inosinic-acid and methyl-inosine-monophosphate

Methyl inosine 5'-monophosphate (MIMP) was designed and synthesized in an endeavor to generate compounds with immunostimulatory activity based on the precedent of purines, particularly inosine playing a central role in the development and function of the immune system. This review will summarize the immune-enhancing effects of MIMP on a variety of immunological responses both in vitro and in vivo. Among these studies, MIMP displays protective effects in several in vivo models of infectious disease following administration by one of several routes including oral. Furthermore, MIMP enhanced responses to Hepatitis B and influenza vaccines. Vaccination represents an extremely powerful tool for combating a variety of diseases, perhaps even cancer. However, to date, vaccines have been limited by their inability to produce cell-mediated responses and by the low immunogenicity of soluble/subunit antigens. In addition, there are difficulties in eliciting sufficient responses in immunocompromised individuals, which includes the elderly, due to the natural immunosenescence that occurs with aging. The data described here suggest that MIMP could be used to overcome some of these limitations. The application of MIMP as an adjuvant to the influenza vaccine, focusing on the elderly, at-risk populations will be discussed in more detail; however, several other bacterial and viral vaccine and/or disease targets merit further consideration.

Topics: Adjuvants, Immunologic; Aging; Animals; Communicable Diseases; Humans; Immunization; Inosine Monophosphate; T-Lymphocytes

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. The diverse array of natural, synthetic, and recombinant immunomodulators discussed in this review succinctly demonstrate the potential of these agents to stimulate host defense mechanisms for prophylaxis and treatment of various microbial infections.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Amino Acid Sequence; Animals; Antiviral Agents; Bacterial Vaccines; Colony-Stimulating Factors; Cytokines; Glucans; Humans; Infections; Inosine Monophosphate; Inosine Pranobex; Interferons; Interleukins; Molecular Sequence Data; Thymopentin; Thymus Hormones; Tumor Necrosis Factor-alpha

Topics: Animals; Antibody Formation; Antiviral Agents; Humans; Immunity; Immunity, Cellular; Inosine Monophosphate; Lymphocyte Activation; T-Lymphocytes

Topics: Adjuvants, Immunologic; AIDS-Related Complex; Animals; Antiviral Agents; HIV Infections; Humans; Immunotherapy; Infections; Inosine Monophosphate; T-Lymphocytes

Effectors secreted by microbes contribute to pathogen virulence and/or avirulence on host plants in the interaction of plants and microbes. Also, the effector repertoire determines the host specificity of a pathogen. Fusarium oxysporum f. sp. cubense (Foc) is the causal agent of banana wilt; however, knowledge about Foc effector genes is very limited. In this study, genome-wide effector gene identification was performed in Foc race 1 (Foc 1) and Foc race 4 (Foc 4) based on the context association between the effector genes and the transposable element mimp. A total of 20 candidate effector genes were identified, of which 3 were Foc 1-specific, 6 were Foc 4-specific, and 11 were present in both Foc 1 and Foc 4. Most genes (14 out of 20) showed a significant transcriptional burst in planta compared with in-culture conditions, from more than 10-fold to 1,617-fold, and at the highest 32,725-fold. In addition to Foc 1- and Foc 4-specific genes, the genes Foc 283, Foc 495, and Foc 594 also exhibited transcriptional race specificity. Sixteen of the twenty genes were predicted to have a signal peptide, nine genes might encode real effectors predicted by EffectorP 2.0, and eight genes had predicted motifs. To validate the pathogenicity of the candidate effector genes, we generated knockout mutant and complementants of the gene Foc 1324 and tested their virulence on banana plants. The results showed that Foc 1324 was a virulent factor and required for the pathogenicity of Foc 4.

Topics: Fungal Proteins; Fusarium; Gene Expression Profiling; Gene Expression Regulation, Fungal; Gene Knockout Techniques; Genome, Fungal; Inosine Monophosphate; Musa; Plant Diseases; Transcription Factors; Virulence

An inbred murine model (BALB/c) was utilized to assess the protective effect of the immunomodulator methyl inosine 5'-monophosphate (MIMP) against infection with influenza A/PR/8/34 (H1N1) virus. Contrary to the data reported for outbred mice (NMRI) infected with the aerosolized virus (Masihi, Hadden, 2003. J. Int. Immunopharmacol. 3, 1205-1215), there were no improvements in the outcomes of infection in the inbred animals treated with MIMP intranasally 1 day before the challenge and/or orally after the challenge for 5 days (up to 10 mg/kg/day). Nevertheless, complete protection against lethality was afforded by the treatment with the neuraminidase inhibitor peramivir given once daily for 5 days after the challenge (10 mg/kg/day). We speculate that the rapid progression of the disease in inbred mice caused by the intranasal challenge may render the MIMP-treatment ineffective. Our results emphasize the need for careful consideration of murine strains and routes of virus challenge in the design of experiments utilizing lethal influenza virus infection.

Topics: Acids, Carbocyclic; Age Factors; Animals; Antiviral Agents; Body Weight; Cyclopentanes; Disease Models, Animal; Female; Guanidines; Influenza A Virus, H1N1 Subtype; Inosine Monophosphate; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections

Methyl inosine monophosphate (MIMP) is a novel thymomimetic purine immunomodulator capable of enhancing a wide variety of immune responses. Intravenous (i.v.) administration of MIMP 1 day prior to influenza virus infection could confer partial protection and significantly increase the mean survival of treated mice. Intranasal (i.n.) administration of MIMP improved survival rates and incorporation of MIMP in squalane-saline emulsion 1 day prior to or 1 h after influenza infection conferred complete protection. Mice administered MIMP had reduced levels of lung virus and lower titers of circulating serum hemagglutination-inhibition (HI) antibodies. Complete survival and reduction of viral load after influenza challenge infection suggests effective stimulation by MIMP of protective responses against influenza virus.

Topics: Aerosols; Animals; Female; Influenza A virus; Inosine Monophosphate; Mice; Orthomyxoviridae Infections; Survival Rate

Methyl inosine monophosphate (MIMP) augments preferentially the in vitro responses of human and murine lymphocytes to a T-cell mitogen such as phytohemagglutinin (PHA) and inconsistently to a B-cell mitogen such as pokeweed or lipopolysaccharide (LPS). In a normal interleukin-2-dependent cell line (CTLL), MIMP showed little or no effect on IL-2 action; however, in a murine CTLL line exhibiting impaired responses to IL-2, MIMP stimulated thymidine incorporation and restored the response to IL-2. MIMP augments the PHA responses of both CD4+ and CD8+ human peripheral blood T-cells. The effect of MIMP to augment the PHA response of human lymphocytes is paralleled by the parent molecule, IMP. MIMP, but not IMP, is resistant to hydrolysis by 5'nucleotidase; thus, MIMP appears to be a protected analogue of IMP which is capable of in vivo action. MIMP (100 micrograms/ml) augments the PHA responses of 15 to 24 elderly humans. MIMP also augments the PHA responses of eight HIV-infected pre-AIDS patients but not of eight AIDS patients. When PHA responses of human lymphocytes are suppressed in vitro by an HIV-derived immunosuppressive peptide, interferon alpha, or prostaglandin PGE2, MIMP (0.1-100 micrograms/ml) progressively restores the depressed response; however, when the suppression is severe (greater than 50%), MIMP cannot restore the response. These data indicate that MIMP potentiates normal T-lymphocyte mitogen responses and restores those impaired by a variety of inflammatory and immunosuppressive influences.

Topics: Animals; Antiviral Agents; Cells, Cultured; Dinoprostone; Dose-Response Relationship, Drug; HIV Infections; Humans; Immunosuppressive Agents; Inosine Monophosphate; Interferon-alpha; Mice; Mitogens; Spleen; T-Lymphocytes

Inosine 5'-methyl monophosphate (MIMP) is a new immunomodulator designed to improve upon the activity of other thymomimetic purines. In Balb/c mice, MIMP was assessed for toxicity and activity on immune responses. The lethal dose for half the mice (LD50) exceeded 500 mg/kg of body weight by both the parenteral and oral routes. At doses of 1-100 mg/kg, the mice showed no visible untoward effects. The antibody response of splenocytes to sheep erythrocytes (SRBC) was measured by IgM plaque-forming cells (PFC) in soft agar under optimal conditions of immunization and challenge. MIMP (1-100 mg/kg) was given by both the intraperitoneal and oral routes (gavage) at the time of SRBC injection and 4 days thereafter. The PFC response was found to be significantly augmented. The maximum effect (approximately 2x) was observed at 50 and 100 mg/kg, via intraperitoneal (i.p.) and oral routes, respectively. Increases (maximally 1.5x) in the responses of splenic lymphocytes to mitogen stimulation with phytohemagglutinin (PHA) and concanavalin A (Con A) were observed under similar conditions of MIMP treatment. SRBC-induced delayed-hypersensitivity (DTH) was also measured under optimal conditions. By both i.p. and oral routes, enhancement of DTH response was produced by the lower doses of MIMP (0.01-1 mg/kg). Again, a second peak of optimum stimulation of DTH response was produced by 50 mg/kg of MIMP when administered by both routes. The effect was observed mainly on the sensitization rather than on the expression phase. MIMP qualifies as an effective immunopotentiator in normal mice.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Antibody-Producing Cells; Female; Hypersensitivity, Delayed; Inosine Monophosphate; Lethal Dose 50; Lymphocyte Activation; Mice; Mice, Inbred BALB C; T-Lymphocytes

MIMP is a new thymomimetic purine under development for immunorestorative therapy. Lymphocytes were obtained from eight patients with acquired immunodeficiency disease (AIDS), eight with symptomatic pre-AIDS (ARC), and 22 normal controls and were stimulated in vitro with phytohemagglutinin (PHA). AIDS patients (mean CD4 counts of 40) showed PHA responses less than 10% of control while ARC patients (mean CD4 counts of 544) showed responses approximately 50% of the control responses. MIMP (0.1, 1, 10 and 100 micrograms/ml) progressively augmented the PHA responses in all these groups. The augmentation of the responses of the leukocytes of AIDS patients while statistically significant was minimal. The augmentation of the responses of ARC patients was significant and their maximal responses approached control levels. The effect of 1 micrograms/ml MIMP was comparable with that observed with indomethacin (10(-6) M) and interleukin-2 (IL2 - 4 units/ml) and was additive with each of these stimulants. In a parallel manner, MIMP restored the suppression of control lymphocytes induced by the immunosuppressive 17 amino acid fragment of the P41 peptide of HIV. In vivo experiments showed that MIMP significantly delayed death in a murine FLV AIDS model at a dose of 1 mg/kg by the oral or parenteral route. MIMP is under preclinical development for early HIV disease to forestall progression to AIDS by attenuating virus-induced immunosuppression.

Topics: Adjuvants, Immunologic; Adult; Animals; Female; Friend murine leukemia virus; HIV Infections; Humans; In Vitro Techniques; Indomethacin; Inosine Monophosphate; Interleukin-2; Leukemia, Experimental; Lymphocytes; Mice; Mice, Inbred BALB C; Middle Aged; Phytohemagglutinins

Prior work has documented the thymomimetic and immunotherapeutic activity of purine molecules related in structure to inosine. Synthesis of a series of new structures has yielded a stable methylated form of IMP resistant to hydrolysis by 5' nucleotidase. With both human peripheral blood lymphocytes and murines splenocytes, Methyl Inosine Monophosphate (MIMP) augments proliferative responses to T-cell mitogens like phytohemagglutinin (PHA), but less so, or not at all, to B-cell mitogens like pokeweed or endotoxin (LPS). MIMP does not directly stimulate lymphocytes alone in the absence of mitogen. The optimal effects of MIMP parallel the optimal effects of PHA. The magnitude of the effect is greater and more consistent than with other purine immunomodulators. MIMP is non-toxic in vitro and in vivo and is orally active in mice. Significant effects are observed as low as 0.1 and 1 micrograms/ml in vitro and 0.1 or 1 mg/kg in vivo. MIMP is a candidate third generation purine under development for immunotherapeutic purposes.

Topics: Adjuvants, Immunologic; Animals; HIV Infections; Humans; Inosine Monophosphate; Lymphocyte Activation; Mice; Mice, Inbred BALB C; T-Lymphocytes