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)

Long-term therapy of AIDS patients with 3'-azido-3'-deoxythymidine (AZT) remains of concern because of resulting hematopoietic toxicity. While the mechanism(s) of this toxicity remains elusive, alternative strategies are being developed to reduce these toxic effects, including combination therapy with nonmyelotoxic antihuman immunodeficiency virus drugs and/or administration of protective or rescue agents, including cytokines and growth factors. By using a particularly relevant human CD34+ liquid culture system, the unique profiles of dideoxynucleoside (ddN) toxicities to both proliferation and differentiation were demonstrated, with decreased potencies in the order of 3'-fluoro-3'-deoxythymidine (FLT) = 3'-amino-3'-deoxythymidine (AMT) = 2',3'-dideoxycytidine > AZT for inhibition of proliferation and in the order of FLT = AMT > AZT >> 2',3'-dideoxycytidine for inhibition of hemoglobin synthesis. Hemin selectively protected erythroid-lineage human burst-forming unit-erythroid cells from AZT- and AMT-induced inhibition but had no effect on FLT toxicity under similar conditions. Myeloid-lineage human CFU-granulocyte-macrophages were also not protected by hemin against all three ddN analogs. The simultaneous exposure of cells to hemin and AZT resulted in a complete protection of both cell proliferation and hemoglobin synthesis. In contrast, in reversal studies only the inhibition of the percentage of hemoglobin-synthesizing cells returned to control levels, but the inhibition of proliferation of cells previously exposed to AZT was not reversed by hemin. These studies further define the unique and multifactorial mechanism(s) of ddN-induced toxic effects during hematopoietic development of pluripotent stem cells and suggest that the use of hemin could be beneficial in alleviating the toxicity of certain ddN analogs.
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PMID:Protection and rescue from 2',3'-dideoxypyrimidine nucleoside analog toxicity by hemin in human bone marrow progenitor cells. 878 4

Flow cytometry represents an interesting methodologic approach to human neutrophil biology and pathology. Several aspects of neutrophil activation can be evaluated by flow cytometry: phagocytosis, respiratory burst (superoxide anion generation, intracellular hydrogen peroxide production), intracellular pH, actin polymerization, membrane potential, aggregation, cytotoxicity, degranulation, and surface marker expression. In several instances whole blood methods have been developed and have been shown to be very specific and sensitive. Neutrophils can easily be distinguished from other circulating cells, including eosinophils, and methods for the evaluation of neutrophil phagocytosis and hydrogen peroxide production are currently used. In addition whole blood procedures for the determination of the expression of neutrophil function-associated surface antigens have been recommended in order to avoid the artifactual changes resulting from isolation methods. Purified neutrophil have to be used to study other parameters such as actin polymerization and cytotoxicity. Flow cytometry permits a multiparametric evaluation of neutrophil functions, and advances in software technology facilitate a wide variety of choices for the handling, storage, and evaluation of data. The applications of flow cytometry in human neutrophil diseases include the diagnosis of chronic granulomatous disease and leukocyte adhesion syndrome types 1 and 2, and the evaluation of granulocyte biology in several clinical conditions such as immunodeficiency conditions, recurrent infections, hematologic diseases, and noninfectious diseases caused by uncontrolled neutrophil activation.
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PMID:Applications of flow cytometry in the study of human neutrophil biology and pathology. 879 47

We report a patient with systemic vasculitis who developed a Pneumocystis carinii pneumonia whilst he was on steroid n cyclophosphamide treatment. Severe lymphopenia was noted with a CD4 count of 0.023 x10(9)/1 with no evidence of Human Immunodeficiency virus infection. A literature review of recent reports about this particular topic reveals that the development of lymphopenia in patients under immunosuppressor treatment is a fact of a paramount importance. In that sense, a periodic monitorization of both the granulocyte and the lymphocyte count is widely recommended in patients under cytotoxic treatment. A dose adjustment or even suppression of drug administration would be necessary if severe lymphopenia was observed.
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PMID:[Pneumocystis carinii pneumonia. Complications of cytotoxic treatment in a systemic vasculitis]. 880 72

Since modulation of the glutathione (GSH) level has been implicated in the regulation of human immunodeficiency virus (HIV) transcription and expression, we have undertaken an analysis of the effect of sodium valproate (VPA) on HIV-1 replication. VPA, which is an anti-epileptic drug in widespread use in clinical medicine, has been shown to depress the activity of GSH reductase, an enzyme required for maintaining high cellular levels of reduced GSH. The effect of this drug on HIV-1 replication has been studied in primary infected cells, i.e. peripheral blood mononuclear cells (PBMC) and monocyte/macrophages, in the CEM-SS cell line, and in chronically infected stimulated and non-stimulated U1 cells. We have shown that VPA markedly enhanced viral replication in all infected cells tested. Virus production was induced in U1 cells by VPA treatment and the stimulatory effects of tumour necrosis factor-alpha, interleukin-6 and granulocyte/macrophage colony-stimulating factor were augmented. The LTR-driven gene expression in Jurkat T cells was increased. However, the elevated viral production did not correlate with the effect of VPA on the intracellular GSH level. Thus, VPA stimulated in vitro HIV-1 replication in acutely and chronically infected cells and enhanced LTR-driven gene expression. These effects were observed for concentrations that are reached in the plasma of VPA-treated patients. Therefore, although the clinical significance of these data remains to be demonstrated, these results should be considered in the choice of an anticonvulsant drug in HIV-infected individuals.
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PMID:Sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels. 881 Sep 95

Despite the fact that nucleoside analogues, such as aciclovir and ganciclovir, and DNA-polymerase inhibitors, such as foscarnet, have a proven antiviral effect on oropharyngeal-Epstein-Barr virus (EBV) replication, they have been unable to show any effect on the severity or duration of infectious mononucleosis (IM), a condition for which there is currently no established treatment. Clinical symptoms may be due to an EBV-induced polyclonal humoral, as well as cellular, immunoreactivity with limited pathology caused by viral replication itself. However, despite an extensive immune response, 90% of tested IM patients (n = 36) had a spontaneous outgrowth of in vivo EBV-infected B-lymphocytes at onset of disease, indicating lack of specific EBV-restricted cellular cytotoxicity at this time. Establishment of an EBV-specific T-lymphocyte response occurred 90-180 days after onset of disease (human leukocyte antigen-restricted cytotoxicity against EBV-infected B-cells). Thus, development of a specific cytotoxic response was a gradual and slow process. Assessment of cytokine pattern, at the single cell level, was performed by immunocytochemical technique and by enzyme-linked immunosorbent assay. This revealed an increased production of interleukin (IL)-2, interferon (IFN)-gamma, IL-6 and tumour necrosis factor (TNF) beta in all IM patients. Those with disseminated disease were characterized by lack of IFN-gamma production. This loss was selective since in vitro stimulation with superantigen, such as streptococcal pyrogenic exotoxin A, induced a normal response. These patients lacked signs of EBV-specific T-cell cytotoxicity in vitro. Treatment with intravenous or subcutaneous IFN-gamma, 1.5 MU every second day, in combination with intravenous immunoglobulin G (0.5 g/kg three times per week) and oral aciclovir, 800 mg 5 times daily, has shown promising results in some patients. Cytokine production in tonsil tissue in 4 patients with fulminant IM and respiratory tract obstruction showed a concomitant expression of IL-2, IFN-gamma, IL-6, TNF beta, transforming growth factor (TGF) beta 1-3, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, IL-4 IL-1alpha, IL-beta and TNF alpha. The number of IL-2, IFN-gamma, IL-6 and TNF beta producing cells was significantly higher compared to tonsil tissue obtained from children with tonsillar hypertrophy. Thus, IM is associated with extensive local cytokine production. It is suggested that this extensive cytokine production is closely involved in the pathology of IM and that patients with atypical IM have a dysregulation in the cytokine network. However, the mechanism by which EBV-infected B-lymphocytes triggers this cytokine cascade is still unknown. These findings show the need for evaluation of patients with immunodeficiency and EBV-induced lymphoproliferative disorders and perhaps the introduction of new immunoregulatory treatment strategies.
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PMID:Clinical and immunological considerations in Epstein-Barr virus-associated diseases. 886 Mar 57

Interleukin-1 (IL-1) is elevated in brain tissue of individuals who died with acquired immunodeficiency syndrome (AIDS) and other diseases where this cytokine likely stimulates reactive astrocytosis. IL-1 stimulates, among others, production of interleukin-6 (IL-6), granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) in cultured astrocytes and astrocytoma cell lines. These and other cytokines may contribute to the neuropathogenesis after infection by human immunodeficiency virus type-1 (HIV-1). For example, concentration of TNF-alpha is increased in brain tissue of individuals who died with AIDS and correlates with the severity of AIDS Dementia Complex (ADC). TNF-alpha and IL-6 have been immunocytochemically detected in brain tissue but they have not been localized to astrocytes. We, therefore, examined the expression of IL-6, GM-CSF, and TNF-alpha in human primary astrocytes and astrocytoma cell lines U251 and 253 exposed to IL-1 in serum-free medium. In addition, we immunocytochemically assayed GM-CSF expression by astrocytes in brain tissue (n = 8). The three cytokines were differentially induced in cultured astrocytes by IL-1. The astrocytoma cell lines recapitulated cytokine-specific patterns of expression in astrocytes. The patterns were characterized by amounts produced, compartmentalization (intra- and/or extracellular), time courses, and optimal doses of IL-1 for induction. GM-SCF-like immunoreactivity was detected in some but not all, GFAP+ cells. GM-CSF+/GFAP+ cells were detected in only three of seven cases containing GM-CSF immunoreactivity. Thus, a discrepancy may exist between human astrocytic cytokine expression in vitro and in tissue. Novel methods therefore may need to be developed to recapitulate in vitro the heterogeneity of astrocytic cytokine expression in AIDS and other brain tissue.
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PMID:Distinct expressions of three cytokines by IL-1-stimulated astrocytes in vitro and in AIDS brain. 890 54

CD1a+ dendritic cells (DC) differentiate from a major population of nonadherent CD13(hi)lin- cells that appear when human cord blood CD34+ hematopoietic progenitor cells are cultured with stem-cell factor, granulocyte/macrophage (MA) colony-stimulating factor, and tumor necrosis factor-alpha (TNF-alpha) for 5 days. CD13hilin- cells, which also comprise MA and granulocyte precursors, are CD4+ and can thus be targets of human immunodeficiency virus (HIV). Low replication was noted when these day 5 cells were infected with lymphotropic HIV-1LA1 (p24: < or = 4 ng/mL on day 8 postinfection [PI]), while high virus production occurred with MA-tropic HIV-1Ba-L, HIV-1Ada, or HIV-1-m-n. (p24: 50 to > or = 1,000 ng/mL). Strong cytopathicity (CPE) was then observed in nonadherent cells as in adherent MA. However, FACS analysis on day 7 PI showed that HIV did not affect differentiation of DC that survived CPE: apart from CD4 downmodulation related to HIV production, overall expression of CD40, CD80, and CD86 costimulatory molecules, and of HLA-DR, was unchanged relative to controls. At that time, the capacity of DC from HIV-infected cultures to stimulate the mixed leukocyte reaction was only altered less than 10-fold. Immunocytochemistry on day 7 PI showed that most HIV-infected cells were included in syncytia that were stained by anti-CD1a, anti-S100, and anti-CD14 antibodies, indicating that syncytia consisted of DC and cells of the MA lineage. Polymerase chain reaction analysis of FACS-sorted CD1a+ cells confirmed that they harbored then HIV DNA. Viral DNA was also detected in CD1a+ DC from noninfected cultures that had been exposed to HIV only after sorting. Therefore, we examined whether in infected cultures DC precursors were infected at the onset or if virus spread later from other infected cells to differentiated DC. This was answered by showing that, 24 hours postexposure to HIV, viral DNA was preferentially detected in day 5 sorted CD13hilin- versus CD13hilin- cells, and that it was found in the CD1a+ progeny of CD13(hi)lin- cells 48 hours later. In addition, HIV replication did not affect myeloid clonogenic progenitors in day 0 to day 7 PI cultures, although viral DNA was detected in colony-forming unit-granulocyte/macrophage (CFU-GM)/CFU-M colonies derived from day 3 and 7 PI cultures. Thus, precursors of DC and their progeny are susceptible to HIV in vitro, but, apart from CPE, the effect of virus production on DC differentiation or function is limited.
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PMID:The effect of in vitro human immunodeficiency virus infection on dendritic-cell differentiation and function. 894 57

Deficiency of the cytokine receptor common gamma chain (gamma c) results in abnormal lymphoid development and a severe immunodeficiency disease due to the combined loss of the receptors for interleukins (IL)-2, -4, -7, -9, and -15. We have observed the development of secondary hematopoiesis with circulating hematopoietic progenitor cells in adult mice harboring a null mutation in gamma c. These extramedullary changes were not secondary to bone marrow failure or to an inability to maintain circulating blood counts. These results suggested that gamma c-dependent cytokine signaling pathways modulate hematopoietic development. An intrinsic defect in gamma c- hematopoietic stem cell commitment appeared unlikely, as fetal liver hematopoiesis was unaltered in gamma c- embryos. Furthermore, the absence of natural killer cells in gamma c- mice was not responsible for the observed hematopoietic changes. Peripheral TCR alpha beta T cells from gamma c- mice were characterized by an activated phenotype (CD62Llo, CD44hi, CD69hi) and showed increased levels of transcripts for hematopoietic stimulating cytokines, including IL-3 and granulocyte/macrophage-colony-stimulating factor. A predominance of these cells was detected in the bone marrow, suggesting a role for residual T cells in the enhanced hematopoiesis. Strikingly, the elimination of residual T cells from gamma c- mice reduced splenic and circulating hematopoietic precursor frequencies to normal levels. These results clearly implicate a deregulated TCR alpha beta T cell population in the observed hematopoietic changes in gamma c- mice, and emphasize the importance of gamma c-dependent cytokine interactions in modulating mature T cell responses.
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PMID:Deregulated TCR alpha beta T cell population provokes extramedullary hematopoiesis in mice deficient in the common gamma chain. 913 Jun 55

Feline bone marrow cells treated with the soybean agglutinin (SBA) lectin are separated into two populations, the agglutinated SBA(+) fraction containing predominantly cells of myeloid origin and the nonagglutinated SBA(-) fraction consisting of cells primarily of the erythroid lineage. FACScan analyses revealed a clear distinction of the cells based on their light scattering properties, i.e., large cells and cells with high granularity were found in the SBA(+) fraction, whereas cells having a low forward light scatter and side light scatter were found in the SBA(-) fraction. Colony-forming assays showed colony-forming unit-granulocyte/monocyte (CFU-GM) cells to have a strong affinity for SBA because these were found almost entirely in the SBA(+) fraction; in contrast, burst-forming unit-erythroid (BFU-E)-forming cells were concentrated in the SBA(-) fraction. When the marrow was fractionated by counterflow centrifugal elutriation (CCE), a differential binding to SBA among the CFU-GM forming cells was found. The SBA(-) fractions of cells collected at 21 and 25 ml/min contained primarily BFU-E forming cells, similar to that observed with whole marrow; the later CCE fractions, those collected at 32 ml/min and the rotor off fraction, when treated with SBA showed a small but significant number of CFU-GM cells in the SBA(-) fraction. T lymphocytes were found predominantly in the SBA(+) fractions of whole bone marrow and the CCE fractions. Successful autologous marrow transplants were performed with the early CCE SBA(-) fractions. The latter cells were used for our initial transplant attempts because ongoing studies in our laboratory had shown these cells to be free of any viral-containing cells when the marrow had been obtained from animals infected with the feline immunodeficiency virus. In summary, although SBA treatment of feline marrow yields a marked separation of CFU-GM and BFU-E progenitors, select CCE SBA(-) fractions contain stem cells capable of providing hematopoietic reconstitution of lethally irradiated animals.
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PMID:Fractionation of feline bone marrow with the soybean agglutinin lectin yields populations enriched for erythroid and myeloid elements: transplantation of soybean agglutinin-negative cells into lethally irradiated recipients. 927 20

The transplantation of hematopoietic and lymphopoetic stem and progenitor cells has become a standard procedure for the treatment of many malignant diseases. Autologous stem cells are derived from the patient himself, allogeneic cells from an HLA-identical or HLA-compatible family or unrelated donor. Hematopoietic stem cells can be obtained from bone marrow, blood and fetal cord blood. After 3 to 5 days treatment, the granulocyte-colony stimulating factor (G-CSF) mobilizes stem- and progenitor cells from the marrow into the blood. This method is now standard in autologous transplantation and is increasingly preferred in allogeneic transplantation. The time to hematopoietic recovery is shorter with blood stem cells than with bone marrow cells. With myeloablative high dose therapy followed by stem cell transplantation, long term disease free survival is possible in many cases and great proportions of patients can be cured (see part II). Improvements of supportive care have reduced toxicity of treatment substantially, however severe complications still occur at oropharynx, gastrointestinal tract, liver, lung, skin, kidney, urinary tract and nervous system. After allogeneic transplantation immunocompetent donor cells can react with the recipients tissue. In HLA-identical donor and recipients differences in the minor histocompatibility antigens account for this graft-versus-host-reaction (GvH), which is mainly mediated by transplanted T-cells. The GvH-reaction can affect skin, liver, gut and other organs and cause clinically relevant GvH-disease (GvHD). The GvHD is more severe in HLA-mismatched or unrelated transplantations. Immunodeficiency and organ dysfunction due to GvHD may predispose infections and impair the outcome of transplantation. Unrelated cord blood stem cells may have a minor risk of inducing acute GvHD, as stem and T-cells are immature. After allogeneic stem cell transplantation, the relapse rate of leukemia or lymphoma is significantly reduced by immunoreactive cells:graft-versus-tumor (GvT) or graft-versus-leukemia effect (GvL).
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PMID:[Transplantation of hematopoietic stem cells. I: Definitions, principle indications, complications]. 934 Apr 73


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