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Immunomodulating activities of staphylococcal enterotoxins. I. Effects on in vivo antibody responses and contact sensitivity reaction.

The immunomodulating effects of staphylococcal enterotoxins on in vivo immune responses in C57BL/6 mice were examined. Of the five serological types A (SEA), B, C, D, and E (SEE), only SEA and SEE markedly suppressed the antibody response to sheep red blood cells (SRBC) when injected 1 day before or on the day of immunization with SRBC. Further study of SEA revealed that it did not affect the antibody response to a thymus-independent antigen, salmonella flagella, but did affect the T-cell-mediated immune response. Contact sensitivity to dinitrofluorobenzene (DNFB) was suppressed when SEA was injected before sensitization or before challenge with DNFB, indicating that SEA affected both the afferent and efferent phases of DNFB contact sensitivity. As the suppression of DNFB contact sensitivity could be transferred by anti-Thy-1.2 antibody-sensitive spleen cells of SEA injected donors into normal or DNFB-sensitized recipients, the suppression was thought to be an active one. However, SEA could augment the DNFB contact sensitivity when injected on the third day after sensitization with DNFB. These results indicate that the immunomodulating effects of SEA can be mediated by the T-cell function.

Animals↗

Immunomodulation in mice by experimental infection with Yersinia enterocolitica.

Intraperitoneal infection of mice with two strains of Yersinia enterocolitica resulted in an inflammatory response and immunomodulation which appeared to be related to the invasive properties of the bacteria. The primary antibody response to sheep erythrocytes was enhanced by noninvasive cultures of Y. enterocolitica (serotype O:4-33 grown at 22 C and at 37 C, and serotype O:3 grown at 37 C), when given at the same time or two days after the antigen (invasiveness was tested on HeLa cells). In contrast, invasive cultures of serotype O:3 grown at 22 C, injected three days before the antigen suppressed the antibody response; enhancement was caused by these cultures only when given on the day of immunization. Delayed-type hypersensitivity to sheep erythrocytes was also suppressed by invasive cultures of Y. enterocolitica. These data indicate that the temperature of growth as well as some serotype-linked factors play a role in immunomodulation by Y. enterocolitica.

Animals↗

Immunomodulating cytokines in atopic dermatitis and psoriasis: production of tumour necrosis factor and lymphotoxin by mononuclear cells in vitro.

The immunomodulating cytokines, tumour necrosis factor/cachectin (TNF) and lymphotoxin (LT) are thought to play an essential role as mediators of inflammatory reactions. To evaluate the role of TNF and LT in atopic dermatitis (AD) and psoriasis, we investigated their production by mononuclear cells (MNC) in vitro. The 24-h supernatants of lipopolysaccharide (LPS)- and phytohaemagglutinin (PHA)-stimulated and unstimulated MNC from 26 patients with AD and 20 with psoriasis and from 17 non-atopic healthy controls were tested for the concentrations of TNF and LT using an ELISA technique. In patients with AD, TNF levels were significantly decreased in the supernatant of PHA-stimulated (P less than or equal to 0.005) and LPS-stimulated (P less than or equal to 0.02) MNC in comparison to controls. There was no significant difference in TNF production between psoriatic patients and the control group. Release of LT in the supernatant of PHA-stimulated MNC by patients and controls did not differ significantly. There was no significant spontaneous production of TNF and LT by MNC of patients and controls. These studies indicate that different immunomodulating mechanisms are responsible for triggering the inflammatory response in AD and psoriasis.

Adolescent↗

Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis.

The Epstein-Barr virus (EBV), or human herpesvirus-6 (HHV-6) associated haemophagocytic lymphohistiocytosis, has been found prevalent in Taiwan; it affects previously healthy children and is always fatal when treated only supportively. Recognition of the underlying pathogenesis for this disease prompted adoption of an immunomodulatory regimen of intravenous immunoglobulin (IVIG) and/or etoposide on 17 such patients treated between 1990 and 1993. Remarkable improvement in patients' prognoses was demonstrated. Eight patients are still alive with a median follow-up of 1 year and 2 months post-treatment. Both IVIG and etoposide had positive immunomodulation effects such as alleviation of fever and normalization of haematological and hepatic parameters. Sustained complete response was obtained in two of nine cases of EBV-associated diseases treated with IVIG only. EBV transcripts became undetectable after etoposide and/or IVIG treatment without antiviral agents. Etoposide given by split-doses schedule appeared to be superior to conventional three-consecutive-days schedule for both remission induction and disease-free survival. Our preliminary trial apparently provides a promising improvement in the treatment of this previously fatal disease. IVIG or etoposide is effective in reversing the process of lymphohistiocytic dysregulation resulting from virus infection of immune cells in this syndrome and probably helps hosts to control active virus replication in certain cases, through immunomodulation.

Adolescent↗

Adjuvant effect of synthetic oligodeoxyribonucleotides (CpG-ODN) from the Paracoccidioides brasiliensis gp43 gene on the Th2-Th1 immunomodulation of experimental paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is caused by the dimorphic fungus Paracoccidioides brasiliensis. Immunostimulatory effects of P. brasiliensis DNA and CpG-oligodeoxyribonucleotides (CpG-ODN) have shown a Th2-Th1 immunomodulation of the isogenic murine model of susceptibility, which develops a progressive and disseminating disease. In this study, we investigated the optimum time interval and doses of CpG-ODN which are able to induce Th2-Th1 immunomodulation. The optimum concentrations for the induction of a decrease in antibody production were 0.5 and 1 microg. Mice immunized twice with CpG-ODN and gp43 (5 and 7 days before the challenge) showed a 60% higher chance of survival compared with the control group (nonimmunized), and an increase in Th1 isotype (IgG2a) was also observed. In vitro assays of naive and preimmunized mice showed discrete cellular proliferation when stimulated by suitable concentrations of CpG-ODN. Type 1 cytokines interleukin-12 (IL-12) and interferon-gamma were increased in cell culture supernatants, but no significant difference was found in Th2 IL-4 cytokines in stimulated or nonstimulated cell cultures. Concerning the Th2-Th1 kinetics in experimental PCM models by adjuvant effect of CpG-ODN, there are still many questions to be answered and clarified. However, the gathering of data obtained in this investigation has led us to suggest that the modulation of Th2-Th1 in experimental PCM depends on time and CpG-ODN concentration.

Adjuvants, Immunologic↗

The antiatherogenic effect of DiNAC: experimental findings supporting immunomodulation as a new treatment for atherosclerosis related diseases.

Inflammatory processes in the arterial wall are important in atherogenesis. The present review discusses the development of DiNAC as a potential new treatment modality for atherosclerosis related diseases. DiNAC, N,N'-diacetyl-L-cystine, is the disulphide dimer of N-acetyl cysteine, NAC. It was selected as an immunomodulating drug candidate due to its ability to modify contact sensitivity/delayed type hypersensitivity (CS/DTH) reactions in vivo. Initial structure-activity relationship (SAR) studies indicated that an intact disulfide bridge was essential for this effect. Antioxidants, like probucol and some close analogs with two sulphurs in close proximity (but not disulphides), were also found to have similar effects on CS/DTH reactions. These antioxidants have antiatherosclerotic effects, while structurally related compounds without sulphurs do not. Therefore, it was hypothesized that DiNAC might also possess antiatherosclerotic effects. This was investigated in WHHL rabbits and mice. In both species, DiNAC had antiatherosclerotic activity similar to that of probucol. The effect of DiNAC was not due to an alteration of lipid metabolism. Impaired endothelium mediated relaxation is known to be associated with atherosclerosis. DiNAC was shown to reverse this process in WHHL rabbits with advanced atherosclerosis, probably due to an action on the vessel wall itself that is not related to the extent of atherosclerosis or to plasma lipid levels. Preliminary data from a clinical investigation in hypercholesterolemic subjects suggest that DiNAC is likely to have similar effects also in patients. Taken together, these findings suggest immunomodulation to be a potential new therapy for atherosclerosis related diseases. DiNAC may represent a new treatment modality for such diseases.

Adjuvants, Immunologic↗

Immunomodulating effects of vitamin D analogs in hemodialysis patients.

Apart from its well-known functions in calcium homeostasis and parathyroid hormone regulation, 1,25-(OH)2D3 and its synthetic analogs are being increasingly recognized for their potent antiproliferative, pro-differentiative and immunomodulating activities. The effects of these drugs are exerted either via vitamin D receptor-dependent genomic, or cell-surface receptor-mediated, non-genomic pathways. Several vitamin D analogs with fewer hypercalcemic side effects have been developed for use in secondary hyperparathyroidism. These analogs may potentially improve treatment of autoimmune disorders and graft rejection, and in dialysis patients may open a new opportunity for amelioration of the chronic inflammatory status. It has recently been shown that hemodialysis (HD) patients treated with paricalcitol have lower total and cardiovascular mortality and morbidity rates and experience improved hospitalization outcomes compared with HD patients treated with calcitriol, suggesting a potential beneficial effect in chronic inflammation and the development of cardiovascular disease. Specific studies on the immunomodulating effects of vitamin D are needed in the HD population.

Humans↗

Potential of using lactic acid bacteria for therapy and immunomodulation in man.

There is in 1993 no proven medical indication of lactic acid bacteria (LAB) for therapy or immunomodulation in man. However, within the bulk of publications, rigorous trials have now opened rational fields of research on beneficial effects of LAB. These include lactose digestion, cholesterol metabolism, diarrheal disorders, prophylaxis of intestinal or urogenital infections, immunomodulation or even oral vaccination. We try here to analyse these studies, considering LAB as pharmacological agents, and conclude that pursuit of research could be promising for ecological therapy of mucosal diseases, and for development of original and flexible vectors for targeting in the gastrointestinal tract.

Colonic Neoplasms↗

Products of psoralen photooxidation possess immunomodulative and antileukemic effects.

It has been proposed that the therapeutic effect of PUVA (psoralens+UVA radiation) is connected to its immunomodulative properties, and that the molecular basis of such properties is the oxygen-independent photoaddition of psoralens to DNA. We have investigated effects of preliminary photooxidized psoralens (POP) on the delayed-type hypersensitivity reaction (DTH) to sheep red blood cells and on growth of grafted T-cell lymphoma EL-4 in mice. We have shown that intravenous injection of POP at low concentrations activated, and at high concentrations suppressed, DTH. The POP products are thermolabile. They preserved their immunosuppressive activity for 3 days at room temperature and lost it in several min at 58 degrees C. Incubation of POP in the presence of Fe2+ during 2 h before intravenous injection leads to complete loss of its immunomodulative activity, suggesting a peroxidic nature of POP products. The POP-inhibited growth of grafted T-cell lymphoma independent of the mode of POP application in mice (intravenous or subcutaneous injections, oral or nasal administration). Our data suggest that photooxidative reactions of psoralens, in addition to oxygen-independent photoaddition to DNA, form the basis for biological activity of these drugs.

Adjuvants, Immunologic↗

Probiotics: immunomodulation and evaluation of safety and efficacy.

The intake of probiotics has been associated with beneficial effects on the immune system, such as improved disease resistance and diminished risk of allergies. This review gives an overview of the immunomodulatory effects of probiotics investigated with in vitro assays, experimental animal models, and clinical trials, and explores possible mechanisms underlying the immunomodulatory effects. Immunomodulation, however, is not always beneficial and might induce detrimental effects; therefore, a scheme is proposed for benefit-risk assessment of immunomodulation by probiotics. Within this scheme, expert judgment based on data derived from a panel of in vitro assays, animal models, and clinical trials should lead to conclusions on efficacy and safety aspects of probiotics.

Animals↗

Human monocytes activated by immunomodulators in liposomes lyse herpesvirus-infected but not normal cells.

Highly purified peripheral blood monocytes from normal human donors were activated in vitro by incubation with liposomes containing immunomodulators such as recombinant human gamma interferon, human lymphokines, or muramyl dipeptide. The ability of liposomes containing immunomodulators to activate monocytes to a cytotoxic state capable of discriminating between virus-infected and uninfected cells was shown by activated monocytes recognizing and destroying herpes simplex virus type 2-infected cells while leaving uninfected cells unharmed .

Acetylmuramyl-Alanyl-Isoglutamine↗

Microbial infections, immunomodulation, and drugs of abuse.

The use of recreational drugs of abuse has generated serious health concerns. There is a long-recognized relationship between addictive drugs and increased levels of infections. Studies of the mechanisms of actions of these drugs became more urgent with the advent of AIDS and its correlation with abused substances. The nature and mechanisms of immunomodulation by marijuana, opiates, cocaine, nicotine, and alcohol are described in this review. Recent studies of the effects of opiates or marijuana on the immune system have demonstrated that they are receptor mediated, occurring both directly via specific receptors on immune cells and indirectly through similar receptors on cells of the nervous system. Findings are also discussed that demonstrate that cocaine and nicotine have similar immunomodulatory effects, which are also apparently receptor mediated. Finally, the nature and mechanisms of immunomodulation by alcohol are described. Although no specific alcohol receptors have been identified, it is widely recognized that alcohol enhances susceptibility to opportunistic microbes. The review covers recent studies of the effects of these drugs on immunity and on increased susceptibility to infectious diseases, including AIDS.

Cannabis↗

Cell walls, peptidoglycans, and teichoic acids of gram-positive bacteria as polyclonal inducers and immunomodulators of proliferative and lymphokine responses of human B and T lymphocytes.

In this study, the mitogenic and immunomodulating effects of bacterial cell wall preparations were investigated. Cell walls, peptidoglycans, and teichoic acids from Bacillus subtilis and Staphylococcus aureus Wood 46 activated both human T cells (supplemented with 10% monocytes) and B cells to proliferative and to produce leukocyte migration inhibitory factor. Similar results were obtained with adult and umbilical cord blood cells, suggesting that these bacterial preparations acted as mitogens. Cell walls and peptidoglycans had a modulating effect on purified protein derivative-induced and protein A-induced proliferation. In the presence of suboptimal concentrations of these stimulants, bacterial components enhanced the proliferative response. However, at optimal concentrations of purified protein derivative or protein A, bacterial components suppressed lymphocyte proliferation. Peptidoglycans solubilized by lysozyme activated B lymphocytes but not T cells. Solubilization had no effect on immunomodulating capacity.

Age Factors↗

Cell walls, peptidoglycans, and teichoic acids of Gram-positive bacteria as polyclonal inducers and immunomodulators of proliferative and lymphokine responses of human B and T lymphocytes.

In this study the mitogenic and immunomodulating effects of bacterial cell wall preparations were investigated. Cell walls, peptidoglycans, and teichoic acids from Bacillus subtilis and Staphylococcus aureus Wood 45 activated both human T cells (supplemented with 10% monocytes) and B cells to proliferate and to produce leukocyte-inhibitory factor. Similar results were obtained with adult and umbilical cord blood cells, suggesting that these bacterial preparations were acting as mitogens. Cell walls and peptidoglycans had a modulating effect on purified protein derivative- or protein A-induced proliferation. In the presence of suboptimal concentrations of these stimulants, bacterial components enhanced the proliferative response. However, at optimal concentrations of purified protein derivative or protein A, bacterial components suppressed lymphocyte proliferation. Peptidoglycans solubilized by lysozyme activated B lymphocytes but not T cells. Solubilization had no effect on the immunomodulating capacity.

B-Lymphocytes↗

Resistance to infections in mice with defects in the activities of mononuclear phagocytes and natural killer cells: effects of immunomodulators in beige mice and 89Sr-treated mice.

Beige mice, which are a homolog of the Chediak-Higashi syndrome, and mice treated with 89Sr to destroy the bone marrow provide animal models of defects in mononuclear phagocyte and natural killer cell functions. The innate resistance of these mice to viruses such as herpes simplex and encephalomyocarditis viruses, however, is normal. Moreover, treatment of the mice with immunomodulators such as Propionibacterium acnes (formerly designated Corynebacterium parvum) and pyran produced a significant increase in resistance to encephalomyocarditis virus. The antiviral effect of P. acnes in 89Sr-treated mice was exhibited during marked monocytopenia and without evidence for an inflammatory influx of macrophages into the peritoneal cavity. Treatment with P. acnes was also effective in increasing the resistance of beige mice to infection with Listeria monocytogenes. Thus, immunomodulators can be effective in mice that exhibit impaired macrophage and natural killer cell functions.

Adjuvants, Immunologic↗

An orally administered bacterial immunomodulator primes rabbit neutrophils for increased oxidative burst in response to opsonized zymosan.

To assess the potential effect of an orally administered immunomodulator, consisting of a lysate of seven different bacteria, on polymorphonuclear leukocyte (PMN) function, rabbits were fed this preparation for five consecutive days via a gastric tube. On day 6, PMN were separated from peripheral blood and oxidative burst was triggered by opsonized zymosan or 12-O-tetradecanoylphorbol-13-acetate and quantitated on a single-cell basis. This study presents the extension of an existing flow cytometric method, leading to the possibility of quantitating single-cell oxidative burst triggered by particulate (instead of only soluble) stimuli. By this means, treated animals showed statistically significant increased oxidative burst reactions compared with the control group. The data provide evidence that oral application of a bacterial immunomodulator leads to a primed state in PMN for increased oxidative activity in response to a particulate stimulus. This offers the possibility that the beneficial effect of similar treatment in humans may in part be due to comparable mechanisms.

Adjuvants, Immunologic↗

Induction of common mucosal immunity by hormonally immunomodulated peripheral immunization.

The study described in this report demonstrates that peripheral lymph nodes draining nonmucosal tissues can effectively serve as induction sites for the establishment of common mucosal immunity if the microenvironmental conditions are altered to mimic those normally present within mucosa-associated lymphoid tissues (e.g., Peyer's patches). Lymph node lymphocytes exposed in situ to the immunomodulatory influences of the hormone 1 alpha, 25-dihydroxy vitamin D 3 were found to produce less gamma interferon and interleukin-2 (IL-2) and far more IL-4, IL-5 and IL-10 than lymphocytes from control animals. When couples with vaccination with hepatitis B surface antigen (HBsAg), the hormone, immunomodulated switch from a peripheral lymph node phenotype to a Peyer's patch-like pattern promoted the induction of both a systemic and a common mucosal immune response. This was determined by the observed increased concentrations of serum anti-HBsAg antibody and by finding that anti-HBsAg secretory antibodies were detectable in urogenital, lachrymal, fecal and oral secretions only in the hormone-treated animals. In addition, specific antibody-secreting cells were detectable in the lamina propria of the lungs and small intestines of the hormone-treated animals subsequent to vaccination, indicating that the homing properties of antigen-specific B cells were being affected by the treatment procedure. The humoral and mucosal immune responses were further augmented if both 1 alpha, 25-dihydroxy vitamin D 3 and dehydroepiandrosterone were used together as hormonal immunomodulators. This novel immunization technique may afford new opportunities to effectively intervene in sexually transmitted diseases and other diseases caused by mucosal pathogens.

Adjuvants, Immunologic↗

Identification of an Immunomodulating Agent from Mycobacterium leprae.

A search for an immunomodulating agent from mycobacteria was carried out using Mycobacterium leprae. The antigenicity of each fraction of the bacterial membrane, which contains the most antigenic components of M. leprae, was assessed by using sera from paucibacillary leprosy. N-terminal sequencing of the serum-reactive protein and functional assessment of the membrane fractions using monocyte-derived dendritic cells (DCs) identified major membrane protein II (MMP-II) as one of the efficient T-cell-activating candidates. Purified MMP-II stimulated DCs from healthy individuals to produce interleukin-12 p70 and up-regulated the surface expression of major histocompatibility complex class I and II, CD86, and CD83 molecules. Also, there was an increase in the percentage of CD83(+) cells in the DC population. Furthermore, MMP-II-pulsed DCs expressed their derivatives on their surfaces. Using Toll-like receptor 2 (TLR-2)-dependent receptor constructs, we found that TLR-2 signaling was involved in DC maturation induced by MMP-II. Taken together, MMP-II can be recognized as an immunomodulating protein in terms of activation of antigen-presenting cells and innate immunity.

Antigen-Presenting Cells↗