Overview of biologic response modifiers in infectious disease.

The conventional treatment of infectious agents is increasingly encountering antimicrobial resistance. This resistance has led to an intense search for novel treatment modalities for infectious diseases. Elucidation of the mechanisms underlying the inhibitory activity of chemokines has been instrumental in the rational design of anti-human immunodeficiency virus chemokine drugs.

Novel concepts for anti-infective activity of cytokines, chemokines and diverse agents.

Access to an array of cytokines and synthetic immunomodulators represents a significant milestone in the development of effective therapies for infectious diseases. Several recombinant human cytokines, including interferons and colony-stimulating factors, are licensed and being widely used in clinical practice in patients. The identification of the essential role of coreceptors for the entry of HIV into the host cell has focused attention on chemokines as important targets for pharmacological intervention and several new compounds possessing therapeutic potential as inhibitors of chemokine receptors have been advocated.

Low dose oral combination chemoprophylaxis with oseltamivir and amantadine for influenza A virus infections in mice.

In the present study, the effect of combining anti-influenza drugs active at different steps of the influenza virus replication cycle, oseltamivir as a neuraminidase (NA) inhibitor and amantadine targeting M2 protein, was investigated in vivo by oral administration in a mouse model of aerosol influenza virus infection and in vitro in MDCK cells. In mice, doses of oseltamivir and amantadine providing 50-60% survival against A/Hongkong/1/68 (H3N2) or A/PR/8/34 (H1N1) were capable of conferring complete protection when used simultaneously, suggesting that increased inhibition of influenza virus replication by combining oseltamivir and amantadine in vitro translates into protection from lethal infection of mice. The combination of amantadine with oseltamivir required 15-fold less oseltamivir than monotherapy to confer complete protection against lethal aerosol influenza virus infection.

Natural products and synthetic compounds as immunomodulators.

Research on immunomodulation by natural products or synthetic derivatives is of key interest for anti-infective therapy for a number of reasons. Many plant remedies well-known in traditional medicine or refined natural products in clinical use exert their anti-infective effects not only (if at all) by directly affecting the pathogen. At least part of their effect is indirect, by stimulating natural and adaptive defense mechanisms of the host.

Combinatorial immunotherapies for infectious diseases.

Combating pathogenic organisms by combinatorial approaches involving appropriate immune response molecules and antimicrobial drugs represents a progessively more apparent and successful therapeutic paradigm for the treatment of acute and chronic persistent infectious diseases. This review explores areas of current innovation and provides an update of the present state of knowledge concerning combination of chemotherapy with several immune-based interventions in infections. In the future, a better understanding of microbial immune modulation and evasion may continue to open new avenues of inquiry and carefully targeted application of adjunctive immunotherapies.

Protection by methyl inosine monophosphate (MIMP) against aerosol influenza virus infection in mice.

Methyl inosine monophosphate (MIMP) is a novel thymomimetic purine immunomodulator capable of enhancing a wide variety of immune responses. Intravenous (i.v.

Fighting infection using immunomodulatory agents.

The last decade has seen the emergence of immunomodulators as promising therapeutic agents in infectious diseases. A diverse array of recombinant, synthetic and natural immunomodulatory preparations for prophylaxis and treatment of various infections are available today. Some of these substances, such as granulocyte colony-stimulating factor (G-CSF), interferons, imiquimod and bacterial-derived preparations are already licensed for use in patients.

Immunomodulators in infectious diseases: panoply of possibilites.

Infections which caused ravages in the past centuries are again resurgent and newly emerging pathogens capable of human diseases continue to surface. Multidrug antibiotic resistance has turned into a major medical problem. Judicious concepts for combating infections in the 21st century have acquired a new poignancy.

Immunomodulatory agents for prophylaxis and therapy of infections.

The advent of the antibiotic era ushered in a shift towards non-pathogen-specific therapy of infectious diseases. This led to an overt emphasis on targeting microbial pathogens while strategies directed towards enhancing host immunity were neglected. In an effort to decrease sole reliance on antimicrobials, the time has come for a critical reappraisal of nonantibiotic, albeit immune response-enhancing substances.

Down-regulation of tumor necrosis factor-alpha, moderate reduction of interleukin-1beta, but not interleukin-6 or interleukin-10, by glucan immunomodulators curdlan sulfate and lentinan.

The effects of glucan-based immunomodulators curdlan sulfate (CRDS) and lentinan on cytokine production stimulated by lipopolysaccharide (LPS) in bacillus Calmette-Guerin (BCG)-primed mice were investigated. Pretreatment with CRDS or lentinan before LPS administration induced a striking inhibition of up to 89% of circulating tumor necrosis factor-alpha (TNF), a moderate reduction of 25% of interleukin (IL)-1beta, no significant differences in IL-6 or IL-10 levels, and a marked depression of chemiluminescence activity. Animals receiving CRDS prior to infection with alpha-hemolysin positive Escherichia coli inhibited measurable TNF production by 63%.

A highly sensitive cytotoxicity assay based on the release of reporter enzymes, from stably transfected cell lines.

The well-established methods of generating stably transfected cell lines, and the detection of nanomolar amounts of an enzyme in a fast and reproducible assay, were utilised to establish non-radiometric cytotoxicity assays. In these assay systems, the detection of released enzymes was used to quantitate the leakage of intracellular proteins after membrane disintegration. Target cell lines were transfected with a luciferase reporter gene under the control of a strong eucaryotic promoter.

Effects of trinitrotoluene (TNT) metabolites on chemiluminescence response of phagocytic cells.

The effects of TNT metabolites on the generation of activated oxygen species was investigated by a sensitive luminol-dependent chemiluminescence (CL) assay. Spleen cell suspensions containing 2,4-diaminotoluene, 2,4,6-triaminotoluene, 2-amino-6-nitrotoluene, 4-amino-3,5-dinitrotoluene and 2-amino-4,6-dinitrotoluene were stimulated with zymosan. Aminotoluenes and amino-nitrotoluenes induced a dose-dependent inhibition of CL response.

Production of lipopolysaccharide-induced tumour necrosis factor during influenza virus infection in mice coincides with viral replication and respiratory oxidative burst.

Increased morbidity and mortality occur regularly during influenza epidemics. The exact mechanisms involved are not well defined but bacterial superinfection of influenza virus infected patients is considered to play an important role. In the present study, the effect of influenza virus infection on in vivo production of turnout necrosis factor (TNF) in response to bacterial stimuli was investigated.

Stimulation of microbicidal host defence mechanisms against aerosol influenza virus infection by lentinan.

The ability of polysaccharide immunomodulator lentinan to stimulate non-specific resistance against respiratory viral infections was investigated. Significant protection was conferred by lentinan administered intranasally before lethal influenza virus infection and could be corroborated by a reduction of the lung virus titres. Since the lung is the target organ of influenza virus infection, lentinan was also administered by the intravenous route.

Effect of immunomodulator adamantylamide dipeptide on antibody response to influenza subunit vaccines and protection against aerosol influenza infection.

Adamantylamide dipeptide (AdDP) is a novel synthetic compound combining the antiviral properties of amantadine and the essential adjuvant activity of immunomodulator muramyl dipeptide. Mice were immunized with influenza A/Taiwan/1/86 (H1N1), A/Sichuan/2/87 (H3N2) and influenza B/Beijing/1/87 subunit vaccines containing AdDP or aluminium hydroxide (Al(OH)3). Induction of homologous haemagglutination-inhibition (HI) antibodies and correlation to protection against lethal aerosol influenza A/PR/8/34 (H1N1) infection were investigated.

Muramyl dipeptide inhibits replication of human immunodeficiency virus in vitro.

In the search for compounds capable of inducing endogenous production of colony-stimulating factor (CSF) and possessing activity against human immunodeficiency virus (HIV), an immunomodulator, muramyl dipeptide (MDP), was investigated. MDP can enhance monocyte-macrophage CSF in serum and promote nonspecific resistance against a variety of microbial pathogens. MDP exhibited an inhibitory activity against HIV infection of CD4+ H9 lymphocytes and U937 monocytoid cells.

Exacerbation of human immunodeficiency virus infection in promonocytic cells by bacterial immunomodulators.

Common bacterial infections are increasingly being diagnosed in HIV-infected individuals. Cells of the monocyte-macrophage lineage kill invading bacterial pathogens and subsequently release immunoadjuvant components from the degraded cell walls. Since monocytes can be infected with HIV, effects of bacterial immunomodulators on infected promonocytic U937 cells were investigated.

Muramyl peptides confer hepatoprotection against murine viral hepatitis.

The hepatoprotection induced by synthetic muramyl peptides was investigated using a model of lethal murine mouse hepatitis MHV-3 virus infection. MDP and a nonpyrogenic analog, Murametide, inhibited the steep elevation of serum transaminases induced by MHV-3 irrespective of whether the immunomodulators were administered before or after the infection. A significant proportion of MDP or Murametide-treated animals, in contrast to controls, survived the MHV-3 infection.

Effects of nontoxic lipid A and endotoxin on resistance of mice to Toxoplasma gondii.

Mice were administered nontoxic monophosphoryl lipid A (MPL) or refined standard bacterial endotoxin (RSE) prior to, simultaneously with, or after infection with Toxoplasma gondii. MPL and RSE given before or with the toxoplasma infection induced significant resistance. Administration of toxic RSE, but not nontoxic MPL, after the establishment of toxoplasma infection significantly shortened the survival time of mice.

Biomedical applications of chromatographic fraction containing trehalose dimycolate in squalane emulsion.

Trehalose dimycolate extracted from mycobacteria is a potent immunomodulator. Incorporation of trehalose dimycolate in a squalane-in-water emulsion leads predominantly to the formation of vesicular structures, which are observable by electron microscopy. The interaction between vesicles of trehalose dimycolate and the immunocompetent cells results in an enhancement of the host defence mechanisms and induction of non-specific resistance against viral, parasitic, and bacterial pathogens and certain tumors.

Modulation of natural killer cytotoxicity by muramyl dipeptide and trehalose dimycolate incorporated in squalane droplets.

The effect on natural killer (NK) cytotoxicity of splenic cells from BALB/c mice pretreated i.v. with squalane-in-water preparations of muramyl dipeptide (MDP), trehalose dimycolate (TDM), or the combination of MDP-plus-TDM was investigated.