Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

With progressive disease, the majority of patients with human immunodeficiency virus (HIV) infection develop bone marrow failure with anemia, leukopenia, and thrombocytopenia, the cause of which has not yet been clarified. Besides direct infection of bone marrow progenitor cells and immune-mediated cytolysis, the action of inhibitory cytokines, like transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha), has to be discussed with regard to their pathophysiological role in HIV-induced bone marrow failure. Therefore, the influence of recombinant human TGF-beta and TNF-alpha on colony growth of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells from the bone marrow of HIV-1-infected persons and normal controls was assessed in methylcellulose cultures. Both cytokines inhibited the colony formation of hematopoietic progenitor cells from HIV-positive persons. When added to unseparated bone marrow cells from HIV-infected persons and normal controls, the 50% inhibition (ID50) of BFU-E by TGF-beta occurred at 1.3 ng/ml and 3.7 ng/ml, respectively, while the ID50 of CFU-GM occurred at 15.5 ng/ml and 142.7 ng/ml. Concentrations of TNF-alpha, causing 50% inhibition of colony formation by bone marrow cells from HIV-infected or noninfected individuals were 6.3 U/ml and 17.0 U/ml for BFU-E, and 24.4 U/ml and greater than 3,000 U/ml for CFU-GM, respectively. The ID50 of the CFU-GEMM growth was below the lowest concentration of both cytokines tested. The suppressive effects were specifically abolished by antibodies against TGF-beta and TNF-alpha, thus confirming that the inhibitory activities were due to the cytokine preparation used.
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PMID:Effect of recombinant human transforming growth factor beta and tumor necrosis factor alpha on bone marrow progenitor cells of HIV-infected persons. 204 59

Replication of various strains of human immunodeficiency virus can be increased in vitro by certain colony-stimulating factors (CSFs), but the protective effect of zidovudine (AZT) on macrophages is not antagonized in the presence of those factors--specifically, in the presence of granulocyte-macrophage CSF (GM-CSF). In clinical studies, GM-CSF given alone dramatically increased counts of white cells, particularly neutrophils and band cells. Very small doses of GM-CSF, self-administered subcutaneously, restored white cell production in leukopenic patients with AIDS. Combination treatment with AZT and GM-CSF in AZT-intolerant patients allowed resumption of AZT treatment and increased bone marrow cellularity. Treatment of anemic patients who have AIDS or AIDS-related complex with recombinant human erythropoietin (r-HuEPO) produced promising results. After 12 weeks of treatment with r-HuEPO, the need for transfusions to maintain hematocrit values within the normal range was reduced significantly or eliminated in patients with low baseline levels of endogenous erythropoietin. Studies combining AIDS chemotherapy with CSF or erythropoietin treatment are proposed.
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PMID:Management of the hematologic complications of human immunodeficiency virus infection. 223 34

Increased extracellular concentrations of uridine (Urd) have been reported to reduce, in vitro, azidothymidine (AZT)-induced inhibition of human granulocyte-macrophage progenitor cells without impairment of its antihuman immunodeficiency virus (HIV) activity. Because of the clinical toxicities associated with chronic Urd administration, the ability of benzylacyclouridine (BAU) to effect, in vivo, AZT-induced anemia and leukopenia was assessed. This agent inhibits Urd catabolism and, in vivo, increases the plasma concentration of Urd in a dose-dependent manner, without Urd-related toxicity. In mice rendered anemic and leukopenic by the administration of AZT for 28 days in drinking water (1.5 mg/mL), the continued administration of AZT plus daily BAU (300 mg/kg, orally) partially reversed AZT-induced anemia and leukopenia (P less than .05), increased peripheral reticulocytes (to 4.9%, P less than .01), increased cellularity in the marrow, and improved megaloblastosis. When coadministered with AZT from the onset of drug administration, BAU reduced AZT-induced marrow toxicity. In vitro, at a concentration of 100 mumol/L, BAU possesses minimal anti-HIV activity and has no effect on the ability of AZT to reverse the HIV-induced cytopathic effect in MT4 cells. The clinical and biochemical implications of these findings are discussed.
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PMID:Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity. 225 94

The relative antiviral potencies of five nucleotide heterodimers of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-3'-deoxythymidilyl-(5',5')-2'-3'-dideoxy-5'-adenylic acid (AZT-P-ddA), 3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI), and the corresponding 2-cyanoethyl congeners AZT-P(CyE)-ddA and AZT-P(CyE)-ddI, were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The homodimer 3'-azido-3'-deoxythymidilyl-(5',5')-3'-azido-3'-deoxythymidilic acid (AZT-P-AZT) was also included for comparison. The potencies of the compounds were AZT-P-ddA greater than or equal to AZT-P-ddI greater than AZT-P(CyE)-ddA greater than or equal to AZT-P(CyE)-ddI greater than or equal to AZT greater than AZT-P-AZT. Whereas AZT-P-ddA and AZT-P-ddI had in vitro therapeutic indices greater than that of AZT, the homodimer of AZT had a low therapeutic index. AZT-P-ddI exhibited the lowest toxicity in peripheral blood mononuclear, Vero, or CEM cells. Combination studies between AZT and 2',3'-dideoxyinosine (ddI) at nontoxic concentrations indicated a synergistic interaction at a drug ratio of 1:100. At higher ratios (1:500 and 1:1,000), the interactions were synergistic only at concentrations that produced up to 75% virus inhibition. At higher levels of antiviral effects, this combination was antagonistic, as determined by the multiple drug effect analysis method. AZT-P-ddI was about 10-fold less toxic than AZT to human granulocyte-macrophage progenitor cells. However, no significant difference was apparent when the compounds were evaluated against cells of the erythroid lineage. The greater antiviral activity and lower toxicity of this compound could not be attributed to the extracellular decomposition of the dimer in media at physiological temperature and pH. However, in acidic solutions, AZT-P-ddI decomposed in a pH-dependent manner. Advanced preclinical studies with this heterodimer of two clinically effective antiretroviral agents should be considered.
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PMID:Activities of 3'-azido-3'-deoxythymidine nucleotide dimers in primary lymphocytes infected with human immunodeficiency virus type 1. 239 66

The CD4 molecule is a high-affinity cell-surface receptor for the human immunodeficiency virus (HIV-1) and a soluble truncated form of CD4 produced by recombinant DNA technology is a potent inhibitor of HIV-1 replication and HIV-1-induced cell fusion in vitro. Rhesus monkeys infected with the simian immunodeficiency virus of macaques (SIVMAC), a virus closely related to HIV-1, develop an AIDS-like syndrome, and so provide an important model for the evaluation of potential AIDS therapies. We have assessed the therapeutic effect of recombinant soluble CD4 in SIVMAC-infected rhesus monkeys. Virus was readily isolated from peripheral blood lymphocytes and bone marrow cells of these animals before starting treatment with soluble CD4, but became difficult to isolate soon after treatment had begun. Moreover the diminished growth of both granulocyte-macrophage and erythrocyte progenitor colonies from the bone marrow of these monkeys rose to normal levels during treatment. These findings indicate that soluble CD4 could prove valuable in the treatment of AIDS.
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PMID:Effect of recombinant soluble CD4 in rhesus monkeys infected with simian immunodeficiency virus of macaques. 253 40

Therapy of patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) with azidothymidine (AZT) and 2'-3'-dideoxycytidine (ddC) is complicated by severe anemia, neutropenia, and thrombocytopenia, the cause of which is unknown. We therefore tested the effect of AZT, ddC, and an additional 2'-3'-dideoxynucleoside analogue, 2'-3'-dideoxyadenosine (ddA), on the hematopoietic progenitor cells derived from the bone marrow of normal persons and patients with AIDS/ARC. All three substances dose-dependently inhibited the in vitro colony formation of the pluripotent (CFU-GEMM), as well as the erythroid (BFU-E) and granulocyte-macrophage progenitor cells (CFU-GM). The 50% inhibition of normal progenitors by AZT occurred at 0.13 microM for CFU-GEMM, 0.32 microM for BFU-E, and 1.9 microM for CFU-GM, by ddA at 15 microM for CFU-GEMM, 40 microM for BFU-E, and 140 microM for CFU-GM. ddC was the most toxic agent and already inhibited 71% +/- 16% (mean +/- standard error of the mean [SEM]) of CFU-GEMM and 52% +/- 22% of BFU-E at 0.1 microM, whereas the 50% inhibition of CFU-GM was reached at 0.3 microM. Hematotoxicity occurred at concentrations lower than necessary to inhibit the human immunodeficiency virus (HIV), except for ddA, which is 100 times less toxic than AZT whereas its antiviral effect is only 10 times less. The inhibition of progenitor cells from AIDS patients by the 2'-3'-dideoxynucleosides was comparable to normal progenitors, except for a higher sensitivity of AIDS-derived CFU-GEMM and BFU-E to AZT.
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PMID:Inhibitory effect of azidothymidine, 2'-3'-dideoxyadenosine, and 2'-3'-dideoxycytidine on in vitro growth of hematopoietic progenitor cells from normal persons and from patients with AIDS. 254 17

HPA-23 is a competitive inhibitor of the RNA-dependent DNA polymerase (reverse transcriptase) of the human immunodeficiency virus (HIV). It may therefore potentially benefit patients with HIV infection. This study aimed at defining the haematopoietic toxicity of this drug and particularly its effects on the normal human granulocyte-macrophage progenitor cells (GM-CFU). Our in vitro studies, in semi-solid agar, have shown an inhibitory effect of increasing concentrations of HPA-23 on colony and cluster formation. This effect is probably dose-dependent. An almost complete inhibition of colony formation was observed at doses of more than 20 micrograms/ml. Regarding cluster formation, a similar although much more progressive inhibitory effect was found. Our experimental data should be extrapolated with caution to clinical situations. However, they must be kept in mind for optimal design of HPA-23 therapy in HIV infected patients.
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PMID:Toxicity of HPA-23 (ammonium-21-tungsto-9-antimoniate) for normal human myeloid progenitor cells (GM-CFU) in vitro. 259 Jul 21

The aim of this study was to test whether colony stimulating factors (CSF) and other cytokines facilitate the recovery of a variety of immunohematopoietic functions in lethally irradiated mice undergoing bone marrow transplantation (BMT). Two experimental systems were employed: (a) lethally irradiated mice transplanted with syngeneic or T cell-depleted semi-allogeneic bone marrow (BM) cells (0.1-10 x 10(6)), subsequently treated by multiple doses of cytokines; and (b) lethally irradiated mice transplanted with BM cells that had previously been cultivated with cytokines. The cytokines used were: pure natural mouse interleukin-3 (IL-3); recombinant mouse granulocyte-macrophage CSF (rGM-CSF); recombinant human interleukin-2 (rIL-2); and crude cytokine preparations obtained from the culture supernatants of murine leukemia WEHI-3b cells (containing mainly IL-3), and of phorbol myristate acetate (PMA)-stimulated EL4 leukemia cells and concanavalin A-stimulated rat splenocytes (each containing a multitude of cytokines). For BM cultures (1-9 days), the cytokines were used at a dosage of 1-100 U/ml; for in vivo treatment, 2 x 10(2)-5 x 10(4) units were administered intraperitoneally and subcutaneously at different schedules for varying periods (1-3 weeks). The following parameters were tested 1-10 weeks post-BMT: white blood cell count, colony formation in agar and in the spleen of lethally irradiated mice, proliferative responses to mitogens and alloantigens, allocytotoxicity and antibody production (serum agglutinins and plaque-forming cells) against sheep red blood cells. Under appropriate conditions, cytokine treatment either in vitro or in vivo significantly enhanced (2- to 50-fold compared with controls) most functions tested at 2-8 weeks post-BMT, and shortened the time interval required for full immunohematopoietic recovery by 2-5 weeks. In recipients of semi-allogeneic, T lymphocyte-depleted BM no evidence of graft-versus-host disease was found. It is suggested that judicious application in vitro and/or in vivo of certain pure cytokines (e.g. GM-CSF, IL-3) or cytokine 'cocktails' might be beneficial in enhancing hematopoiesis and in the treatment of immunodeficiency associated with BMT.
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PMID:In vitro and in vivo cytokine-induced facilitation of immunohematopoietic reconstitution in mice undergoing bone marrow transplantation. 304 95

Patients infected with the human immunodeficiency virus (HIV) often present with neutropenia. To elucidate the mechanism(s) of this HIV-related neutropenia, we assessed the proliferative capacity of the granulocyte-macrophage progenitor cell (CFU-GM) from the bone marrow (BM) of 78 patients within the AIDS spectrum manifesting symptoms or signs related to HIV infection. Of these, 70 had a significant deficit in the growth of this committed progenitor when compared with normal controls (P less than .01). Further analysis revealed that the nucleated bone marrow cells from AIDS and AIDS-related complex (ARC) patients inhibited the growth of CFU-GMs from normal individuals when cocultured in agar (P less than .001). Control CFU-GMs were also inhibited when they were cultured over feeder layers containing patients' BM cells (P less than .001). Conditioned media obtained from the liquid culture of patients' BM cells did not inhibit normal control CFU-GM growth to a degree different from that of the cells themselves (P greater than .4). Analysis of these conditioned media by polyacrylamide gel electrophoresis (PAGE) revealed a unique glycoprotein (gp) with a mol wt of 84 kd. Further studies revealed that this gp possessed the inhibitory activity. These data suggest that this gp may be an important factor in HIV-related neutropenia. The presence of gp84 was independent of drugs administered to the patients.
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PMID:A glycoprotein inhibitor of in vitro granulopoiesis associated with AIDS. 366 34

The restoration of immune functions was followed in dogs for 101 days after fractionated total body irradiation and autologous transfusion of peripheral blood leukocytes (PBL) or bone marrow (BM) cells. Median numbers of 0.9 X 10(5) granulocyte-macrophage progenitor cells per kilogram of body weight were transferred in either group of recipients. The following parameters recovered more rapidly in PBL recipients as opposed to BM recipients: total blood lymphocyte, T- and B-cell counts, serum levels of immunoglobulins IgM and IgA, in vitro blastogenic responses after stimulation with concanavalin A and pokeweed mitogen, and in vitro plasma cell formation after polyclonal B-cell activation with pokeweed mitogen with or without lipopolysaccharide. No major differences were noted for the restoration of serum IgG levels. Circulating lymphocyte and T-cell numbers remained subnormal for more than three months in both groups, whereas B-cell numbers and serum levels of IgA continued to be depressed in BM recipients only. Thus, autologous PBL restored immune functions more rapidly than did BM. Transplantation of PBL, alone or in addition to autologous BM, might also shorten the period of immunodeficiency after cytoreduction in a variety of malignancies in man.
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PMID:Recovery of immune functions in dogs after total body irradiation and transplantation of autologous blood or bone marrow cells. 389 1


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