transplanted with anti-HBs immunized cells (with or without oral immune modulation) manifested similar tumor suppression (3.5 ng/mL and 0.5 ng/mL, respectively). Immunoregulation for HBV antigens augmented the HBV specific T-cell immune response, as manifested by an increase in HBV specific T-cell proliferation and IFNgamma ELISPOT assays in mice orally immune regulated with HBV proteins compared with naïve mice. Tumor suppression was mediated through increased IFNgamma production in immune regulated and immunized mice. CONCLUSIONS: The induction of oral immune regulation for HBV antigens modulated the antitumor immune response, thus suppressing the growth of HCC in mice. This effect was mediated by the enhancement of anti-HBV specific T-cell immunity.

Administration, Oral↗

PubMed2004

Molecules of infectious agents as immunomodulatory drugs.

Microbes produce a wide range of molecules that can modulate eukaryotic immune responses. These include factors that subvert protective mechanisms in order to facilitate pathogen colonization and persistence. Viral, bacterial and parasite-derived molecules have been identified that can inhibit inflammatory responses. However, in addition to the plethora of microbial factors that suppress immune responses, the most potent immune activators are also of microbial origin. These include the bacterial enterotoxins, parasite-derived excretory-secretory products and viral nucleic acids. In fact, there are examples of immune modulators that can exert either stimulatory or suppressive effects depending on the mode of delivery, dose and experimental model. There is presently great interest in the therapeutic exploitation of these factors, for example as a means to stimulate enhanced immune responses to a new generation of subunit vaccines or to inhibit deleterious immune mediated diseases. This short review, describes representative microbial immunomodulators, their modes of action and the potential for therapeutic application.

Adjuvants, Immunologic↗

PubMed2002

Intestinal immune system modulating polysaccharides in a Japanese herbal (Kampo) medicine, Juzen-Taiho-To.

A commercially available dried extract (TJ-48) of Japanese herbal (Kampo) prescription, Juzen-Taiho-To has been found to enhance functions of Peyer's patch cells (intestinal immune system modulating activity) in vitro and in vivo. When TJ-48 was fractionated, the dialyzable fraction (F-3) and the polysaccharide fraction (F-5) expressed the in vitro activity. Oral administration of F-5 (150 mg/kg/day) to mice showed the intestinal immune system modulating activity. When the galacturonan moiety of pectic polysaccharides in F-5 was degraded enzymatically by endo-polygalacturonase, the digestion products significantly increased the activity of F-5. Purification the polygalacturonase-digested F-5 indicated that the active substances were composed mainly of the enzyme-resistant or undigestable polysaccharide molecules. Gel filtrations and anion-exchange chromatographies of F-5 gave 12 kinds of polysaccharides, and among them, 7 polysaccharides had significant intestinal immune system modulating activity. Component sugar analysis suggests that some active polysaccharides are grouped into pectic polysaccharides containing arabinogalactan or heteroglycan chains. Single radial gel diffusion analysis using beta-D-glucosyl-Yariv antigen indicated that some of the active polysaccharides comprised arabino-3,6-galactan moiety, and this moiety was suggested to play an important role partly for expression of the activity by single linear regression analysis between degree of the activity and reactivity with beta-D-glyucosyl-Yariv antigen.

Adjuvants, Immunologic↗

PubMed2003

Inflammatory bowel disease: dysfunction of GALT and gut bacterial flora (II).

The precise cause(s) of Crohn's disease and ulcerative colitis are unknown. From animal models and human studies it is well established that gut bacterial flora are essential for inducing the bowel inflammation. Animal models, when kept in a germ-free environment, do not develop colitis until the gut flora is reconstituted. It is not clear whether the bacterial antigens (Ags) from the normal flora or some other pathogenic bacterial Ags induce/propagate the inflammatory process in inflammatory bowel disease (IBD). Despite extensive research it has not been possible to identify any specific bacteria or virus as a credible cause of IBD. Recent understanding of quorum sensing molecules (QSMs) secreted by bacteria helps to explain the community behaviour in bacterial species. When QSMs reach a defined concentration, they activate bacterial proliferation and a number of virulence genes. Also, these molecules have been found to modulate the immune system to the advantage of the gut bacteria. They have not been well studied, however, in the gut. Inappropriate secretion of QSMs may alter the gut-associated lymphoid tissue (GALT) and, thereby, deregulate the immune tolerance normally present. Usefulness of probiotics and their immune modulating effects are being increasingly reported. Probiotics are also being used in the treatment of IBD. The interaction between the epithelial cells and the gut flora is very important as this is the first line of contact; this interaction may determine the induction of tolerance and mucosal integrity or immune activity, tissue inflammation and abnormal permeability. The latter is documented in patients with IBD and their healthy relatives. This may be an important factor in disruption of mucosal integrity and GALT dysfunction.

Animals↗

PubMed2004

Structure of oligosaccharide side chains of an intestinal immune system modulating arabinogalactan isolated from rhizomes of Atractylodes lancea DC.

An intestinal immune system modulating arabino-3,6-galactan (ALR-5IIa-1-1) has been found in rhizomes of Atractylodes lancea DC. [Planta Medica 1998, 64, 714-719; Carbohydr. Polyms. 2001, 46, 147-156], however other arabino-3,6-galactans from Larix and Acacia failed to express the modulating activity. Degradation of the galactosyl side chains in Araf-side chain-trimmed ALR-5IIa-1-1 (AF-ALR-5IIa-1-1) with an endo-beta-D-(1-->6)-galactanase remarkably decreased the activity of AF-ALR-5IIa-1-1. Structural analysis indicated that the major endo-beta-D-(1-->6)-galactanase-digestable side chains in ALR-5IIa-1-1 are composed of beta-D-(1-->6)-galactopyranosyl oligosaccharides having d.p. 1-8. Because degradation of the beta-D-(1-->3)-galactan backbone in AF-ALR-5IIa-1-1 also significantly reduced its activity, some of these galactosyl side chains attached to beta-D-(1-->3)-galactan backbone are suggested to be responsible for expression of the activity of ALR-5IIa-1-1.

Atractylodes↗