Immunobiological activities of nontoxic lipid A: enhancement of nonspecific resistance in combination with trehalose dimycolate against viral infection and adjuvant effects

The ability of nontoxic monophosphoryl lipid A (MPL) to stimulate nonspecific resistance against viral infection was investigated. Mice pretreated intravenously with squalane-in-water emulsions of MPL, alone or in combination with other immunostimulants, were given an aerosol of influenza virus three weeks after the pretreatment. Complete protection against lethal influenza virus infection was conferred when MPL was combined with trehalose dimycolate (TDM). The protective activity of MPL plus TDM combination was corroborated by a significant reduction of the lung virus titers. Combination of lower doses of MPL with TDM extracted from Mycobacterium bovis, but not with that of M. phlei, induced significant resistance to influenza virus. Preparations containing MPL alone, or combined with mycobacterial cell wall skeleton or muramyl dipeptide, were not effective. The adjuvant activity of MPL on bivalent influenza subunit vaccine was also studied. The primary antibody responses to influenza A and influenza B antigens were enhanced by the addition of MPL and were higher than the vaccine associated with aluminum hydroxide. The adjuvant activity of MPL was confirmed by the elevated secondary response. High levels of circulating antibodies were still present in the MPL group when antibody titers in the controls were waning.     

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. The histopathological examination of the liver revealed marked necrosis of the hepatic parenchymal cells and infiltration of the inflammatory cells in controls but not in MDP-treated animals.     

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. Subunit vaccine containing A/Sichuan (H3N2) and Al(OH)3 stimulated high HI antibody titres but failed to provide protection against heterologous influenza A (H1N1) challenge infection following either the primary or the secondary immunizations. In contrast, similar treatment with A/Sichuan subunit vaccine containing AdDP conferred significant protection against heterologous challenge despite low levels of circulating antibody. Primary immunization with even influenza B/Beijing subunit vaccine containing AdDP, but not Al(OH)3, provided partial protection against influenza A challenge. These results suggest that appropriate immunomodulators like AdDP can convert restricted homotypic immunity induced by inactivated influenza subunit vaccines to advantageous cross-reacting type of heterologous response.     

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. The immune-based therapies, in combination with antimicrobial drugs, for viral hepatitis have attracted much attention. Recognition of toll-like receptors by synthetic immunomodulators is used for certain viral infections. New methodologies have the potential to identify novel targets and foster the development of individually tailored immunomodulatory drug treatments.     

Trehalose dimycolate from various mycobacterial species induces differing anti-infectious activities in combination with muramyl dipeptide.

Significant resistance against influenza virus and Mycobacterium tuberculosis infections was induced when trehalose dimycolate from M. tuberculosis or M. bovis but not M. avium was combined with muramyl dipeptide. Trehalose dimycolate from M. tuberculosis, in contrast to that from M. avium, could confer resistance against Toxoplasma gondii infections.     

Effects of muramyl dipeptide and trehalose dimycolate on resistance of mice to Toxoplasma gondii and Acanthamoeba culbertsoni infections

The effects of synthetic muramyl dipeptide (MDP) and natural trehalose dimycolate (TDM) against parasitic infections by intracellular Toxoplasma gondii and free-living Acanthamoeba culbertsoni were studied. Significant resistance against oral T. gondii infection was induced by intraperitoneal pretreatment with TDM but not with MDP. The protective effect of TDM against T. gondii was corroborated by a significant reduction in the number of cysts in brains of pretreated animals and elevated serum antibody levels. Partial protection against lethal intranasal A. culbertsoni infection was conferred by specific immunization with viable trophozoites of nonpathogenic Acanthamoeba lugdunensis. The nonspecific resistance induced by intravenous pretreatment with MDP was similar to, whereas that stimulated by TDM was lesser than the protection conferred by A. lugdunensis. The Fc receptor-mediated phagocytosis of 51Cr-labeled sheep red blood cells by alveolar macrophages was enhanced by MDP. The phagocytic activity of peritoneal macrophages was increased by lower doses of TDM.     

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. Remarkably, amantadine-based combination chemoprophylaxis was even effective against amantadine-resistant A/PR/8/34 influenza virus. Thus, combination chemotherapy may be more efficacious than monotherapy against newly emerging Influenza A subtypes.     

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. These findings have now given many empirical therapies a rationale, scientific basis and thereby a means for 'intelligent' improvement. In discovering the molecular mechanisms by which known remedies exert their effects, chosen elements further down the 'chain of command' might be synthesized and applied directly for more rapid and selective cure, omitting unwanted side effects. The direct use of recombinant cytokines, often in combination with antibiotics, is one consequence of this rationale.