Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological response modifier r(I)n.r(C12-U)n, referred to here as mismatched double-stranded (ds) RNA, was examined for antihuman immunodeficiency virus (HIV) activity in vitro because of its known antiviral activity and ability to induce interferon (IFN) in other biological systems [Carter, W. A., Strayer, D. R., Hubbell, H. R. & Brodsky, I. (1985) J. Biol. Response Modif. 4, 495-502]. We found that cultures of the highly HIV-permissive T-cell line C3 were afforded significant protection from HIV infection when incubated in growth media supplemented with mismatched dsRNA at 10-50 micrograms/ml prior to virus challenge. Similar results were obtained at 50 micrograms of mismatched dsRNA per ml in cultures of the T-lymphoblastoid cell line CEM. Infections were monitored by indirect immunofluorescence of cells for viral p24 antigen expression, reverse transcriptase activity in culture fluids for virus production, and vital dye uptake for cytopathic effect. Antiviral activity was increased by the continued presence of mismatched dsRNA in cultures following virus challenge. A one-time exposure to mismatched dsRNA (50 micrograms/ml) provided greater antiviral activity than either a one-time exposure to recombinant IFN-alpha [250 international units (IU)/ml], IFN-beta (250 IU/ml), or IFN-gamma (50 IU/ml) in cultures of CEM cells, or a one-time exposure to a combination of all three IFNs (150 IU each per ml) in cultures of C3 cells. Mismatched dsRNA at 50 micrograms/ml had no effect on cell division, RNA and protein synthesis, or virus replication in all T-cell lines examined. A clear distinction between the activities of mismatched dsRNA and IFN was the ability of IFN to suppress the in vitro replication of HIV that occurred at IFN concentrations (150 IU each of alpha, beta, and gamma per ml) that provided less antiviral activity than mismatched dsRNA (50 micrograms/ml). The results of these in vitro studies suggest a potential therapeutic value for mismatched dsRNA in the treatment of acquired immunodeficiency syndrome (AIDS).
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PMID:Antiviral activity of mismatched double-stranded RNA against human immunodeficiency virus in vitro. 310 82

The cell interactions that take place between Toxoplasma gondii trophozoites and the human immune system have been investigated by using an in vitro model of infection. PBMC were co-cultured with live, appropriately attenuated, trophozoites. When cells from immune (seropositive) donors were used, a proliferative response was observed. At the same time, the proliferating T cells proved capable of controlling the growth of live trophozoites. By contrast, cells from seronegative donors failed to mount a proliferative response and intracellular overgrowth of trophozoites with subsequent cell injury occurred. Actively proliferating T cells were expanded in continuous cell lines with IL-2 and periodical restimulation with Ag in the presence of autologous irradiated mononuclear cells. From some of the lines obtained, clones were also derived. Ten clones were selected for further studies. They proliferated in response to trophozoites but not to unrelated Ag. Their response required the presence of autologous monocytes-macrophages isolated from peripheral blood on Percoll density gradients. B cells that were obtained from the same donors and immortalized by EBV infection proved inefficient as APC. These data suggest that live trophozoites have to be processed by macrophages in order to be presented to T cells. Upon appropriate antigen stimulation, all of the clones produced IL-2 and IFN-gamma, a finding that was consistent with both their CD4+ surface phenotype and their helper capacity on B cell proliferation and differentiation in vitro. The supernatants of all of the stimulated clones released a factor that activated macrophages to kill intracellular trophozoites as well as an unrelated pathogen, Listeria monocytogenes. This factor was identified as IFN-gamma because it was neutralized by specific anti-IFN-gamma antibodies. The present in vitro model of response to live protozoa may prove suitable to assess the role of both T lymphocytes and macrophages in intracellular parasite infections in man. Furthermore, this experimental system may be applied to detect specific lesions of cell mediated immunity in a number of immunodeficiency syndromes.
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PMID:An in vitro model for Toxoplasma infection in man. Interaction between CD4+ monoclonal T cells and macrophages results in killing of trophozoites. 312 96

Irradiated CBA/J mice transplanted with H-2 compatible, minor histocompatibility disparate B10.BR bone marrow develop graft-versus-host disease (GVHD) if mature T lymphocytes are added to the marrow inoculum. In the setting of mild GVHD (receiving 10(4) or 10(5) T cells), by phenotypic analysis, lymphoid reconstitution occurs normally within 4 to 6 wk but there is a profound deficiency in the ability of splenic lymphocytes to respond to polyclonal activators such as LPS and Con A. This unresponsiveness is attributable to active suppression mediated by cells that express Thy-1 and can be removed with leucine methyl ester treatment. Thus, splenocytes from mice with GVHD suppress responses of normal T and B lymphocytes. Moreover, depletion of these suppressor cells restores normal function to splenocytes from mice with GVHD, and B cells isolated from these mice respond normally to T-dependent and -independent stimulation. Finally, IFN-gamma plays an important role in this suppression, because a neutralizing anti-IFN-gamma mAb significantly removes suppression of normal cells and restores functional responses of lymphocytes from mice with GVHD. These results provide insights into the mechanisms of immunodeficiency associated with GVHD, and suggest novel strategies for possible therapies for this disorder.
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PMID:Immunodeficiency in graft-versus-host disease. I. Mechanism of immune suppression. 312 5

We have selected 11 patients with primary immunodeficiency disorders predominantly affecting T lymphocyte function (four with ataxia-telangiectasia (AT), four with common variable immunodeficiency (CVI) and one each with Wiskott-Aldrich syndrome, hyper-IgE syndrome and combined immunodeficiency) with defective gamma interferon (IFN-gamma) production in vitro. Induction with phytohaemagglutinin showed low interleukin 2 (IL-2) production concomitant with reduced IFN-gamma titres. However the addition of 10 U/ml of rIL-2 to cultures stimulated with staphylococcal enterotoxin B or galactose oxidase failed to restore IFN-gamma production in defective cases. IFN-gamma was titrated by both bioassay and immunoradiometric assay, ruling out the possible release of inactive or altered IFN-gamma molecules. Normal levels of IFN-gamma were found in patients of patients with AT, as well as in two AT and two CVI cases, demonstrating heterogeneity of defects within these syndromes. Soluble inhibitors or cellular suppression of IFN-gamma were not observed in mixing experiments. The possibility that defective interaction between accessory cells and T lymphocytes might account for the poor response to the inducing agents was ruled out as no IFN-gamma was produced using a calcium ionophore--which bypasses this step--in seven patients with absolute IFN-gamma deficiency.
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PMID:Evidence that defective gamma interferon production in patients with primary immunodeficiencies is due to intrinsic incompetence of lymphocytes. 313 28

Avarol is a cytostatic and anti-human immunodeficiency virus (HIV) agent. In this study, the avarol caused induction of gamma-interferon (IFN-gamma) in buffy coat cells (human peripheral blood lymphocytes) is demonstrated by immunological and molecular biological techniques. IFN-gamma production was detected after a 24-hr incubation period with avarol; maximal production was obtained after 5 days in the presence of the optimal avarol concentration of 0.75 microgram/ml. Blotting experiments using human IFN-gamma cDNA and beta-actin cDNA containing plasmids showed that in the absence of avarol no IFN-gamma transcripts were present in lymphocytes. Already after a 24-hr incubation with avarol, IFN-gamma gene induction was detected, and maximal induction was found after a 5-day incubation period. The enhanced IFN-gamma production seems to be caused by a change at the transcriptional and/or post-transcriptional level, but not during subsequent nucleocytoplasmic transport of mRNA. This molecular event is specific, at least in relation to the expression of the beta-actin gene. Our studies demonstrate that avarol displays, besides its potential anti-tumor and anti-HIV activity, a potential immunomodulating effect.
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PMID:Induction of gamma-interferon by avarol in human peripheral blood lymphocytes. 313 18

Human immunodeficiency virus (HIV) infection is associated with abnormalities of both T-cell and B-cell immunity in patients with acquired immunodeficiency syndrome (AIDS). Previous studies demonstrated deficient production of the cytokines interleukin-1 (IL-1), interleukin-2 (IL-2), and gamma interferon (IFN-gamma). Tumor necrosis factor alpha and tumor necrosis factor beta have not been previously investigated in AIDS. In this study we demonstrate that peripheral blood mononuclear cells from patients with HIV infection who have either AIDS-related complex or acquired immunodeficiency syndrome are deficient in the production of tumor necrosis factor alpha and tumor necrosis factor beta. These cytokines, derived predominantly from monocytes or lymphocytes, respectively, function as immunoregulatory, antitumor, and antiinfective proteins. A deficiency in their production may therefore be responsible for many of the complications associated with HIV infection in patients with AIDS-related complex or acquired immunodeficiency syndrome.
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PMID:Tumor necrosis factors alpha and beta in acquired immunodeficiency syndrome (AIDS) and aids-related complex. 369 21

HIV-infected monocytes form highly invasive network on basement membrane matrix and secrete high levels of 92-kd metalloproteinase (MMP-9), an enzyme that degrades basement membrane proteins. In the present study, using matrigel as a model basement membrane system, we demonstrate that treatment of human immunodeficiency virus (HIV)-infected monocytes with interferon-gamma at 50 U/ml inhibited the ability of infected monocytes to form an invasive network on matrigel and their invasion through the matrigel matrix. These effects were associated with a significant reduction in the levels of MMP-9 produced by HIV-infected monocytes treated with interferon-gamma 1 day prior to infection with HIV as compared with that of untreated HIV-infected monocytes. Monocytes treated with interferon-gamma 1 day after HIV infection showed the presence of integrated HIV sequences; however, the levels of MMP-9 were substantially lower than those produced by monocytes inoculated with live HIV, heat-inactivated HIV, or even the control uninfected monocytes. Exposure of monocytes to heat-inactivated HIV did not result in increased invasiveness or high MMP-9 production, suggesting that regulation of metalloproteinase by monocytes was independent of CD4-gp120 interactions and required active virus infection. Furthermore, addition of interferon-gamma to monocytes on day 10 after infection inhibited MMP-9 production by more than threefold with no significant reduction of virus replication. These results indicate that the mechanism of interferon-gamma-induced down-regulation of MMP-9 levels and reduced monocyte invasiveness may be mediated by a mechanism independent of antiviral activity of IFN-gamma in monocytes. Down-regulation of MMP-9 in HIV-infected monocytes by interferon-gamma may play an important role in the control of HIV pathogenesis.
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PMID:Interferon-gamma inhibits HIV-induced invasiveness of monocytes. 749 70

Infection with several DNA or RNA viruses induces a state of increased sensitivity to cell lysis mediated by tumor necrosis factor (TNF), particularly in the presence of gamma interferon (IFN-gamma). Infection of human cells with the human immunodeficiency virus (HIV) may induce a similar phenomenon. However, TNF and IFN-gamma are known upregulators of HIV replication, raising the question of the potential role of these cytokines in the selective elimination of cells infected with this virus. The present study demonstrates that chronically infected U1 cells were killed with much greater efficiency by costimulation with TNF-alpha and IFN-gamma than their uninfected parental cell line U937. However, synergistic induction of viral expression also occurred in U1 cells as a consequence of treatment with the two cytokines. Cell death in U1 cells was not caused by the massive production of virions, in that costimulation with glucocorticoid hormones and TNF-alpha or IFN-gamma resulted in high levels of virion production without cytopathicity. To investigate the nature of the selective cytotoxic effect observed in U1 cells costimulated with TNF-alpha plus IFN-gamma, a panel of uninfected cell clones was generated by limiting dilution of U937 cells and tested for response to TNF-alpha and/or IFN-gamma. In contrast to the uncloned bulk parental U937 cell line, most uninfected cell clones showed a very high susceptibility to being killed by TNF-alpha and IFN-gamma. Similar findings were obtained when both infected U1 cells and several uninfected U937 cell clones were costimulated with an anti-Fas monoclonal antibody in the presence of IFN-gamma, although, unlike cells stimulated with TNF-alpha, cells treated with anti-Fas antibody did not express virus. Therefore, the increased susceptibility to cytokine-mediated lysis observed in cell lines infected with HIV is likely due to the selection of preexisting cell clones rather than viral infection.
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PMID:Cytokine-mediated induction of human immunodeficiency virus (HIV) expression and cell death in chronically infected U1 cells: do tumor necrosis factor alpha and gamma interferon selectively kill HIV-infected cells? 751 Nov 75

Induction of an IgE response involves several discrete steps: 1) induction of epsilon germ line transcription, 2) DNA recombination, and 3) mature RNA transcription/translation. Here we show that ligation of B cell CD58 by CD2, its natural ligand on T cells, or by mAb, provides a novel IL-4-dependent signal for the latter two steps. Highly purified human B cells were induced to produce IgE by costimulation with IL-4 and CD58 mAb. Although CD58 ligation alone was unable to induce epsilon germ-line transcription, in concert with IL-4-stimulated epsilon germ-line transcription it induced the appearance of productive epsilon transcripts and IgE production. The direct involvement of CD2 was demonstrated: B cells cultured with IL-4 plus murine T hybridoma cells transfected with human CD2 produced IgE. A CD40 Fc fusion protein had no effect on CD58-driven IgE production while inhibiting CD40-dependent responses. Furthermore, cells from patients with common variable immunodeficiency produced IgE in response to IL-4 plus CD40 mAb but not to IL-4 plus CD58 mAb. CD58-driven IgE synthesis was IFN-gamma independent and was not enhanced by exogenous IL-6. Functional differences between CD40 and CD58 IgE stimulation were demonstrated. Thus, the CD2:CD58 ligand/counterligand system provides an alternative pathway by which cell contact signaling may regulate IgE. Given the relative importance of CD2 triggering on mucosal T cells and the mucosal location of IgE production, this may be especially true on mucosal surfaces.
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PMID:CD58 (LFA-3) stimulation provides a signal for human isotype switching and IgE production distinct from CD40. 751 20

There still remains several unanswered questions concerning the pathogenesis of human immunodeficiency virus (HIV) infection. Interferons (IFNs), as well as other cytokines, are both dysregulated in HIV infection and serve as effector molecules that modulate the replicative capacity of HIV. Acid-labile IFN-alpha, an aberrant form of interferon earlier described in certain autoimmune diseases, has been detected in HIV-infected individuals. Conversely, a deficient expression of IFN-alpha may occur usually associated with HIV disease. Although conflicting findings have been reported on whether IFN-gamma, a product of activated T and natural killer (NK) cells, is elevated in the peripheral blood (PB) compartment, high levels of its expression have been observed in the germinal centers of the lymph nodes during HIV disease. IFN-alpha and IFN-beta have shown potent anti-retroviral effects in several in vitro systems of both acute and chronic HIV infection. These findings have served as the basis of the rationale for their therapeutic application, resulting in some positive effects at least in those patients with relatively high CD4+ T cell counts and healthy immune functions. Furthermore, IFN-alpha has shown important therapeutic effects on HIV-associated Kaposi's sarcoma (KS). Both suppressive and inductive effects on HIV replication in vitro have been described for IFN-gamma, whereas no clear clinical benefits have been reported following its administration to HIV-infected individuals. In conclusion, IFNs are involved in several pathogenic aspects of HIV infection and AIDS, and certain IFNs may serve as important tools to limit the spread of the virus and the progression of disease.
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PMID:Interferons in the pathogenesis and treatment of human immunodeficiency virus infection. 752 93


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