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PubMed1992

Immunomodulators: current and future development and application.

It has been amply demonstrated that immunomodulators have a place in the armamentarium with other therapeutic modalities for the treatment of various diseases. They presently are, and in the future will be, most effective in preventing diseases which cause, or are the result of, immunodeficiencies. For future development the biological agents that are potent immunomodulators can be more purified and their molecular structures defined and synthesized, such as muramyldipeptides are products of BCG, etc. The active moiety of Picibanil (OK 432), a very powerful immunostimulator should be defined. Further investigations in isolating and characterizing biological agents as immunomodulators should continue in view of the success that has been achieved with BCG in treating superficial transitional cell bladder carcinoma. This mode of treatment is much less toxic to the patient than treatment with the cytotoxic agents thiotepa, mitomycin C. Chemically defined immunomodulators have been used successfully when combined with other therapeutic modalities. Levamisole and its additive therapeutic effect when combined with 5-FU in the treatment of Stage C colorectal carcinoma establishes the potential usefulness of chemicals which specifically augment the immuno response. The explosive growth of cytokine research has led to many technical advances which were key to give cloning and the availability of recombinant cytokines which have extended and modified our concepts of cytokines. The capability of cloning to provide considerable quantities of pure cytokines, permitted studies of immunological, physiological, and therapeutic roles of cytokines. All three classes of immunomodulators: biologicals; chemical; and cytokines will continue to play a major role in advancing and improving the quality of treatment of several of human as well as animal diseases.

Adjuvants, Immunologic↗

PubMed1989

[Immunomodulating properties of interferon inducers].

Data on the immunomodulating activity of interferon inductors are presented. It was revealed that the inductors increased the animal vaccinal response. Schemes for combined use of the interferon inductors and immunomodulators were developed. The immunomodulators were shown to increase the host interferon response evident from synergistic increasing of the interferon titers or prolongation of interferon circulation in blood of the animals. The efficiency of the schemes for combined use of the interferon inductors and immunomodulators was obvious from stimulation of the antibody production. As a result the time of the antibody circulation in blood increased. The effect of the combined use of the immunomodulators and interferon inductors was studied. The combined use of the preparations significantly increased the average life-span of the animals and the rate of their survival.

Animals↗

PubMed1988

[Screening of immunomodulators by using the system of mononuclear phagocytes].

Immunomodulating effects of various agents can be mediated by the system of mononuclear phagocytes (SMP). Immunomodulators are able to interfere with the initial events in activation of mononuclear phagocytes (MP) on their membranes which inevitably has its impact on molecular manifestations of the MP activation: the oxidative outburst events. At the initial (tentative) stage of the screening potential immunomodulators it is expedient to use tests providing estimation of the oxidative outburst intensity by the activity of glucoso-6-phosphate dehydrogenase, the key enzyme of the hexose monophosphate shunt and by the level of superoxydanions production judged by reduction of nitroblue tetrasolium (NBTT). The use of transplantable macrophage-like lines J.744 and P 338D as the targets instead of murine peritoneal MP made it possible to increase reproducibility of the results in screening of immunomodulators. An experimental model of the mouse abdominal cavity clearance within the first hours after intraperitoneal administration of the test bacteria was used for estimating the effect of the potential immunomodulators on the barrier function of the SMP in the host. Experimentally modeled quantitative and functional defects in the SMP served as and adequate test system for study of immunostimulating agents.

Adjuvants, Immunologic↗

PubMed1984

Early cellular responses in the peritoneal cavity of mice to antitumor immunomodulators.

The early cellular responses to antitumor immunomodulators and conventional inducers, especially the polymorphonuclear leukocyte (PMN) responses, were examined in the peritoneal cavity of mice to investigate their effect on primary defense mechanisms. Immunomodulators were classified into 5 groups in terms of PMN response on the basis of its duration (declining or persistent) and extent (high or low induction): 1) TAK (beta-1,3-glucan)-type (high, persistent), 2) lentinan-type (high, declining), 3) yeast mannan-type (low, declining), 4) LPS (lipopolysaccharide)-type (low, persistent), 5) others (no effect). Since the general PMN response is of the declining type, the persistence of PMN with TAK- and LPS-type immunomodulators is a characteristic of the PMN-inducing activity. With respect to the extent, TAK- and lentinan-type immunomodulators induced larger numbers of PMN and macrophages than conventional inducers. These results suggest that some types of immunomodulators have effects on the early host-defense mechanism. From the viewpoint of the general self-defense mechanism we also compared these PMN responses with those to bacteria and to tumor inoculation, and the properties of substances inducing high PMN response, i.e., those with the quality of "foreignness," are discussed.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1995

Enhancement of nonspecific resistance by liposome-encapsulated immunomodulators does not affect skin graft rejection in mice.

Administration of liposome-encapsulated immunomodulating agents muramyl tripeptide phosphatidyl ethanolamine (LE-MTPPE) or interferon-gamma (LE-IFN-gamma), or co-encapsulated MTPPE and IFN-gamma (LE-(MTPPE/IFN-gamma)) resulted in a dramatic increase of the nonspecific antimicrobial resistance in mice, as shown before. This kind of treatment is especially of use in immunocompromised hosts who are prone to severe infections. Application of these immunomodulators might protect these patients, e.g., transplant recipients, from opportunistic infections. However, accelerated rejection of the graft, resulting from augmentation of the antimicrobial defense in a nonspecific way, has to be avoided. In this study, the effect of treatment with LE-MT-PPE, LE-IFN-gamma, or LE-(MTPPE/IFN-gamma) on skin graft rejection in mice was investigated. It was found that prophylactic treatment of skin-grafted mice with immunomodulating formulations did not influence rejection of the graft. Moreover, in T cell-depleted mice, which showed a prolonged graft survival compared with immunocompetent recipients, the administration of immunomodulators did not change the survival time of the grafts compared with T cell-depleted mice that did not receive immunomodulators. The results clearly show that, in this experimental setting, application of the antimicrobial resistance-enhancing formulations (LE-MTPPE, LE-IFN-gamma, and LE-(MTPPE/IFN-gamma)) is allowed in graft-bearing recipients, without influencing graft survival.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMedDate not supplied

[The effect of immunomodulators on the development of antibodies to the diphtheria antigen in mice vaccinated with the DTP adsorbed vaccine].

An animal model for the study of the influence of immunomodulators on the development and preservation of postvaccinal antidiphtheria immunity was experimentally selected and the corresponding study was carried out. In this work the following immunomodulators were used: dibasol, prodigiosan, splenin, thymalin, reaferon, tactivin, methyluracyl. The study revealed that by day 120 of observation all immunomodulators stimulated the production of antibodies in higher titers than adsorbed DPT vaccine, introduced without immunomodulators. The most effective action was exhibited by splenin and prodigiosan (injected subcutaneously), dibasol and methyluracyl (administered orally). Two latter immunomodulators, if introduced prior to immunization, are the most promising preparations to be used in practical immunoprophylaxis.

Adjuvants, Immunologic↗

PubMed2006

[Clinical study and long-term evaluation of immunomodulation therapy on trauma, severe sepsis and multiple organ dysfunction syndrome patients].

OBJECTIVE: To study the clinical effect and long-term evaluation of immunomodulation therapy on trauma, severe sepsis and multiple organ dysfunction syndrome (MODS) patients. METHODS: Prospective, randomized, blind and controlled clinical analysis of 70 patients conforming to the enrolled standard was carried out. They were divided into two groups at random. One was control group (n=34) with regular therapy, and the treatment group (n=36) with ulinastatin plus thymosin-alpha1 on the base of regular therapy for 1 week. The immunological indexes were determined before and after therapy on the 1 st, 3 rd, 7 th, 14 th and 28 th day, including the changes in lymphocyte count, CD14(+) monocytes human leukocyte antigen (locus) DR (HLA-DR), clinical data and long-term follow-up. RESULTS: During hospitalization, 20 patients died in the control group and 13 patients died in the treatment group. There was significant difference between two groups (P<0.05). After 7 up to 28 days of therapy, the counts of lymphocyte and CD14(+) monocytes HLA-DR were significantly higher than those in control group (all P<0.05). The duration of using mechanical ventilation and pressor agent in the treatment group were shorter than those in the control group (both P<0.01). The length of stay and the cost in the intensive care unit (ICU) were not significantly increased in the treatment group (both P>0.05). The long-term survival time in the treatment group was much longer than that in the control group (P<0.05). CONCLUSION: Immunomodulation therapy can improve the prognosis of trauma, severe sepsis and MODS patients in a period of 28 days of observation, and lymphocyte counts and CD14(+) monocytes HLA-DR were increased significantly, showing that immunosuppression can be ameliorated. Immunomodulation therapy can shorten the time of mechanical ventilation and the use of pressor agent, and it does not increase the length of stay and the cost in ICU, and therefore the cost-effectiveness is high. It also can prolong the long-term survival time. The results show that immunomodulation therapy is one of successful therapeutic strategies in the care of critical illness.

Adjuvants, Immunologic↗

PubMed2006

Systematic review of postoperative complications in patients with inflammatory bowel disease treated with immunomodulators.

BACKGROUND: This systematic review examined the use of immunomodulators and the risk of postoperative complications after abdominal surgery in patients with inflammatory bowel disease. METHODS: Electronic databases (PubMed, Embase, Ingenta, Zetoc and Ovid) were searched and the reference lists in all articles identified were hand-searched for further relevant papers. Studies were included if they evaluated postoperative complications and defined exposure to individual immunomodulators. RESULTS: All 11 studies that met the inclusion criteria were observational studies; two were reported only in abstract form. Five studies reported risks associated with azathioprine, five reported risks associated with cyclosporin and three reported risks associated with infliximab. None showed an increased risk of either total or infectious complications associated with immunomodulator use. However, subgroup analysis in one study, published as an abstract, suggested increased rates of anastomotic complications and reoperation associated with azathioprine. CONCLUSION: Available evidence does not suggest an increased rate of postoperative complications associated with immunomodulator use.

Aged↗

PubMed1997

Hexachlorobenzene-induced immunomodulation and skin and lung lesions: a comparison between brown Norway, Lewis, and Wistar rats.

Strain dependence of the induction of skin and lung lesions by hexachlorobenzene (HCB) in the rat was studied to further the insight into the etiology of the lesions. To this end, 3- to 4-week-old female Brown Norway (BN), Lewis, and Wistar rats received diets supplemented with 150 mg (BN and Lewis), 450 mg (BN, Lewis, and Wistar) or 900 mg (BN and Wistar) HCB per kilogram diet for 4 weeks. Gross skin lesion development during exposure as well as pathologic changes in skin and lungs and various parameters of immunomodulation after exposure were assessed. General toxicity as judged by a slight increase in body weight gain and induction of liver cell hypertrophy was similar in BN and Lewis rats exposed to 450 mg/kg HCB and in Wistar rats exposed to 900 mg/kg HCB. Skin lesions ranged from redness to large exudating sores with crusts. With regard to dose, time of onset, incidence, and severity, skin lesions were very severe in BN, moderate in Lewis, and negligible in Wistar. Porphyrins could not be detected in the skin, whereas porphyrins in the liver were seen only in Lewis rats. Histology showed epidermal hyperplasia, deep dermal venules with activated endothelium, and deep dermal inflammatory infiltrates mainly consisting of eosinophilic granulocytes in BN and of mononuclear cells in Lewis and Wistar. Nonlesional skin of HCB-exposed rats showed very similar, though less prominent, changes. Lung pathology appeared negligibly strain-dependent; histology showed venules with an activated endothelium surrounded by a perivascular infiltrate as well as focal alveolar macrophage accumulations in all strains. Parameters of immunomodulation showed moderate strain dependence; relative spleen weights were dose-dependently increased in BN and Wistar and in the 450 mg/kg group in Lewis rats. BN rats showed a more marked splenomegaly than the other strains. Relative popliteal lymph node weights were increased significantly in BN and Lewis rats exposed to 450 mg/kg HCB. In all strains, HCB increased lymph node HEVs. Serum IgE and IgG levels were increased significantly in a dose-dependent way in BN rats only. Total serum IgM levels were elevated significantly in BN, Lewis, and Wistar rats that received 450 mg/kg and in Wistar rats that received 900 mg/kg HCB. Serum IgM levels against ssDNA were dose-dependently increased in all strains, being more marked in BN and Lewis than in Wistar rats. It is concluded that the HCB-induced inflammatory skin and lung pathologies have different etiology. Pronounced strain differences in the skin lesions suggest a specific involvement of the immune system. Skin lesions correlated significantly with all assessed parameters of immunomodulation in BN, with some in Lewis and with none in Wistar rats. No correlation was observed between the parameters of immunomodulation and lung lesions.

Animals↗

PubMed1992

Immunomodulators. Future prospects.

The future role of the immunomodulators in medical practice is yet to be defined. The key question is whether these new substances will bring remarkable progress in transplantation or in the treatment of such conditions as cancer, AIDS, and autoimmune diseases, or whether they will be of only minor adjunctive importance. As background to the discussion of immunomodulating agents, the immune system is explained, with emphasis on the roles of T and B lymphocytes, macrophages, phagocytes, human leukocyte antigen and the complement system. Special attention is given to the cytokines, particularly the lymphokines. The immunomodulators can be divided into three main groups: immunosuppressive agents, such as FK 506 and rapamycin; immunostimulating agents, of which BCG vaccine is most important; and the remaining immunomodulators, which include the biological response modifiers. The last group, which encompasses the colony-stimulating factors (GM-CSF, G-CSF, and M-CSF), the interleukins, the interferons, and the tumour necrosis factors, is described in detail. Innovative research and medical applications of these cytokines, including indications, contraindications, and adverse reactions, are discussed. The role of monoclonal antibodies against endotoxins is also described.

Adjuvants, Immunologic↗

PubMed2006

Immunomodulation the marine green mussel Perna viridis exposed to sub-lethal concentrations of Cu and Hg.

Environmental pollution is a growing concern and, more importantly, pollution of the aquatic ecosystem is alarming. Marine pollution may be one of the reasons for disease incidence in marine organisms, which is caused due to adverse effects of pollutants on the immune system. Bivalves are commonly used as bio-indicators of marine pollution, and immunomodulation due to toxicants is one of the important bio-markers used. Perna viridis too have been used as a bio-indicator, but this study is, to our knowledge, a first report on immunomodulation produced by metals, in P. viridis. Animals were exposed to copper and mercury at their sub-lethal concentrations of 20 microg L(-1) and 10 microg L(-1), respectively. Immune parameters including phenoloxidase, reactive oxygen species generation, and phagocytosis were monitored. The study period was for 25 days (chronic long-term exposure) and objectives established whether metals produced immunomodulation and to understand the effects of long-term exposure on immunomodulation. Results showed that both metals adversely affected immune parameters studied and, interestingly, there appears to be some level of recovery (depuration) from the toxic effects of metals.

Animals↗

PubMed1992

Effect of protein malnutrition and immunomodulation on immune cell populations.

Malnutrition has deleterious effects on immune functions, which predispose to an increased risk of infection. To study the effect of protein malnutrition on such immune functions and resistance to infection, we divided C57BL/6 mice into three groups: (1) control-standard diet, (2) protein-malnourished for 14 days, and (3) protein-malnourished for 14 days followed by standard diet for 3 days. The animals were further divided into subgroups: (1) an untreated group, (2) a muramyl dipeptide (MDP)-treated group, and (3) an interferon-gamma (IFN-gamma)-treated group before cecal ligation and puncture (CLP). Malnourished mice had significantly (P less than 0.05) lower body weight, serum albumin, spleen/body weight, percentage of splenic macrophages with Ia expression (%MOIa), increased splenic T suppressor cells, and greater mortality after CLP. Refeeding plus IFN-gamma or MDP significantly increased %MOIa (P less than 0.05) and also abrogated the increase in splenic lymphocytes seen in the malnourished animals. The increase in splenic suppressor T cells was not affected by refeeding or immunomodulation. Mortality after CLP was increased from 15% in the controls to 85% in the malnourished group and was significantly decreased by refeeding, MDP, and the combination of refeeding plus immunomodulators (P less than 0.05). These data show that 14-day malnutrition adversely affected the immune response to infection and increased mortality from CLP. Refeeding and immunomodulation restored macrophage Ia expression without CLP but not after the procedure, despite the significant reduction in mortality. The use of immunomodulation in protein malnourished conditions may serve as an adjuvant role to nutritional support.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1996

Enhanced immunity to Hyalomma anatolicum anatolicum ticks in cross-bred (Bos indicus x Bos taurus) calves using ascaris extract immunomodulator with the tick salivary gland extract antigens.

Development of acquired immunity in cross-bred (Bos indicus x Bos taurus) calves against Hyalomma anatolicum anatolicum, a tick vector of bovine tropical theileriosis was studied using ascaris extract (AE), an immunomodulator of IgE responses, along with the tick salivary gland extract (SGE) antigens in Freund's incomplete adjuvant (FIA) emulsion. Calves immunised with SGE + FIA showed significant rejection (47.4 +/- 2.8%) of larvae, whereas only marginal rejection (12.47 +/- 1.5%) of nymphs was observed. In contrast, calves immunised with the immunomodulator AE in addition to SGE + FIA showed significant enhanced rejection of nymphs (50.25 +/- 5.2%), while the rejection of larvae was only slightly higher (55.8 +/- 11.4%), and not statistically different. In addition, incorporation of the immunomodulator AE also resulted in significant enhancement in the percentage recovery of abnormally fed larvae and nymphs. This abnormal feeding was characterised by their white to pale-yellow colour instead of the dark-grey colour of normally fed ticks. It may possibly be attributed to their inability to gain access to the blood vessels owing to the host immunological reaction at the bite sites. Consequently, the ticks fed on extravascular fluid devoid of red blood cells resulting in their white to pale-yellow colour. Difference in the disease transmission potential of normally and abnormally fed ticks is of future interest. Sera from all the immunised calves after 2 weeks of immunisation were positive for anti-tick SGE antibodies in the dot enzyme immunoassay (DOT-EIA). The immunised calves were positive for immediate type hypersensitivity (ITH) skin reaction on intradermal inoculation of the tick SGE antigens. There was no apparent difference in the DOT-EIA antibody titres between the two immunised groups. However, ITH skin swelling was significantly higher in AE + SGE + FIA immunised calves. The study indicates that use of the AE as an immunomodulator along with the tick SGE antigens enhanced anti-tick immunity.

Adjuvants, Immunologic↗

PubMed1987

Natural and synthetic peptides (other than neuropeptides) endowed with immunomodulating activities.

A large number of peptides, in most cases of low or relatively low molecular weight, exert immunomodulating activities, i.e., they interact in vitro with various cell populations of the immune system and, in vivo, enhance or depress, according to the case, cell-mediated and humoral immune functions. Immunomodulating peptides include glycopeptides from the bacterial cell wall, natural acyloligopeptide ciclosporin, peptidic hormones from the thytide cyclosporine, peptidic hormones from the thymus, peptidic fragments of immunoglobulins and other plasma proteins, as well as peptides isolated from food proteins. An amazing diversity of structure exists among the various immunomodulating peptides. The molecular mechanisms of interaction between these peptides and the cells of the immune system remain, in most cases, to be elucidated. Possibilities of therapeutic applications exist for many of these immunomodulating peptides: one of them (ciclosporin) is widely used as an immunosuppressive drug, several others (glycopeptides, lipopeptides, tuftsin, thymic peptides) are under clinical investigation as immunostimulating and/or immunorestoring agents.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMedDate not supplied

Varying role of alpha/beta interferon in the antiviral efficacy of synthetic immunomodulators against Semliki Forest virus infection.

The question of whether interferon alpha/beta is the common mechanism of antiviral action of synthetic immunomodulators was investigated in B6C3F1 mice infected with Semliki Forest virus. Mice were treated with various concentrations of normal sheep serum or potent anti-alpha/beta interferon antiserum, inoculated with the immunomodulators, and infected 24 hours later with virus. Three patterns emerged. The antiviral action of the pyrimidinone (ABMP) and the oral interferon inducer (CL246,738) appeared to be mediated primarily by interferon alpha/beta; their protective ability was almost completely abrogated by treatment with low levels of anti-alpha/beta interferon antiserum. The antiviral action of two other immunomodulators, a mismatched polyribonucleotide (Ampligen) and a polyanionic copolymer (MVE-2) at least partially involved interferon. Activity of these compounds was reduced, but not consistently eliminated by treatments with high doses of antiserum. The antiviral activity of another polyribonucleotide, polyriboinosinic-cytidylic acid complexed with lysine carboxymethylcellulose (poly ICLC), was not affected by treatment with even the highest amount of antiserum (two injections of 100,000 neutralizing units each). Almost complete protection by poly ICLC was observed despite the fact that this high concentration of antiserum, when given alone, caused a decrease in natural resistance to Semliki Forest virus infection. Taken together, these results indicate that induction of interferon alpha/beta does not appear to be the major common mechanism of antiviral activity among these diverse synthetic immunomodulators.

Acridines↗

PubMed1989

Different inhibitory actions of immunomodulating agents and immunosuppressive agents on bone resorption of mouse calvaria.

In this study, we have investigated the in vitro effects of the immunomodulators lobenzarit and traxanox and a newly synthesized immunosuppressant, mizoribine, as well as cyclosporin A, on bone resorption using neonatal mouse calvariae labelled with 45Ca. As stimulators of bone resorption, bovine parathyroid hormone (PTH), lipopolysaccharide (LPS), interleukin 1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were used. Lobenzarit, traxanox, mizoribine and cyclosporin A inhibited or tended to inhibit bone resorption stimulated by PTH, LPS, IL-1 beta or TNF-alpha in a dose-dependent manner. Basal bone resorption was inhibited by immunosuppressant cyclosporin A or mizoribine, while immunomodulators lobenzarit and traxanox failed to inhibit basal bone resorption. Removal of lobenzarit from the culture medium resulted in the recovery of bone resorptive activity. These results suggest that the inhibitory effect of immunomodulators on bone resorption is reversible and nonselective. Also, it raises the possibility that immunomodulators and immunosuppressants may affect bone resorption by different mechanisms.

Adjuvants, Immunologic↗

PubMed1986

Regulation of prostaglandin E2 and plasminogen activator by various immunomodulators in human monocytes.

Mononuclear phagocyte populations and monocytes are able to produce, among numerous substances, a neutral protease, i.e. plasminogen activator (PA) and prostaglandins. Since it has been shown that prostaglandins (PGs) and particularly PGE2 could exert an inhibitory effect on PA production by macrophages, we have measured the in vitro production of PA and PGE2 by monocytes isolated from healthy donors. These monocytes were cultured either in the absence or the presence of various immunomodulators: lipopolysaccharide from E. coli, concanavalin A and RU 41740 or Biostim a broad spectrum immunostimulating agent isolated from Klebsiella pneumoniae (Cassenne Laboratories, France). The production of PGE2 was proportional to the number of monocytes per incubation, and at a given cell concentration varied greatly from one subject to another. When considering PGE2 productions, the type of the response to the different immunomodulators varied from subject to subject and ranged from stimulation to no effect, or even inhibition. Moreover, a statistically significant, inverse relationship exists between the spontaneous production of PGE2 and the effect of each immunomodulator. For a given subject, all agents always acted in the same way and there was an inverse relationship between the effects of the immunomodulators on plasminogen activator and PGE2 production.

Adjuvants, Immunologic↗

PubMed1992

Enhancement of the effectiveness of antimicrobial therapy by muramyl peptide immunomodulators.

Besides promoting nonspecific resistance to experimental infection, muramyl peptide immunomodulators also potentiate the effects of antimicrobial agents. These substances have been evaluated in combination with appropriate anti-infective agents in various models of bacterial, fungal, parasitic, and viral infection. For the combined regimens to be effective, the immunomodulator apparently must be administered prophylactically; anti-infective efficacy is then increased in situations where the muramyl peptide is capable of promoting at least some resistance to the infection independent of the antimicrobial agent. Adjunctive administration of the muramyl peptide may reduce the required dosages of potentially toxic antimicrobial agents and hence may lower the risk of toxic side effects. Because of the way in which they stimulate the inflammatory/immune systems, muramyl peptide immunomodulators may improve the outcome of therapy for infections in immunocompromised hosts. Initial clinical applications could involve the use of these immunomodulators in combination with antimicrobial agents as prophylaxis in high-risk individuals without overt infections.

Acetylmuramyl-Alanyl-Isoglutamine↗