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)

There has been a growing body of evidence suggesting that CD4+ Th1/Th2 cell responses participate in pathologic and immunologic processes in infectious disease. Bacterial meningitis is a fatal disease of children and is associated with a spectrum of clinical syndromes. This study provides evidence of CD4+ enhanced interleukin (IL)-4 and IL-6 but decreased IL-2 and interferon-gamma (IFN-gamma) production, the induction of characteristic Th2 cell response cytokines in bacterial meningitis, which may play an important role in disease mechanism. Additionally, monocyte-induced enhanced IL-6, IL-8, and tumor necrosis factor-alpha production may be associated with distinct clinical features such as fever, seizures, and neurological sequelae. A striking finding was also the highly deficient monocyte-induced granulocyte-macrophage colony-stimulating factor production. Of particular interest, the CD(8+)-enhanced IFN-gamma production may be required for the cytolytic activity or protective response to be maintained in this disease. Taken together, these data reveal that monocytes and CD4+ (Th2) and CD8+ subsets produce distinct cytokines in bacterial meningitis, which may exert an immunoregulatory and immunopathologic effect and thus mediate some of the clinical manifestations of the disease.
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PMID:CD4+ Th2 cell response cytokine production in bacterial meningitis. 857 20

Interleukin 12 (IL-12) is a heterodimeric cytokine that is produced primarily by antigen-presenting cells and plays a primary role in the induction of cell-mediated immunity. This function is promoted by the IL-12 induced production of interferon-gamma (IFN-gamma) from both resting and activated NK and T cells, by the proliferative activity of IL-12 on activated NK and T cells, by enhancing the cytotoxic activity of NK cells, and by supporting cytotoxic T lymphocyte generation. IL-12 and IL-12-induced IFN-gamma promote the development of naive T cells into Th1 cells and the proliferation and IFN-gamma secretion by differentiated Th1 cells in response to antigen. IL-12 has been found to exhibit many of these activities in vivo, as well as in vitro, and thus IL-12 plays an important role in both innate resistance and antigen-specific adaptive immunity to intracellular bacterial, fungal, and protozoan pathogens. Due to its effects on T cells, recombinant IL-12 has been shown to have therapeutic activity in a variety of mouse tumor and infectious disease models and is being evaluated in clinical trials in human cancer patients. IL-12 also appears to play a role in the genesis of some forms of immunopathology, including endotoxin-induced shock and some autoimmune diseases associated with aberrant Th1 activity. Therefore, IL-12 antagonists may also have therapeutic potential in the treatment of auto immune disorders.
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PMID:Interleukin-12 an integral cytokine in the immune response. 859 14

Infection with Mycobacterium bovis bacillus Calmette-Guerin (BCG) confers mice with strong abilities to produce nitric oxide (NO) and cytokines. Because the peritoneal macrophages taken from the mice immunized with live or heat-killed BCG can produce NO without any accessory cells and stimulants, it is difficult to clarify the immune regulation on NO production by manipulating the macrophages. Therefore, we investigated the participation of immune T cells and cytokines in NO production by using in vitro co-cultures of macrophages from non-immune mice with T cells prepared from BCG-infected mice in the presence or absence of a mycobacterial antigen, purified protein derivative (PPD). Although the non-immune thioglycollate (TGB)-elicited macrophages could not produce any detectable NO in the presence of PPD, supplementation of the macrophage cultures with CD4+ T cells prepared from BCG-infected mice enabled the macrophages to produce NO. Immunocytostaining showed that the macrophages, hut not the immune T cells, expressed inducible NO synthase (iNOS), indicating that they were NO producers. PPD could only induce NO production if there was cell-cell contact of the CD4+ T cells in the immune cells and antigen-presenting macrophages were required for the NO production in response to PPD; this interaction led to the production of soluble mediators that induced NO production by the TGB macrophages. NO production by the co-cultured cells was abrogated by adding either anti-interferon-gamma(IFN-gamma) or anti-tumor necrosis factor alpha (TNF-alpha) antibody. Furthermore, the roles of immune T cells and PPD could be replaced by adding recombinant IFN-gamma together with TNF-alpha to the macrophage cultures, but neither alone was sufficient to induce NO production by the macrophages. Our present data indicate that TNF-alpha produced by PPD-stimulated macrophages and IFN-gamma produced by cell-cell interaction of BCG-immune T cells and antigen-engulfed macrophages together activate the macrophages to produce NO.
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PMID:Nitric oxide production by peritoneal macrophages of Mycobacterium bovis BCG-infected or non-infected mice: regulatory role of T lymphocytes and cytokines. 869 Oct 77

Although in vitro systems have provided important information about the composition and nature of various immune responses, understanding physiologically relevant function and regulation requires evaluating in vivo conditions. Two different models of acute viral infections have made possible the characterization of a variety of responses to these agents, including natural killer (NK) cell activation and regulation during infection; these are mouse infections with lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). The results of our characterization of the NK cell responses elicited in these models and the methods used to dissect the regulation of these responses are reviewed here. Cytotoxicity, proliferation, and cytokine expression assays as well as flow cytometric analyses are used to characterize the in vivo responses. Both of the infections induce early NK cell cytotoxicity and blastogenesis. Infection with MCMV but not LCMV also induces NK cell production of the antiviral cytokine, interferon-gamma (IFN-gamma). Antibodies, to mediate in vivo cell subset depletion or cytokine neutralization, and mice, genetically altered to have cell subset or cytokine deficiencies, are utilized to identify the regulatory pathways and mechanisms controlling endogenous NK cell responses to the infections. The major mediators of the regulation of NK cell function during viral infection of normal mice are IFN-alpha/beta and interleukin-12 but not interleukin-2. Furthermore, the induction of later T-cell responses contributes to the negative regulation of NK cells by promoting the production of inhibitory factors including biologically active transforming growth factors-beta. Thus, the study of immune responses to viral infections has provided and will continue to provide important insights into the characteristics of endogenous NK cell responses and the cells and factors that regulate these responses in vivo.
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PMID:Function and Regulation of Natural Killer (NK) Cells during Viral Infections: Characterization of Responses in Vivo 881 91

One of the first target cells at the site of inoculation with an alphavirus may be monocytes or macrophages. The replication kinetics of virulent and attenuated molecularly cloned Venezuelan equine encephalitis virus (VEE) in murine macrophages were therefore compared. Infection of both quiescent and activated mouse primary peritoneal macrophages with a molecularly cloned, virulent VEE termed V3000 resulted in peak virus titres of 10(4) plaque forming units (PFU)/ml supernatant by 24 h post-infection (pi), followed by rapidly decreasing virus titres. In contrast, a molecularly cloned attenuated VEE mutant, V3032, that differs from V3000 by a single amino acid at E2 glycoprotein position 209 (glu-->lys) replicated more slowly and to higher titres (10(8) PFU/ml supernatant) that peaked at 72 h pi. Replication of V3032, but not V3000, was sharply restricted by prior activation of macrophages with lipopolysaccharide or interferon-gamma. These results indicate that virulent V3000 and attenuated V3032 differ in their growth kinetics in both quiescent and activated macrophages. Thus, macrophages, and their specific activation state, may play a major role in virulent and attenuated VEE replication and pathogenesis.
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PMID:Virulent and attenuated mutant Venezuelan equine encephalitis virus show marked differences in replication in infection in murine macrophages. 884 52

Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity by facilitating type 1 helper T-lymphocyte responses, enhancing the lytic activity of natural killer cells, augmenting specific cytolytic T-lymphocyte responses, and inducing the secretion of interferon-gamma. It can also boost the production of some subclasses of IgG antibodies. IL-12 has demonstrated activity in several mouse models of infectious diseases caused by viruses, protozoans, fungi, and mycobacteria. It has the potential for use either as a single immunotherapeutic agent, in combination with chemotherapeutic agents, or as a vaccine adjuvant. Endogenous IL-12 appears to play an important role in the host defence against intracellular pathogens; poor IL-12 production observed in mononuclear cells from patients infected with the human immunodeficiency virus may be involved in the susceptibility of this patient group to opportunistic infections. Clinical trials are being initiated to evaluate the possible therapeutic uses of IL-12.
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PMID:Interleukin-12: potential clinical applications in the treatment and prevention of infectious diseases. 886 32

The pathogenesis of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is still controversial. Our hypothesis is that primary infection of oligodendrocytes (OLGs) is not a crucial event in the pathogenesis of demyelination in this model. In fact, it has been proposed that myelin may be destroyed, as an innocent bystander, following an antiviral delayed-type hypersensitivity (DTH) response. This hypothesis would not need widespread oligodendroglial infection, because virus present in other cells would be sufficient to trigger a DTH response. The present study demonstrates that cultured OLGs and astrocytes from susceptible strains of mice (SJL and DBA) and immortalized OLGs can be infected with TMEV in vitro. Infection of OLGs, however, is at very low levels and does not result in overt cytolytic effect. In contrast, infection of immortalized OLGs is very efficient and results in clear cytolysis. Because an important characteristic of DTH responses is the liberation of potentially injurious cytokines into adjacent tissues, we also examined the effects of mouse recombinant tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and interferon-gamma (IFN-gamma) on cultured OLGs and immortalized OLGs. We found that TNF-alpha caused immortalized OLG cytotoxicity in a time- and dose-dependent manner. In contrast, no cytotoxicity was observed on primary OLGs with any of the above cytokines. To determine whether functional effects could be demonstrated on primary OLGs by either virus or cytokines, we measured mRNA expression of different myelin proteins in primary and immortalized OLGs exposed to virus or TNF-alpha. Neither the BeAn strain or the GDVII strain of TMEV interfered with myelin protein mRNA expression in primary OLGs, whereas GDVII virus dramatically reduced myelin OLG glycoprotein (MOG) mRNA in immortalized OLGs. Interestingly, although even high concentrations of TNF-alpha (10,000 U/ml) did not produce primary OLG cytotoxicity, they resulted in a significant reduction in mRNA for both myelin basic protein (MBP) and MOG in these cells. TNF-alpha (at 500 U/ml) also specifically reduced MOG mRNA in immortalized OLGs. Because immortalized OLGs are considered to be arrested at an early stage of maturation, our results suggest that immature OLGs are susceptible to both virus- and cytokine-dependent cytotoxicity, whereas mature OLGs are resistant to cytolysis by either TMEV or cytokines. TNF-alpha, however, is capable of reducing mRNA expression of myelin proteins in primary OLGs; therefore, it may participate in the induction of demyelination, as suggested by the DTH-mediated hypothesis.
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PMID:Effect of Theiler's murine encephalomyelitis virus and cytokines on cultured oligodendrocytes and astrocytes. 887 96

The consequences of complexing an antigen with specific antibodies upon the antigen-induced immune response were studied with respect to secretion of interleukin-2 (IL2), interleukin-6 (IL6), interleukin-10 (IL10) and interferon-gamma (IFN gamma). We found that the tetanus toxoid antigen-induced cytokine pattern was mainly dependent on the antigen/antibody ratio. While tetanus toxoid antigen alone induced a typical Th1-like cytokine pattern with high levels of IL2 and IFN gamma, equivalent or antibody-excess immune complexes induced a marked secretion of IL6 and IL10 while failing to induce IL2 and IFN gamma secretion. As the cytokine pattern plays a crucial role in the development of specific immune responses towards infectious agents, our results indicate that immune complexes--typically occurring during the course of chronic infectious diseases--may play an important role in the modulation of immune responses. Since a shift from Th1 to Th2 immune responses has been discussed as a pathogenetic factor in HIV-induced immunodeficiency, the role of circulating immune complexes as a possible cause for this shift should be considered.
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PMID:Distinct antigen-induced cytokine pattern upon stimulation with antibody-complexed antigen consistent with a Th1-->Th2-shift. 890 28

In 15 consecutive subjects hospitalized with nephropathia epidemica, a European form of hemorrhagic fever with renal syndrome, the plasma concentrations of nitrate plus nitrite, stable metabolites of nitric oxide, were determined. From day 3 of onset of disease the concentrations increased, peak levels being reached on days 5 to 7. Maximal plasma concentrations of nitrate plus nitrite were correlated to the degree of hypotension (r = -0.64, p = 0.02) and levels of tumor necrosis factor (TNF)-alpha (r = 0.51, p = 0.05) and soluble TNF receptors p55 and p75 (r = 0.58, p = 0.03 and r = 0.54, p = 0.04, respectively) but not to levels of interferon-gamma or interleukin-10 (p > 0.05). The results are compatible with the well-known capacity of TNF-alpha to enhance production of nitric oxide, and suggest that nitric oxide may be of physiologic importance in hemorrhagic fever with renal syndrome.
Infection
PMID:Increased production of nitric oxide in patients with hemorrhagic fever with renal syndrome--relation to arterial hypotension and tumor necrosis factor. 892 42

The T cell-derived macrophage-activating lymphokine, interferon-gamma (IFN-gamma), is the most broadly acting antimicrobial-inducing and host defense-enhancing cytokine thus far identified in experimental models of infectious diseases. The activity induced by IFN-gamma encompasses all classes of non-viral pathogens including intracellular and extracellular parasites, fungi and bacteria. In man, treatment with immuno-enhancing doses of IFN-gamma is safe, well-tolerated and stimulates the antimicrobial mechanisms of blood monocytes, circulating neutrophils and tissue macrophages. Aerosol administration activates alveolar macrophages in a compartmentalized fashion. Monocytes from IFN-gamma-treated patients with cancer, leprosy, and AIDS all respond with the activated phenotype, and suppressed monocyte HLA-DR expression in trauma patients can be up-regulated by IFN-gamma therapy. Thus far, IFN-gamma has been recognized as effective in the prophylaxis of chronic granulomatous disease and as adjunctive treatment in at least one systemic intracellular infection, visceral leishmaniasis. Additional trials suggest beneficial effects as prophylaxis in trauma and as treatment in leprosy, cutaneous leishmaniasis, and HIV- and non-HIV-related disseminated atypical mycobacterial infection. IFN-gamma is also being tested as a prophylaxis in patients with burns and advanced HIV infection and as an adjunct in drug-resistant tuberculosis. Future antimicrobial applications for IFN-gamma include: a) long-term prophylaxis in T cell-deficient states, b) short-term prophylaxis in patients with a reversible host defense defect such as granulocytopenia or immune response suppression induced by trauma or burn injury, and c) adjunctive treatment along with conventional antibiotic therapy for i) nosocomial pneumonia (aerosol administration), ii) opportunistic infections in general, iii) infections which typically respond poorly to available treatment and iv) for infections which require prolonged therapy for cure. In the latter, the addition of IFN-gamma may accelerate the response to conventional therapy and permit a clinically important reduction in the duration of treatment while preserving efficacy.
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PMID:Current and future clinical applications of interferon-gamma in host antimicrobial defense. 892 89


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