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At least 829 records · Page 46Linked to original sources
PubMed2004

Inhibition of human immunodeficiency virus type 1 replication by Z-100, an immunomodulator extracted from human-type tubercle bacilli, in macrophages.

Z-100 is an arabinomannan extracted from Mycobacterium tuberculosis that has various immunomodulatory activities, such as the induction of interleukin 12, interferon gamma (IFN-gamma) and beta-chemokines. The effects of Z-100 on human immunodeficiency virus type 1 (HIV-1) replication in human monocyte-derived macrophages (MDMs) are investigated in this paper. In MDMs, Z-100 markedly suppressed the replication of not only macrophage-tropic (M-tropic) HIV-1 strain (HIV-1JR-CSF), but also HIV-1 pseudotypes that possessed amphotropic Moloney murine leukemia virus or vesicular stomatitis virus G envelopes. Z-100 was found to inhibit HIV-1 expression, even when added 24 h after infection. In addition, it substantially inhibited the expression of the pNL43lucDeltaenv vector (in which the env gene is defective and the nef gene is replaced with the firefly luciferase gene) when this vector was transfected directly into MDMs. These findings suggest that Z-100 inhibits virus replication, mainly at HIV-1 transcription. However, Z-100 also downregulated expression of the cell surface receptors CD4 and CCR5 in MDMs, suggesting some inhibitory effect on HIV-1 entry. Further experiments revealed that Z-100 induced IFN-beta production in these cells, resulting in induction of the 16-kDa CCAAT/enhancer binding protein (C/EBP) beta transcription factor that represses HIV-1 long terminal repeat transcription. These effects were alleviated by SB 203580, a specific inhibitor of p38 mitogen-activated protein kinases (MAPK), indicating that the p38 MAPK signalling pathway was involved in Z-100-induced repression of HIV-1 replication in MDMs. These findings suggest that Z-100 might be a useful immunomodulator for control of HIV-1 infection.

Adjuvants, Immunologic↗
PubMed1997

Differential effects of sunscreens on UVB-induced immunomodulation in humans.

Ultraviolet radiation has been shown to suppress the (skin) immune system both in animal species and in humans. Whether sunscreens can prevent immunosuppression is a matter of debate. This study investigated the protective capacity of a commercial sunscreen lotion in humans. Part of the right arm of healthy volunteers was exposed to erythemagenic ultraviolet B doses of 160 mJ per cm2 for four consecutive days. Before irradiation, sunscreen was applied either directly onto the skin or onto a piece of quartz fixed to the skin (to avoid penetration of the sunscreen in the epidermis where it cannot block the photoisomerization of trans-urocanic acid in cis-urocanic acid in the stratum corneum). The control group was irradiated without prior application of sunscreen. Four h after the last irradiation, epidermal sheets were obtained by the suction-blister method from both arms and epidermal cells were used as stimulator cells in the mixed epidermal cell lymphocyte reaction. Responses directed to epidermal cells derived from irradiated skin were expressed as percentages of responses directed to epidermal cells derived from the nonirradiated left arm. The mixed epidermal cell lymphocyte reaction responses in the control group were found to be significantly increased (205%). This enhancement of the mixed epidermal cell lymphocyte reaction responses was associated with an influx of CD36+DR+ macrophages in the irradiated skin. Application of the sunscreen, either onto a piece of quartz or directly onto the skin, prevented the increase of the mixed epidermal cell lymphocyte reaction responses and the influx of CD36+DR+ cells. In an earlier study, volunteers were exposed three times weekly to suberythemagenic doses of ultraviolet B over 4 wk, resulting in mixed epidermal cell lymphocyte reaction responses that were decreased to 20%. The same sunscreen was not able to prevent this suppression. These contradicting results indicate that the protective effect of sunscreens with respect to ultraviolet-induced immunomodulation is critically dependent on the choice of ultraviolet treatment.

Humans↗
PubMed1999

Potentiation of immune response against the RESA peptides of Plasmodium falciparum by incorporating a universal T-cell epitope (CS.T3) and an immunomodulator (polytuftsin), and delivery through liposomes.

Synthetic peptides representing repeat sequences of ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum have shown poor immunogenicity and protection. In this study, the RESA peptides [(EENVEHDA)2 and (DDEHVEEPTVA)2] were chemically linked to a universal T-cell determinant, CS.T3, derived from the CS protein of P. falciparum. Polytuftsin (TKPR)40, a polymer of naturally occurring immunomodulator "tuftsin," was physically mixed with these conjugates. These preparations in alum and liposomes were immunized in four inbred strains of mice with different genetic backgrounds to study the humoral response. In the case of liposome-entrapped preparations, a 10 microg dose of antigen showed the optimum antibody response. Mice immunized with liposome containing RESA peptide(s)-CS.T3 conjugate along with polytuftsin showed the highest antibody levels in all the strains, whereas the RESA peptide(s) alone, adsorbed on alum or entrapped in liposomes, showed either poor or moderate antibody levels. The antibodies raised against liposome-entrapped preparations in both high-responder strain (SJL/J H-2s) and low-responder strain (FVB/J H-2q) showed 2 4-fold lower Kd values as compared to the alum adsorbed preparations, suggestive of high affinity antibodies. All the antigen preparations predominantly induced IgG2a and IgG2b isotype response, suggesting that the T-helper response involved is of the CD4 Thl type. The in vitro merozoite reinvasion inhibition assay showed 50-92% inhibition with sera raised against different antigen formulations. The highest percentage inhibition was observed with the RESA peptide-CS.T3 conjugate containing polytuftsin in liposomes. Thus, the incorporation of peptide antigens inside liposomes not only reduced the antigen dose by 5-fold but also elicited a high titre with high affinity antibodies and the inhibition of merozoites to RBC in vitro. Therefore, we conclude that the incorporation of these synthetic constructs in liposomes could be a useful strategy for the development of a subunit immunogen against malaria.

Adjuvants, Immunologic↗
PubMed2004

Psoriasis: immunopathogenesis and evolving immunomodulators and systemic therapies; U.S. experiences.

BACKGROUND: Psoriasis is a chronic inflammatory skin disorder that is presently without a permanent cure. Up to 40% of patients with psoriasis also develop psoriatic arthritis. The mainstay armamentarium to treat psoriasis systemically includes methotrexate, cyclosporin and oral retinoids, all with significant potential for toxicity and the need for close laboratory supervision. The although the exact mechanism of psoriasis is still unclear, the involvement of T-cell-mediated cytokine expression in the aetiology of psoriasis is becoming clearer. The goal of modern treatment is to target such immune responses that lead to the formation of psoriatic plaques and psoriatic arthritis using selective immunomodulating pharmacotherapy. The advantages of these biological agents are less toxic systemic side-effect profiles that will improve the quality of life in psoriatic patients. OBJECTIVES: This review article describes current and emerging selective immunotherapies and systemic therapies for the treatment of psoriasis, and will briefly discuss disease immunopathogenesis. METHODS: Literature review. RESULTS AND CONCLUSIONS: Given the role of the inflammatory immune responses in the pathogenesis of psoriasis, the goal of modern medicine and pharmacotherapy lies in the design and use of specific targets in cell-mediated immune reactions and the modulation of the expression of various inflammatory cytokines. The clinical evidence of efficacy of some of these new biological immunomodulatory agents from several U.S.-based research studies and clinical experiences is convincing.

Cytokines↗
PubMed2005

The mode of topical immunomodulators in the immunological network of atopic dermatitis.

For a long time, therapeutic strategies of atopic dermatitis (AD) have been dominated by the application of local or systemic steroids or other immunosuppressive agents, which have been limited by their potential for unwanted local or systemic side effects. Recently, the use of a new generation of topical nonsteroidal, immunomodulatory drugs has revolutionized the therapeutic options of this often recalcitrant allergic-inflammatory skin disease. Research work has focused on the identification of the exact mode of action and the immune specificities of the so-called 'topical immunomodulators' (TIMs) such as tacrolimus and pimecrolimus in AD. In addition to the previous findings about the mode of action of TIMs on T cells, other target cells of TIMs such as keratinocytes, mast cells, eosinophils and dendritic cells have been identified recently as potential therapeutic targets. In this overview, we provide a research update about the anti-inflammatory and anti-allergic properties of TIMs on effector cells of AD that may be involved in the complex pathophysiology of AD.

Acute Disease↗
PubMed1990

The effect of the immunomodulator agent AS101 on interleukin-2 production in systemic lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA antibody.

The role of the synthetic immunomodulator AS101 on the production of interleukin-2 (IL-2) by spleen cells of mice with SLE was investigated. BALB/c female mice, in which SLE was induced by immunization with the pathogenic idiotype of anti-DNA antibody 16/6 Id were treated with AS101 for 7 weeks 2 and 4 months after induction of the disease. The ability of the splenocytes of the mice with SLE to produce IL-2 was restored after administration of AS101. This effect was particularly impressive when the 7-week AS101 treatment was initiated 4 months after immunization. Despite its beneficial effect on IL-2 production, AS101 exerted no influence on the titres of autoantibodies in the sera of the mice. It also had no effect on clinical parameters of SLE, such as the increased sedimentation rate, proteinuria and low white blood cell counts. Our data indicate that defective IL-2 production in SLE is probably secondary to other disease processes and is not necessarily associated with the production of autoantibodies in this disorder.

Adjuvants, Immunologic↗
PubMed1993

Suppression of autoimmune disease in NZB/W F1 mice by treatment with the novel immunomodulator BTS 63155.

Autoimmune disease in NZB/W F1 mice was treated from 23 weeks of age with the novel immunomodulator BTS 63155 and, for comparative purposes, the established immunosuppressive agent cyclosporin A. Both drugs significantly improved survival compared with untreated controls. Lupus nephritis was also significantly reduced in the drug-treated groups, and this was related to reduced glomerular deposition of IgG. Autoantibody (ANA) levels were lowered by treatment with cyclosporin A, but not by BTS 63155. This latter finding may indicate a different mode of action for the two drugs. In a long term study, neither drug effected a complete cure, as autoimmune disease recurred on withdrawal of drug treatment.

Animals↗
PubMed1995

Glucocorticoid-mediated immunomodulation: hydrocortisone enhances immunosuppressive endogenous retroviral protein (p15E) expression in mouse immune cells.

To define glucocorticoid (GC)-regulated genes contributing to the anti-inflammatory and immunosuppressive effects of GC, previous work from our laboratory revealed up-regulation of transcripts from endogenous type B mouse mammary tumour virus (Mtv) and type C murine leukaemia virus (Emv) loci by high dose GC treatment of P388D1 macrophage-like cells. This study demonstrates enhancement of expression from Mtv and Emv loci in P388D1 cells by more physiological hydrocortisone concentrations (1 microM), and shows direct transcriptional mode of regulation by blocking GC-mediated signal transduction at different levels. Furthermore, we found up-regulation of Emv mRNA steady-state levels in murine lymphoid lineage cells (T-like EL4 and BW5147 cells; B-like X63 cells) upon GC treatment. The Emv transcripts shown by us to be GC-up-regulated encode for the transmembrane envelope protein TM/p15E which is highly conserved in several retroviruses. TM/p15E and the p15E-like products found in humans exert immunosuppressive effects in different test systems. Thus, our findings raise the possibility that immunomodulation by GC might be mediated in part by enhanced expression of p15E(-like) products.

Adjuvants, Immunologic↗
PubMed1992

Aplastic anaemia: pathogenetic mechanisms and treatment with special reference to immunomodulation.

Aplastic anaemia (AA) has been defined as a syndrome in which the presence of pancytopenia is accompanied by marrow hypocellularity. Ample laboratory data and clinical observations continue to make immune mediation of bone-marrow failure an attractive hypothesis. Recent progress in the practice of bone-marrow transplantation has led to a survival rate of approximately 80% in the best cases, but such a treatment is only amenable in young patients (less than 45-50 years) with HLA-identical bone-marrow donors. Anti-lymphocyte and thymocyte globulin treatment has been surprisingly effective for AA, resulting in transfusion independence in 40-80% of patients. The mechanism of action is unknown, although effects on immunosuppression appear to be the most likely candidates. Long-term results for patients receiving cyclosporin A treatment will soon be available, and preliminary data show an effect similar to that of antithymocyte globulin. In contrast to successful bone-marrow transplantation, improvement following immunomodulation leaves quantitative abnormalities in all haematopoietic cell lines, and patients are prone to develop clonal (malignant) disease.

Adult↗
PubMed2006

Immunomodulation of Japanese encephalitis vaccine through CpG oligodeoxynucleotides in mice.

Synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine guanine (CpG) dinucleotides motifs act as immune adjuvant and provide means of modulation to immune responses when co-delivered with antigens. They stimulate both innate and adaptive immune responses and induce T helper 1 (Th1) immune responses. We investigated the immunomodulation of Japanese encephalitis (JE) vaccine using CpG ODN as an adjuvant. Mice were immunized with one dose of JE vaccine 0.1 ml with different concentrations (10, 25 and 100 microg) of CpG ODN. The serum antibody level and cytokines were evaluated and compared with mice immunized with two doses of JE vaccine alone. Our studies revealed that anti-JE antibody level in mice immunized with single dose of 0.1 ml JE vaccine and 100 microg CpG ODN were almost equal to mice immunized with two doses of JE vaccine alone. Furthermore, CpG ODN enhanced the production of TNF-alpha and Th1-mediated cytokines, including IFN-gamma and IL-2 compared with JE vaccine alone. In addition, absence of any significant changes in biochemical, haematological and histological studies suggest that CpG ODN are safe adjuvants for JE vaccine. Therefore, it is inferred that CpG ODN are effective and improve the efficacy of JE vaccine.

Adjuvants, Immunologic↗
PubMed2004

Pilot study of patient satisfaction with nonfluorinated topical steroids compared with a topical immunomodulator in atopiform dermatitis.

BACKGROUND: There is clinical uncertainty concerning the effectiveness of the new topical immunomodulators vs. the conventional use of topical steroids for the treatment of atopic dermatitis. OBJECTIVES: To assess patient satisfaction with these two prescription topical remedies for atopic eczema. METHODS: In an open-label, 2-week, comparative study, 10 patients demonstrating atopiform dermatitis were given tacrolimus and 0.1% hydrocortisone butyrate in a 70% oil-in-water base to apply to the eczema on opposite sides of the body. After 2 weeks of applying the agents twice daily to their respective sides of the body surface, the study subjects completed a 12-question survey to assess their opinions of the two products. RESULTS: There was a preference for the nonfluorinated topical steroid over tacrolimus in this cursory head-to-head study. There were no withdrawals from the study or side-effects reported with either product. CONCLUSIONS: Trials of short duration with small numbers of patients do not adequately inform practitioners regarding the use of these topical remedies. However, the higher satisfaction of patients with 0.1% hydrocortisone butyrate in a 70% oil-in-water base over tacrolimus certainly warrants further investigation.

Administration, Cutaneous↗
PubMed2004

The effect of immunomodulators on prevention of autoimmune diabetes is stage dependent: FTY720 prevents diabetes at three different stages in the diabetes-resistant biobreeding rat.

BACKGROUND: Autoimmune diabetes of the diabetes-resistant biobreeding (DRBB) rat shares similarities with diabetes in humans and has stages of diabetes that can be controlled and compared. FTY720 is an immunomodulator that has been efficacious in transplant and autoimmune models without inducing an immunosuppressed state. We determined the stages of diabetes that are affected by FTY720 in the DRBB rat. METHODS: Autoimmune diabetes was induced with RT6.1 T-cell-depleting antibody and polyIC starting at 4 weeks of age. FTY720 (1 mg/kg/d) was started at day 0, 5, 7, and 14 following the start of depletion. The rats that did not develop diabetes were maintained for 60 d following the last dose of FTY720 before undergoing a second course of depletion. RESULTS: FTY720 starting at day 0, 5, 7, and 14 of depletion prevented diabetes in 100, 100, 50, and 20% of the DRBB rats compared to 0% of the control rats. The surviving rats in the 5-, 7-, and 14-d groups developed diabetes after FTY720 treatment was stopped. Histological examination indicated insulitis in the control rats between day 7 and 11 of depletion and end-stage insulitis by day 18 of depletion compared to negligible insulitis in rats without diabetes. Redepletion in the surviving day 0 rats resulted in development of diabetes in 25% of these rats compared to none of the age-matched controls. SUMMARY: FTY720 can prevent autoimmune diabetes, if administered before and/or during stimulation and expansion of the autoreactive T cells or in the early stages of insulitis. The effectiveness diminishes with each successive stage of diabetes.

Adjuvants, Immunologic↗
PubMed1984

Biological activities of analogues of lipid A based chemically on the revised structural model. Comparison of mediator-inducing, immunomodulating and endotoxic activities.

Lipid A analogues were chemically synthesized based on the model structure recently revised, and biological activities of the analogues were tested. The analogue, (beta-1,6)-linked glucosamine disaccharide carrying ester-bound 3-hydroxytetradecanoic acids at 3 and 3' position of reducing and nonreducing glucosamine in addition to amide-bound 3-hydroxytetradecanoic acids and glycosidic-linked and ester-linked phosphate groups, showed much stronger activities for mediator inducing and immunomodulating as well as endotoxic activities than those exhibited by the previously synthesized analogues based on the old model. Among the activities tested, induction of interferon and tumor necrosis factor as well as mitogenicity, adjuvanticity and pyrogenicity were, however, not expressed so strongly as natural lipid A used as controls. In contrast, the analogue exhibited comparable activities to those of control lipid A in the test of lethal toxicity to mice and gelating activity of Limulus amebocyte lysate. Other synthetic analogues carrying a phosphate group showed comparable, slightly stronger or weaker activities depending on the test, but nonphosphorylated analogue exhibited no apparent or only very weak activities.

Adjuvants, Immunologic↗
PubMed2005

Immunomodulation of polyamine biosynthesis in tobacco plants has a significant impact on polyamine levels and generates a dwarf phenotype.

Ornithine decarboxylase (ODC) is a cytosolic enzyme that catalyses the direct decarboxylation of l-ornithine to putrescine, one of the rate-limiting steps of polyamine biosynthesis in plants. In the present study, an ODC-specific murine single-chain antibody fragment (scFvODC1) was generated by phage display technology. To evaluate the effect of the recombinant antibody fragment on ODC activity and polyamine levels, we produced transgenic tobacco plants that accumulated scFvODC1 in the cytosol. Expression levels of up to 4% total soluble protein (TSP) were achieved, resulting in the inhibition of up to 90% of endogenous ODC activity. A significant reduction in putrescine, spermidine and spermine levels was observed in transgenic lines producing high levels of scFvODC1. Furthermore, these lines showed developmental abnormalities and a dwarf phenotype. We show that the immunomodulation of enzyme activity is a powerful approach that can be used to alter complex and tightly controlled metabolic pathways, allowing specific steps in the pathway to be blocked and the resulting physiological effects to be investigated.

Journal Article↗
PubMed2004

Topical immunomodulation in dermatology: potential of toll-like receptor agonists.

BACKGROUND: Topical immunomodulators include both immunostimulatory and immunosuppressive agents. If successful, topical immunotherapy may represent an important improvement in the therapy of inflammatory dermatoses, viral infections, and cancers of the skin and genital mucosa. Topical immunotherapy using obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene has been used against viral (e.g., common warts) and autoimmune diseases (e.g., alopecia areata). RESULTS: Newer agents such imidazoquinolines (imiquimod and resiquimod) act by cytokine secretion from monocytes/macrophages (interferon-alpha, interleukin-12, tumor-necrosis factor-alpha). The locally generated immune milieu leads to a Th1-dominance and cell-mediated immunity that have been clinically used to treat viral infections such as human papillomavirus, herpes simplex virus, and mollusca. Although these agents improve antigen presentation by dendritic cells, they also act on B cells leading to the synthesis of antibodies such as IgG2a. We have also introduced this treatment against cancerous lesions including initial squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. We provide examples of successful treatment of squamous cell cancer using topical imiquimod. CONCLUSION: The available and additional Toll-like receptor agonists will help to improve the specific dermatologic therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents bears potential for effective and patient friendly treatment of inflammatory, infectious, and cancerous skin diseases. Long-term evaluation will define the tolerability and safety profile of these novel topical agents.

Adjuvants, Immunologic↗
PubMed1994

Preliminary study on the effect of substrate size on cellular immunomodulations.

It is well known that the adsorption behavior of lymphocytes on fiber materials is related to the fiber size. In our previous study, murine lymphocytes cultured on various sizes of fibers showed different interleukin 2 (IL-2) activity, and ultrafine fibers of 1.5 microns showed the highest value. Based upon those results and to further evaluate the effects of fibers of different sizes on the modulation of lymphocyte functions, Concanavalin A (Con A) was immobilized on the surface of fibers having different diameters, and murine lymphocytes were cultured on these fibers. Fiber size effects on the lymphocytes were evaluated in terms of IL-2 production and adhesion morphology. The Con A immobilized fibers could stimulate lymphocytes to levels as high as 70-80% of the maximal value induced by the Con A solution. Statistical differences in IL-2 production were not observed among the fiber sizes although as fibers decreased in size, the contact area of the lymphocytes with fibers became smaller. The results suggest that smaller diameter fibers with less contact to adherent lymphocytes can affect lymphocyte function to similar extents on larger diameter fibers and that ultrafine fibers might be useful substrates for immobilizing immunomodulators.

Animals↗
PubMed1996

Current status in extracorporeal immunomodulation: immune disorders.

Today, clinicians can choose from a variety of extracorporeal immunomodulatory procedures such as plasma exchange, double filtration, immunoadsorption, chemoadsorption, photopheresis, and cytoapheresis. The mechanisms underlying extracorporeal immunomodulation (ECIM) comprise removal of pathogenic antibodies and circulating immune complexes as well as reticuloendothelial system deblockage; modification of immune complex structure and processing can be induced by changing the antigen/antibody ratio and by modulation of immune complex solubility via complement activation. Finally, cellular components like lymphocyte subsets, can be modified. Clinical examples of ECIM include lupus erythematosus, Goodpasture's syndrome, anti-neutrophil cytoplasmatic antibodies-mediated systemic vasculitis, myasthenia gravis, and, hypothetically, sepsis.

Adjuvants, Immunologic↗