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)

A cytotoxic monoclonal antibody (anti-Fas mAb) against the 200-kDa cell surface Fas antigen, which is associated with the tumor necrosis factor (TNF) receptor, was examined for its in vitro activity on human immunodeficiency virus (HIV)-infected cells. It was found that both TNF and anti-Fas mAb selectively killed the chronically HIV-infected cells. Uninfected cells were less sensitive to the antibody than those infected with HIV. When the cells were cultured in the presence of anti-Fas mAb immediately after the HIV infection, the spread of HIV-infected cells was suppressed by the antibody. TNF augmented both the synthesis of HIV-specific mRNA in HIV-infected cells and formation of multinucleated giant cells. In contrast, the anti-Fas mAb did not augment HIV replication or enhance the HIV-induced formation of syncytia. The results indicated that anti-Fas mAb mimicks the cytocidal action of TNF but does not augment HIV replication.
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PMID:Anti-Fas monoclonal antibody is cytocidal to human immunodeficiency virus-infected cells without augmenting viral replication. 170 16

We have recently shown that, in unfractioned peripheral blood mononuclear cells (PBMCs), the cross-linking of CD4 molecules (CD4XL) is sufficient to induce T-cell apoptosis. However, the underlying mechanism for the CD4XL-mediated T-cell apoptosis is largely unknown. Several recent studies have shown that Fas antigen (Ag), a cell-surface molecule, mediates apoptosis-triggering signals. We show here that cross-linking of CD4 molecules, induced either by anti-CD4 monoclonal antibody (MoAb) Leu3a or by human immunodeficiency virus-1 (HIV-1) envelope protein gp160, upregulates Fas Ag expression as well as Fas mRNA in normal lymphocytes. Addition of the tyrosine protein kinase inhibitor genistein or of the immunosuppressive agent cyclosporin A abrogated these effects. The upregulation of Fas Ag closely correlated with apoptotic cell death, as determined by flow cytometry. In addition, CD4XL resulted in the induction of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the absence of interleukin-2 (IL-2) and IL-4 secretion in PBMCs. Both INF-gamma and TNF-alpha were found to contribute to Fas Ag upregulation and both anti-IFN-gamma and anti-TNF-alpha antibodies blocked CD4XL-induced Fas Ag upregulation and lymphocyte apoptosis. These findings strongly suggest that aberrant cytokine secretion induced by CD4XL and consequent upregulation of Fas Ag expression might play a critical role in triggering peripheral T-cell apoptosis and thereby contribute to HIV disease pathogenesis.
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PMID:Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion. 752 37

The Fas antigen (Fas), which is a cell surface protein belonging to the tumor necrosis factor receptor family, mediates apoptosis. To assess the contribution of Fas to the pathogenesis of retrovirus-induced immunodeficiency, we examined the kinetics of Fas expression on the lymphocytes during the course of murine acquired immunodeficiency syndrome (MAIDS) induced by a defective LP-BM5 murine leukemia virus. The Fas-positive cells were increased in proportion both in alpha beta T cells and B cells with the progression of MAIDS. The appearance of Fas-positive cells in alpha beta T cells preceded those in B cells during the course of MAIDS. Among alpha beta T cells, about half of the Thy1.2+ alpha beta T cells were positive for Fas, while almost all of Thy1.2- CD4+ alpha beta T cells were of the Fas-positive phenotype. The Fas-positive cells in MAIDS mice, especially unique Thy1.2-CD4+ alpha beta T cells, were easily rendered apoptotic by stimulation via Fas, indicating that Fas expressed on the lymphocytes is functional. Furthermore, concomitant infection with Mycobacterium avium in MAIDS mice caused a marked increase in Fas-positive cells accompanied by a severely impaired T cell reactivity to polyclonal stimuli. Taken together, these results suggest that possible participation of the Fas system in the pathogenesis of retrovirus-induced immunodeficiency.
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PMID:Increased Fas antigen expression in murine retrovirus-induced immunodeficiency syndrome, MAIDS. 752 40

The depletion of CD4+ T cells in AIDS is correlated with high turnover of the human immunodeficiency virus HIV-1 and associated with apoptosis. The molecular mechanism of apoptosis in HIV infection, however, is largely unknown. T-cell apoptosis might be affected by viral proteins such as HIV-1 Tat and gp120 (refs 10, 11). T-cell-receptor (TCR)-induced apoptosis was recently shown to involve the CD95 (APO-1/Fas) receptor. We show here that HIV-1 Tat strongly sensitizes TCR- and CD4(gp120)-induced apoptosis by upregulation of CD95 ligand expression. Concentrations of Tat found to be effective in cultures of HIV-1-infected cells were also observed in sera from HIV-1-infected individuals. Taken together, our results indicate that HIV-1 Tat and gp120 accelerate CD95-mediated, activation-induced T-cell apoptosis, a mechanism that may contribute to CD4+ T-cell depletion in AIDS.
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PMID:Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. 753 92

Mycobacterium avium-M. intracellulare, an intracellular parasite of mononuclear phagocytes, rarely causes disease in immunocompetent individuals. In contrast, in human immunodeficiency virus type 1-infected patients, M. avium-M. intracellulare can infect almost every tissue and organ. This suggests that immunocompetent individuals have a protective mechanism to control or prevent the infection. How mycobacterial may be killed by the host immune response is unclear. We have recently reported that induction of apoptosis of Mycobacterium bovis BCG-infected macrophages with ATP4- was associated with killing of the intracellular mycobacteria. In the present study, a long-term culture of M. avium-M. intracellulare-infected monocytes was used to further evaluate the interaction between M. avium-M. intracellulare and primary human monocytes. In our system, M. avium-M. intracellulare parasitized the human monocytes and appeared to replicate slowly over 14 days within the host cells. To examine the role of apoptotic mechanisms in survival or death of intracellular mycobacteria, M. avium-M. intracellulare-infected human monocytes were treated with a monoclonal antibody to Fas receptor (APO-1/CD95) or with various concentrations of H2O2. Although both of these exogenous agents induced monocyte apoptosis, optimal killing (65% reduction in CFU) of intracellular M. avium-M. intracellulare was observed only when M. avium-M. intracellulare-infected cells were treated with 10 mM H2O2. Fas-induced apoptosis did not affect M. avium-M. intracellulare viability. Our results suggest that not all stimuli of monocyte apoptosis induce killing of intracellular M. avium-M. intracellulare. Since release of H2O2 following phagocytosis of mycobacteria has been documented, H2O2-induced apoptotic death of M. avium-M. intracellulare-infected monocytes and its association with killing of the intracellular bacilli may be a physiological mechanism of host defense against M. avium-M. intracellulare.
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PMID:H2O2 induces monocyte apoptosis and reduces viability of Mycobacterium avium-M. intracellulare within cultured human monocytes. 855 Jan 91

Evidence is accumulating that T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals show accelerated cell death through apoptosis. We have recently demonstrated that the cross-linking of CD4 molecules (CD4XL) results in death of normal peripheral T cells through apoptosis and imbalanced cytokine secretion (ie, induction of tumor necrosis factor-alpha [TNF-alpha] and interferon-gamma [IFN-gamma] in the absence of interleukin-2 [IL-2] or IL-4 secretion). These upregulated cytokines (TNF-alpha/IFN-gamma) largely contributed to upregulation of the apoptosis-inducing cell surface molecule, Fas (APO-1/CD95) and apoptosis induction. The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL-induced T-cell apoptosis. The addition of vesnarinone to peripheral blood mononuclear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apoptosis. This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen upregulation. However, vesnarinone did not block effects of exogenously supplemented TNF-alpha/IFN-gamma on Fas induction. These data suggest that vesnarinone inhibits CD4XL-induced TNF-alpha/IFN-gamma secretion, thereby blocking subsequent Fas upregulation and apoptosis induction. Given the potent pathogenic role of imbalanced cytokine secretion observed in HIV-infection, an agent such as vesnarinone may be of therapeutic value in slowing disease progression.
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PMID:Inhibition of CD4 cross-linking-induced lymphocytes apoptosis by vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas expression and apoptosis by blocking cytokine secretion. 863 Mar 99

Profound immunodeficiency in multicentric Castleman's disease has already been elucidated. In the present study, we investigated CD45RO and Fas antigen expression and apoptosis by T cells in three patients with this disease. T cell expression of CD45RO and Fas antigen was increased in two of the three patients, indicating in vivo lymphocyte activation. Apoptosis of T cells from the two patients with increased CD45RO and Fas antigen expression occurred after overnight culture in the presence of pokeweed mitogen. Occurrence of apoptosis was indicated by DNA laddering and nuclear chromatin condensation. Peripheral blood mononuclear cells from the two MCD patients revealed spontaneous apoptosis following 3 days of culture by quantitative assay using flow cytometry. These findings show that T cells are activated in some patients with multicentric Castleman's disease and suggest that this activation may promote apoptosis.
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PMID:Apoptosis of T cells in multicentric Castleman's disease. 863 86

Human immunodeficiency syndrome (HIV) infection leads to a progressive loss of T-cell-mediated immunity associated with T-cell apoptosis. We report here that CD4+ and CD8+ T cells from HIV-1-infected persons are sensitive to Fas (CD95/APO-1)-mediated death induced either by an agonistic anti-Fas antibody or by the physiologic soluble Fas ligand, although showing no sensitivity to tumor necrosis factor alpha-induced death. CD4+ and CD8+ T-cell apoptosis induced by Fas ligation was enhanced by inhibitors of protein synthesis and was prevented either by a soluble Fas receptor decoy or an antagonistic anti-Fas antibody. Fas-mediated apoptosis could also be prevented in a CD4+ or CD8+ T-cell-type manner (1) by several protease antagonists, suggesting the involvement of the interleukin-1beta (IL-1beta)-converting enzyme (ICE)-related cysteine protease in CD4+ T-cell death and of both a CPP32-related cysteine protease and a calpain protease in CD8+ T-cell death; and (2) by three cytokines, IL-2, IL-12, and IL-10, that exerted their effects through a mechanism that required de novo protein synthesis. Finally, T-cell receptor (TCR)-induced apoptosis of CD4+ T cells from HIV-infected persons involved a Fas-mediated death process, whereas TCR stimulation of CD8+ T cells led to a different Fas-independent death process. These findings suggest that Fas-mediated T-cell death is involved in acquired immunodeficiency syndrome (AIDS) pathogenesis and that modulation of Fas-mediated signaling may represent a target for new therapeutic strategies aimed at the prevention of CD4+ T-cell death in AIDS.
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PMID:Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists. 865 8

CD4+ T-lymphocyte apoptosis has been associated with human immunodeficiency virus (HIV)-1 infection in vitro, paralleling the expression of Fas (APO-1, CD95) on peripheral blood mononuclear cells from patients with HIV disease. However, the link between Fas induction, T-cell activation, and cell death is unclear. We document, for the first time, marked upregulation of expression of mRNA for the ligand for Fas in peripheral blood mononuclear cells from HIV seropositive individuals, and demonstrate the ability of HIV infection to induce such expression in CD4+ T cells in vitro. We also define the relevance of this expression to HIV-mediated CD4+ T cell death. Our ability to downregulate Fas ligand message and suppress HIV-mediated apoptosis with aurintricarboxylic acid, a clinically used protease inhibitor with known activity against programmed cell death in other systems, may open up a new area of therapy for HIV infection.
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PMID:HIV-1 upregulates Fas ligand expression in CD4+ T cells in vitro and in vivo: association with Fas-mediated apoptosis and modulation by aurintricarboxylic acid. 867 12

CD4+ T-cell depletion in AIDS patients involves induction of apoptosis in human immunodeficiency virus (HIV)-infected and noninfected T cells. The HIV type 1 (HIV-1)-transactivating protein Tat enhances apoptosis and activation-induced cell death (AICD) of human T cells. This effect is mediated by the CD95 (APO-1/Fas) receptor-CD95 ligand (CD95L) system and may be linked to the induction of oxidative stress by Tat. Here we show that HIV-1 Tat-induced oxidative stress is necessary for sensitized AICD in T cells caused by CD95L expression. Tat-enhanced apoptosis and CD95L expression in T cells are inhibited by neutralizing anti-Tat antibodies, antioxidants, and the Tat inhibitor Ro24-7429. Chimpanzees infected with HIV-1 show viral replication resembling early infection in humans but do not show T-cell depletion or progression towards AIDS. The cause for this discrepancy is unknown. Here we show that unlike Tat-treated T cells in humans, Tat-treated chimpanzee T cells do not show downregulation of manganese superoxide dismutase or signs of oxidative stress. Chimpanzee T cells are also resistant to Tat-enhanced apoptosis, AICD, and CD95L upregulation.
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PMID:Resistance of chimpanzee T cells to human immunodeficiency virus type 1 Tat-enhanced oxidative stress and apoptosis. 870 90


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