Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009450 (infectious diseases)
 83,438 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interplay between viral infection and lipopolysaccharide (LPS) was studied. Infection with a noncytopathogenic virus, lymphocytic choriomeningitis virus (LCMV), was found to sensitize mice to low doses of LPS. In vivo, this hypersensitivity correlated with hyperproduction of tumor necrosis factor-alpha (TNF-alpha), and in vitro, LPS-stimulated splenic adherent cells produced increased amounts of TNF-alpha. Hyperproduction of TNF-alpha was temporally correlated with virus-induced production of interferon-gamma (IFN-gamma); only marginally increased IFN-gamma and TNF-alpha production was observed in LCMV-infected, T cell-deficient mice and in mice infected with vesicular stomatitis virus, a virus that induces much less T cell activation than does LCMV. Finally, LCMV infection was much less efficient in priming IFN-gamma knockout mice for hyperproduction of TNF-alpha. These findings indicate that clinically silent viral infections may induce hypersensitivity to LPS through T cell activation and subsequent production of IFN-gamma; this sensitizes monocytes/macrophages for hyperproduction of TNF-alpha.
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PMID:Sensitization to lipopolysaccharide in mice with asymptomatic viral infection: role of T cell-dependent production of interferon-gamma. 920 61

A defective-interfering (DI) RNA of the murine coronavirus mouse hepatitis virus (MHV) was developed as a vector for expressing interferon-gamma (IFN-gamma). The murine IFN-gamma gene was cloned into the DI vector under the control of an MHV transcriptional promoter and transfected into MHV-infected cells. IFN-gamma was secreted into culture medium as early as 6 hr posttransfection and reached a peak level (up to 180 U/ml) at 12 hr posttransfection. The DI-expressed IFN-gamma (DE-IFN-gamma) exhibited an antiviral activity comparable to that of recombinant IFN-gamma and was blocked by a neutralizing monoclonal antibody against IFN-gamma. Treatment of macrophages with DE-IFN-gamma selectively induced the expression of the cellular inducible nitric oxide synthase and the IFN-gamma-inducing factor (IGIF) but did not affect the amounts of the MHV receptor mRNA. Antiviral activity was detected only when cells were pretreated with IFN-gamma for 24 hr prior to infection; no inhibition of virus replication was detected when cells were treated with IFN-gamma during or after infection. Furthermore, addition of IFN-gamma together with MHV did not prevent infection, but appeared to prevent subsequent viral spread. MHV variants with different degrees of neurovirulence in mice had correspondingly different levels of sensitivities to IFN-gamma treatment in vitro, with the most virulent strain being most resistant to IFN-gamma treatment. Infection of susceptible mice with DE-IFN-gamma-containing virus caused significantly milder disease, accompanied by more pronounced mononuclear cell infiltrates into the CNS and less virus replication, than that caused by virus containing a control DI vector. This study thus demonstrates the feasibility and usefulness of this MHV DI vector for expressing cytokines and may provide a model for studying the role of cytokines in MHV pathogenesis.
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PMID:Expression of interferon-gamma by a coronavirus defective-interfering RNA vector and its effect on viral replication, spread, and pathogenicity. 921 56

Human T-lymphotropic virus-I (HTLV-I) has been etiologically linked with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurologic disease. The characteristic pathological finding in HAM/TSP is marked mononuclear infiltration of the CNS with destruction of the long tracts of the spinal cord. An increased expression of HLA surface antigens and cytokines in the CNS is associated with this inflammatory response. Furthermore, there is evidence for the presence of HTLV-I in HAM/TSP CNS specimens using in situ hybridization and polymerase chain reaction techniques. The relationship between HTLV-I infection of CNS cells and the observed upregulation of surface antigens in the CNS is not well understood. It has been previously demonstrated that HTLV-I infection of neuroblastoma cells leads to induction of HLA surface antigens. As an extension of these studies, HFGC and HCN-1a, neuronal cell lines of nontumorigenic origin, were infected with HTLV-I and the effect on HLA upregulation was studied. Infection of the neuronal cells was demonstrated by the presence of HTLV-I gp46 surface antigen on CD4 negative cells and by the in situ presence of HTLV-I RNA in neurofilament positive cells. Concurrent to HTLV-I infection, HLA class II surface antigen was observed on neurofilament positive cells. Upregulation of HLA class II was not observed in neuronal cells grown in the presence of interferon-gamma or tissue necrosis factor-alpha.
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PMID:Induction of HLA class II in HTLV-I infected neuronal cell lines. 922 53

Mice infected with bacteria develop an interferon-gamma (IFN-gamma) dependent hypersensitivity to lipopolysaccharide (LPS) and other bacterial components. The broader aim of this study is to find out whether such hypersensitivity also occurs in patients suffering from bacterial infections. The capacity of stimulated peripheral blood cells from infected, intensive-care patients to produce cytokines (IFN-gamma, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)) was compared to that of healthy donors. Culturing of the cells was carried out preferentially in whole blood diluted 1:3. Whole blood cultures (WBC) were stimulated with lipopolysaccharide (LPS), whole killed Salmonella typhimurium and Staphylococcus aureus and concanavalin A (ConA), and the cytokine production was determined. Two main findings emerged from this study: The IFN-gamma production by WBC of patients was, compared to healthy donors, markedly suppressed, regardless of stimulus used. Further, patients' WBC exhibited a suppressed TNF-alpha production after stimulation with LPS. Surprisingly, following stimulation with bacteria (S. typhimurium and S. aureus) an elevated TNF-alpha and IL-6 response was obtained. Thus, in severely infected patients the cytokine responses of peripheral blood cells to LPS may be suppressed, while the response to other bacterial components is enhanced.
Infection
PMID:Differential cytokine production in stimulated blood cultures from intensive care patients with bacterial infections. 926 58

CD69, a member of the natural killer cell gene complex family of signal transducing receptors, represents one of the earliest activation antigens in human and murine lymphocytes. In contrast, human monocytes may express CD69 in a constitutive fashion. We have evaluated the expression and function of CD69 in murine bone marrow-derived macrophages. CD69 expression as determined by flow cytometry was not constitutive but was induced by stimulation with interferon-gamma (IFN-gamma) plus bacterial lipopolysaccharide (LPS) or tumor necrosis factor a (TNF-alpha). Stimulation with LPS alone was equally effective. Infection with the protozoan parasite Leishmania did not induce CD69 expression nor influence CD69 up-regulation by IFN-gamma plus LPS. Induction of CD69 expression was significantly inhibited in the presence of prostaglandin E2 or dibutyryl-cAMP. Stimulation of macrophages with anti-CD69 monoclonal antibody in the presence of IFN-gamma induced both nitric oxide production and TNF-alpha release. Moreover, anti-CD69 stimulation of Leishmania-infected macrophages resulted in elimination of the intracellular parasite. These results suggest that CD69 is an activation antigen for murine macrophages and may serve as a signaling receptor for an as yet uncharacterized ligand.
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PMID:Expression and function of the early activation antigen CD69 in murine macrophages. 930 73

Interleukin-12 (IL-12) is a key regulator of cell-mediated immunity that has therapeutic potential in cancer and infectious disease. In a previous Phase 1 dose escalation study of a single test dose of recombinant human IL-12 (rhIL-12) followed 14 days later by cycles of five consecutive daily intravenous injections every 3 weeks, we showed that a dose level up to 500 ng/kg could be administered with acceptable levels of safety. Based on these results, a Phase 2 study was conducted. In the Phase 2 study, however, administration of rhIL-12 at this same dose level resulted in severe toxicities with some patients unable to tolerate more than two successive doses. Of the 17 patients receiving rhIL-12 in the Phase 2 study, 12 patients were hospitalized and two patients died. A thorough scientific investigation to determine the cause of this unexpected toxicity failed to identify any difference in the drug products used or the patient populations enrolled in the Phase 1 and Phase 2 studies that could have accounted for the profound difference in toxicity. The focus of the investigation therefore shifted to the schedule of rhIL-12 administration. We determined that a single injection of rhIL-12 2 weeks before consecutive dosing included in the Phase 1 study, but not in the schedule of administration in the Phase 2 study, has a profound abrogating effect on IL-12-induced interferon-gamma (IFN-gamma) production and toxicity. This observation of schedule-dependent toxicity of IL-12 has been verified in mice, as well as nonhuman primates. In this regard, a single injection of IL-12 before consecutive daily dosing protected mice and cynomolgus monkeys from acute toxicity including mortality and was associated with an attenuated IFN-gamma response. Because of this unique biologic response, careful attention to the schedule of administration is required to assure safe and effective clinical development of this highly promising cytokine.
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PMID:Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. 932 19

Interleukin (IL)-12 is a pleiotropic cytokine produced by antigen-presenting cells in response to diverse stimuli. IL-12 is a key molecule in the regulation of host's immune responses. In particular, IL-12 influences the balance between the T-helper cells type 1 (TH1) and type 2 (TH2); it modulates macrophage responses through the control of interferon-gamma synthesis by TH1 cells; and, suppresses IgE class antibody production (has a suppressive effect on allergic reactions) and promotes a shift in the IgG subclasses. IL-12 enhances resistance to several infectious diseases, is a powerful antitumor agent in vivo, and acts as a vaccine adjuvant. The biological properties of IL-12 point to the potential therapeutic use in persistent hepatitis B virus and hepatitis C virus infection.
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PMID:Biological properties of interleukin-12 and its therapeutic use in persistent hepatitis B virus and hepatitis C virus infection. 942 14

Alcohol has long been recognized as an immunosuppressive drug and a risk factor for a spectrum of infectious diseases. Among these infections, bacterial pneumonias are most closely correlated with alcohol abuse. One potential mechanism of ethanol-induced immunosuppression is through its ability to suppress alveolar macrophage production of tumor necrosis factor (TNF-alpha). This defect can be reversed by priming macrophages with interferon-gamma (IFN-gamma). We hypothesized that macrophage priming in vivo in a model of acute ethanol intoxication could augment pulmonary host defenses. To test this hypothesis, we used adenoviral-mediated gene transfer of the IFN-gamma gene. This strategy resulted in prolonged expression of IFN-gamma in vivo. Moreover, in a model of acute ethanol intoxication, this vector significantly enhanced lipopolysaccharide-induced TNF-alpha responses and lung polymorphonuclear leukocyte recruitment. Furthermore, pulmonary host defenses against Klebsiella pneumoniae were significantly augmented. These enhanced host defenses were not reversed with pretreatment with a polyclonal anti-TNF-alpha antibody, suggesting that IFN-gamma's effect was through a non-TNF-alpha-dependent mechanism. These data demonstrate that ethanol-induced suppression of pulmonary host defenses can be reversed with IFN-gamma gene therapy.
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PMID:Adenoviral-mediated interferon-gamma gene therapy augments pulmonary host defense of ethanol-treated rats. 951 1

The diverging of T-helper (Th) cells into predominantly Th1 and Th2 subsets on the basis of their cytokine profiles has decisively improved our understanding of the pathogenesis of many chronic infectious diseases. Recent data suggest that the presence of interferon-gamma and the subsequent suppression of interleukin-4 production leads to a Th1-type response that is required for the resolution of infections caused by intracellular pathogens. The ability of the macrophages to respond aggressively during early antigen contact seems to be one crucial factor in the development of an appropriate Th-cell response. Several host-related factors can affect macrophage function and the polarization of T-cell responses, ie the shift from a Th1 response to a Th2 one, and thus dramatically deteriorate the resolution of infections caused by intracellular agents such as Chlamydia pneumoniae. Chronic C. pneumoniae infection has been associated with several common chronic diseases, quite recently with chronic obstructive pulmonary disease. Chronic C. pneumoniae infection may amplify smoking-associated inflammation in the bronchi and may be a contributory factor in the development of irreversible pathological changes.
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PMID:Chlamydia pneumoniae and its role in chronic obstructive pulmonary disease. 955 87

Diethylcarbamazine (DEC) was discovered in 1947 as a potent therapeutic agent in lymphatic filariasis and has been a mainstay of antifilarial therapy over the past five decades (R. I. Hewitt, et al., 1947, Journal of Laboratory and Clinical Medicine 32, 1304-1313). Several hundred million doses of this drug have been administered to people. Despite its widespread and successful use over this prolonged time scale, its mechanism of action remains obscure (R. M. Maizels and D. A. Denham, 1992, Parasitology 105 Suppl. 549-560). Numerous studies suggest that DEC has no direct effect on the parasite (F. Hawking and W. Laurie, 1949, Lancet 2, 146-147) and that it exerts its action by stimulating host immune defense mechanisms (F. Hawking et al., 1948, Lancet 2, 730-731), or by activating host platelets to become microfilaricidal (J. Y. Cesbron et al., 1987, Nature 325(6104) 533-536). Recent data from two different laboratories suggest that NO may be involved in host defense against filarial parasites (T. V. Rajan et al., 1996, Infection and Immunity 64(8), 3351-3353; M. J. Taylor et al., 1996, Parasitology 112, 315-322). We investigated whether DEC stimulates the production of NO from murine macrophages or rat endothelial cells. DEC did not stimulate the synthesis or secretion of NO from either, nor did it synergize with interferon-gamma or tumor necrosis factor-alpha in the induction of inducible NO synthase (iNOS). In addition, there was no consistent increase in the output of inorganic nitrate, the end product of NO metabolism, in the urines of rats treated with DEC. These data suggest that DEC does not achieve its therapeutic efficacy through the induction of host iNOS.
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PMID:Diethylcarbamazine (DEC) does not induce nitric oxide (NO) synthesis. 956 25


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