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[Use of antibiotics and their combinations with immunomodulators in treatment of experimental salmonellosis in albino rats].

Efficacy of the combined therapy of experimental salmonellosis was studied on albino rats with using ampicillin, gentamicin, tetracycline and immunomodulators such as levamisole and quadevite. The influence of the combined chemoimmunotherapy on the indices of the nonspecific resistance of the animals i.e. the titers of lysozyme and beta-lysines, the complement activity and the blood serum bactericidal index was investigated. An increase in the survival of the animals exposed to the combinations of tetracycline with levamisole and quadevite by comparison with the animal survival after the monotherapy was revealed. The combinations of gentamicin with quadevite and tetracycline with the immunomodulators significantly increased the blood serum bactericidal index.

Adjuvants, Immunologic↗

Activation of rat Kupffer cells to tumoricidal cells by the immunomodulator muramyl tripeptide-phosphatidylethanolamine incorporated into the novel drug carrier lactosylated low density lipoprotein.

Lactosylated low density lipoprotein (lac-LDL) is a potential carrier for the site-specific delivery of lipophilic drugs to liver macrophages (Kupffer cells). In the present study we evaluated the application of lac-LDL as a carrier to target the immunomodulator muramyl tripeptide-phosphatidylethanolamine (MTP-PE) to rat Kupffer cells, to specifically activate these cells to tumor-killing cells. The drug carrier 125I-labeled lac-LDL interacted with a galactose-specific recognition system on isolated rat Kupffer cells. The in vitro association of 125I-lac-LDL at 37 degrees was maximal after 20 min, whereas degradation of 125I-lac-LDL was observed after a lag period of 10 min. Cultured rat Kupffer cells were activated after incubation with MTP-PE incorporated into lac-LDL. Lac-LDL-MTP-PE induced a 2-fold increase in the amount of newly synthesized proteins secreted by Kupffer cells. Lac-LDL-MTP-PE induced a concentration-dependent increase in the cytostatic and cytolytic activities of Kupffer cells towards tumor cells (B16F10 melanoma cells) in vitro. Treatment of rats with lac-LDL-MTP-PE also resulted in dose-dependent activation of Kupffer cells to tumoricidal cells, whereas the drug carrier alone had only a minor effect on this activity of Kupffer cells. The present data show that lac-LDL is an effective carrier for the delivery of the lipophilic immunomodulator MTP-PE to rat Kupffer cells. The specific activation of Kupffer cells to tumoricidal cells by lac-LDL-MTP-PE may be beneficial for the treatment of liver metastases.

Acetylmuramyl-Alanyl-Isoglutamine↗

[The costimulating effect of chorionic gonadotropin on lymphokine-activated splenocytes. A new aspect of the immunomodulating action of the pregnancy hormone].

An immunodepressive effect of chorionic gonadotropin (CG) low (40IU) and high (200IU) doses on the processes of lymphocyte antigen-independent differentiation, realizing the primary immune response has been established in the short-term culture of mice splenic intact cells. Splenocyte activation by Con-A or human recombinant IL-2 does not show an expressive immunostimulating effect on the processes of plaque forming cells (PFC) formation. While the immunomodulating effect of CG on the background of these activators changes. In the presence of Con-A or IL-2, hormone in the dose of 40 IU can't effectively suppress the PFC formation processes. On the background of IL-2, CG-200IU shows an expressed opposite effect, increasing the splenocyte ability to form PFC twice as much. It is suggested, that CG appears to be a cofactor, intensifying the processes of immunocompetent cell proliferation and differentiation, connected with this lymphokine. A new aspect of the CG immunomodulating effect during pregnancy is being discussed now.

Adjuvants, Immunologic↗

[Effect of immunomodulators on selected functions of neonatal polymorphonuclear neutrophils in vitro].

Phagocytosis, bactericidal capacity, production of superoxide anions O2- and expression of receptor for the Fc portion of IgG of polymorphonuclear neutrophils (PMN) were estimated in umbilical venous blood of neonates and their mothers. We also evaluated the influence of immunomodulating agents on these parameters. The influence of the maternal serum on the function of neonatal PMN was examined. The obtained results indicate that functional defect of neonatal PMN may be corrected under the influence of the maternal serum and/or immunomodulating agents.

Adjuvants, Immunologic↗

[Are antibiotics immunomodulators?].

This review of the literature, although non complete, involving different observations, experiments and documented demonstrations, suggest the real importance of the interrelations existing between, the pathogenic bacteria, the specific and non specific reactions of the normal or infected host and the antibiotics. The bacterial infections are potent immunomodulators by causing significant alterations in one or more mediators of homeostasis (coagulation, complement, inflammation), inducing cellular and tissular alterations more or less dramatic depending upon the number, the virulence of the bacteria and the immune status of the host. Antibiotics in reducing the number of the infecting pathologic bacteria, in modifying their pathologic and virulence factors might them be considered as immunorestoring molecules. On the other hand, when large numbers of bacteria are killed rapidly by bactericidal antibiotics, their cytoplasmic enzymes or bacterial cell wall structures, are rapidly released locally and are able to amplify the various systems involved in the deleterious inflammatory reaction. Thus depending on their dose and their mode of action, antibiotics could be considered as immunomodulators, albeit indirectly in modifying the pathophysiology of the host, in inhibiting or enhancing the release of immunoreactive bacterial molecules. Moreover antibiotics have been shown to interfere directly on the non specific and specific defenses mechanisms. Until the recent years, only the immunotoxicological aspect has been evaluated, involving mostly the immunopharmacologic screening of the antibiotics effects on phagocytic cells or on the effectors of the immune responses. Several recent examples are given that illustrate a new approach looking at the molecular level of the cellular action of antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

Different immunomodulator regulated patterns of effector-target cell interactions: a novel application of microcalorimetry.

Microcalorimetric studies of target/effector cell interactions are reported. Significant changes in the observed thermal profiles are seen upon pre-incubation of the effector cells with chemical immunomodulators. The results of these latter studies indicate that the microcalorimetric technique can reveal differences in the modes of action of different groups of immunomodulators. It is proposed that the technique can be used to screen drug activities and, following further analytical work, to contribute to an understanding of modes of action.

Calorimetry↗

Immunomodulating factors and immunosuppressive drugs in the therapy of myocarditis.

This review examines the immunologic rationale for immunosuppressive and immunomodulating therapy in man and experimental animal. The controversy if immunosuppressive treatment is beneficial in myocarditis will continue even after the American myocarditis trial. It is obvious that in viral heart disease immunosuppressive drugs should be avoided, in autoreactive forms of myocarditis with proven humoral and cellular effector mechanisms they may be used in controlled randomized trials to validate or negate their benefit. Immunomodulating factors e.g. immunostimulatory or antiviral substances like ribaverin, the interleukins and interferons have demonstrate some effect in experimental animal myocarditis but proof for the efficiency in man is still lacking. Hyperimmunoglobulin therapy appears to be of particular interest because of the little side effects and positive results in CMV associated myopericarditis in man.

Animals↗

[The efficacy of the therapeutic and prophylactic actions of immunomodulators in experimental infection due to the causative agent of Venezuelan equine encephalomyelitis].

The investigation of the prevention and treatment action of some immunomodulators (ridostin, reaferon and polyribonate) used alone and in combinations was conducted on laboratory animals infected aerogenically by Venezuelan equine encephalitis (VEE) virus. A lower death rate of the aerogenically infected mice (10-30 respiratory LD50) was observed after intramuscular injection of ridostin. The preventive affect of ridostin and ridostin + reaferon administered intranasally and intramuscularly was achieved in the aerogenically infected guinea pigs (10 respiratory LD50). The results of the study on the early virus reproduction in the animals were used for the choice of the treatment scheme. The immunomodulators had no effect when the treatment was started 1 day after the VEE virus infection.

Adjuvants, Immunologic↗

[Study of immunobiological properties of specific immunomodulators of the adjuvant type in experimental tuberculosis].

CBA mice served as experimental tuberculosis model to study protective, immunomodulating and toxico-allergic properties of two drugs including cytoplasma and cell walls of BCG mycobacteria as well as of synthetic adjuvant polyoxidonium. Doses and schemes are presented developed for experimental tuberculosis treatment with cytoplasm and not causing toxico-allergic reactions in mice. The specific immunomodulator of cytoplasm, polyoxidonium, proved effective therapeutic modality in experimental mouse tuberculosis.

Adjuvants, Immunologic↗

Immunomodulator OM 163-induced reversal of tumor-mediated immunosuppression and downregulation of TGF-beta 1 in vivo.

Although PROb colonic tumor cells are immunosuppressive, the immunomodulator OM 163 induced the disappearance of macroscopic peritoneal nodules in 50% of rats bearing a peritoneal carcinomatosis (p.c.) induced by PROb cells. When the p.c. developed, the number of T lymphocytes was low and the expression of interferon (IFN)-gamma mRNA in tumor nodules decreased very rapidly. The TGF-beta 1 secreted by PROb cells could be responsible for the immunosuppression, because the PROb cell supernatant inhibited IFN-gamma production and T lymphocyte proliferation. When the rats were treated with OM 163, an infiltration of T lymphocytes was observed in tumor nodules, as well as a high expression of the IFN-gamma mRNA. The antitumor efficiency of the immunomodulator OM 163 could be explained in part by a direct effect of OM 163 on T lymphocytes, because in vitro it stimulated the proliferation and the secretion of IFN-gamma of T lymphocytes. OM 163 could also act at the TGF-beta 1 level. Although OM 163 alone or in combination with IFN-gamma did not modify the TGF-beta 1 secretion by PROb cells in vitro, the expression of the TGF-beta 1 mRNA and the TGF-beta 1 protein content was decreased in vivo in treated tumor nodules.

Adjuvants, Immunologic↗

Immunomodulation as asthma therapy: where do we stand?

There is increasing evidence that chronic inflammation in asthma is mediated via a network of cytokines emanating from inflammatory and structural cells in the airways. The prominent eosinophilic inflammation that characterizes asthma appears to be orchestrated by cytokines derived from type 2 T-helper (Th2)-like lymphocytes, suggesting that immunosuppressants might be beneficial in the control of asthma. Indeed, one of the critical modes of action of glucocorticoids in controlling asthma may be the suppression of Th2-lymphocyte-derived cytokines, such as interleukin-5 (IL-5). Cyclosporin-A may have a similar immunomodulatory role, but its potential beneficial effects are outweighed by its toxicity, at least when given parenterally. Future immunomodulators need to be more selective, either by means of delivery (inhalation, liposomes) or by a more specific effect on Th2, as opposed to Th1, lymphocytes or their products. Such approaches may include new immunomodulators, such as mycophenolate mofetil, specific cytokine inhibitors (such as interleukin-5 antibodies), endogenous suppressors of Th2 cells (interferon-gamma or interleukin-12), or type 4 phosphodiesterase inhibitors.

Adjuvants, Immunologic↗

[Immunomodulating and hepatoprotective action of retinoids in toxic liver involvement induced by D-galactosamine].

The experiments on Wistar rats showed that beta-carotene and retinol acetate decreased the level of the biochemical signs of the hepatocyte injury and lowered or abolished the immunosuppressive effect induced by D-galactosamine. The hepatoprotective and immunomodulating effects of beta-carotene were higher. D-Galactosamine induced the development of the immunosuppressing properties in light erythrocytes and retinol acetate induced the development of the immunostimulating properties in heavy erythrocyte of the poisoned animals. beta-carotene prevented the development of the immunosuppressing properties in such cells. The immunomodulating effect of beta-carotene in the toxic affection of the liver was associated with blocking or retarding of the entry of the suppressing substances to the vascular channel from the hepatocytes and did not depend on their action on the erythrocytes.

Adjuvants, Immunologic↗

[An experimental study of the effect of immunomodulators on the immune response to the anatoxin components of adsorbed DPT vaccine against a background of poisoning].

An experiment of rabbits subjected to artificial lead intoxication revealed that after the immunization of the animals with adsorbed DPT vaccine myelopid and thymoptin exhibited practically the same immunomodulating activity with respect to antibody response to diphtheria and tetanus toxoids, exceeding that of rabbits without intoxication. Still the immunomodulators used in this experiment did not completely compensate the negative effect of intoxication on antibody response to the toxoids. For the first time after immunization with adsorbed DPT toxoid lymphocytes capable of binding diphtheria toxoid were detected and the specific features of their dynamics in comparison with the activity of antitoxin were established. Myelopid and thymoptin were found to modulate immune response, evaluated by the content of antigen-binding lymphocytes, the injection of thymoptin completely compensating the negative effect of intoxication.

Activins↗

[Effect of acupuncture on immunomodulation in patients with malignant tumors].

In order to investigate the role of acupuncture in the regulation of cellular immune function, the changes of T lymphocyte subsets (CD3+, CD4+, CD8+), soluble interleukin-2 receptor (SIL-2 R) and beta-endorphine (beta-EP) in the peripheral blood of patients with malignant tumors before and after acupuncture were observed with double blind method. Forty patients were divided randomly into two groups, 20 for each. One group treated with acupuncture and the other one for control. Results showed that acupuncture has the effect of enhancing the cellular immunity of patient with malignant tumor. Acupuncture treatment could increase the percentage of T lymphocyte subsets CD3+, CD4+ and the CD4+/CD8+ ratio (P < 0.01) and the level of beta-EP, as well as decrease the level of SIL-2 R (P < 0.01). The correlation analysis of the three criteria showed there was a positive correlation between beta-EP and T lymphocyte subsets and a negative correlation between beta-EP and SIL-2 R, there was also a negative correlation between T lymphocyte subsets and SIL-2 R. Based on these results, a discussion on the acupuncture immunomodulation network was conducted in this article in order to explore the possible mechanism of acupuncture on immunomodulation.

Acupuncture Therapy↗

Immunomodulating efficacy of combined administration of galactoside-specific lectin standardized mistletoe extract and sodium selenite in BALB/c-mice.

The immunomodulating abilities of commercially available mistletoe extract standardized for the galactoside-specific lectin (mistletoe lectin-1, ML-1) and sodium selenite (Se) were evaluated in BALB/c-mice and compared to non-treated control animals. Following the optimal schedule of administration (ML-1: 1ng/kg BW; days 1, 2, 3, 5 and Se: 3,5 micrograms/kg BW for 7 subsequent days before evaluation) yielded enhanced counts (thymocytes; peritoneal macrophages, MO; peripheral blood leukocytes; lymphocytes, PBL; monocytes, PBM) and activities (CD-25 positive PBL, MAC-3 positive PBM) of desired immune cells reaching statistical significance for most parameters. However, combined administration of ML-1 and Se proved to be superior to monotherapy since immune cell counts (thymocytes, leukocytes, PBL, PBM) and activities (CD-25 positive PBL) exceeded values obtained after monotherapy. These data are in favour of therapeutical strategies in complementary oncology and suggest that the combination of defined immunomodulating substances might positively enhance the efficacy.

Animals↗

[Naphthoquinones as immunomodulators during intensive exertion].

Naphthoquinones such as phylloquinone, menadione and vicasol normalized or increased the immune response in rats after intensive physical load. The most marked immunomodulating effect was induced by phylloquinone. The naphthoquinones induced the development of immunostimulating properties in heavy red blood cells by the direct action on the cell membranes or indirectly through proteolytic enzymes secreted by hepatocytes. The proteolytic enzymes secreted to the vascular channel in physical load increased the susceptibility of heavy red blood cells to phylloquinone. Glycosaminoglycans accumulating in the vascular channel in physical load increased the resistance of heavy red blood cells to phylloquinone. Heavy red blood cells of physically loaded animals treated in succession with hyaluronidase and phylloquinone and red blood cells of intact rats after the incubation in the presence of trypsin and phylloquinone proved to be effective immunomodulators in physical load.

Adjuvants, Immunologic↗

Delay in the onset of systemic lupus erythematosus following treatment with the immunomodulator AS101: association with IL-10 inhibition and increase in TNF-alpha levels.

It has recently been found that in systemic lupus erythematosus (SLE), a multisystem inflammatory disorder characterized by autoantibody production and decreased cellular immune response, increased spontaneous production of IL-10 occurs. The immunomodulator AS101 (ammonium trichloro(dioxoethylene-0,0')tellurate) was previously shown to significantly decrease IL-10 levels in cancer patients and in murine models. This study shows that AS101 inhibits the development of SLE-related autoimmune pathological manifestations. AS101 decreased the spontaneous IL-10 production by mononuclear cells from SLE patients in vitro. In vivo, systemic injection of AS101 to SCID mice transplanted with mononuclear cells from SLE patients significantly decreased serum human IL-10 levels. There was also a decrease in all serum human Ig isotypes, in anti-dsDNA, and in anti-Sm Igs. In the New Zealand Black/New Zealand White/F1 model, AS101 significantly increased serum TNF-alpha and IFN-gamma while decreasing IL-10 levels; these changes were accompanied by a rapid decrease in anti-dsDNA and anti-ssDNA Igs. More importantly, continuous treatment of New Zealand Black/New Zealand White/F1 mice with AS101 for 6 mo led to the development of proteinuria in 30% of the treated mice compared with 100% in PBS-treated mice (p < 0.001). AS101 treatment reduced the level of immmune complex deposition in the glomeruli, prevented glomerular hypercellularity and mesangial expansion and led to a much smaller mean glomerular volume in treated mice (185 +/- 6 vs 428 +/- 47.103 microm3; p < 0.01). We suggest that treatment with a nontoxic immunomodulator such as AS101, previously used in phase II trials on cancer patients, may be an effective therapeutic approach for controlling SLE.

Adjuvants, Immunologic↗

Strategies for graft immunomodulation in islet transplantation.

Immunomodulation of islets aims at reducing graft immunogenicity and vulnerability to attack by immune competent cells and inflammatory mediators. Data from he International Islet Transplant Registry clearly establish this aspect as a central issue for the future of islet and endocrine cell transplantation. A primary target for graft immunomodulation is donor-derived costimulatory activity. Islet culture at 24 degrees C for 7 days is efficient in decreasing graft immunogenicity without affecting islet viability and can readily be used in clinical transplantation. Low-dose ultraviolet B irradiation may also help improving the effectiveness of immunosuppressive therapy. CTLA4lg appears to be a promising approach to target direct and indirect T-cell activation and may soon be applied to free or encapsulated islet transplants. A second target is the T cell, and strategies rely on a gene transfer approach to switch on T-cell apoptosis using Fas ligand, or to modulate T-cell populations with cytokines. Current results suggest that additional basic investigations are needed. Finally, the beta cell may be manipulated to improve its resistance to inflammatory mediators. Data using transfer of various genes (bcl-2, adenovirus E3, catalase, HSP70) have shown promising perspectives.

Adjuvants, Immunologic↗