Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A xenoantiserum raised in rabbits by immunization with strain 13 guinea-pig antigen-activated T-lymphocytes was previously found to recognize a non-immunoglobulin, 75,000 mol. wt glycoprotein synthesized by guinea-pig T-cells. This protein, p75, has been further characterized to determine its biochemical properties and its expression by various cell types. p75 was found to be a single-chain protein which could be bound by the lectin Lens culinaris hemagglutinin. It has an apparent mol. wt slightly greater than mu-chain as assessed by SDS-polyacrylamide gel electrophoresis and could not be precipitated by anti-guinea-pig immunoglobulin reagents. It exhibited considerable charge heterogeneity during isoelectric focusing and was not affected by neuraminidase treatment, p75 was synthesized by thymus, spleen and lymph node cells, by antigen-stimulated T-cells from strain 13 and strain 2 guinea-pigs, and by guinea-pig B-cell L2C leukemia lines, but not by normal B-lymphocytes or macrophages. No differences between the isoelectric focusing patterns of p75 molecules isolated from different cell types could be demonstrated. The chemical properties of p75 and its expression by the cell types so far examined indicate that p75 is a possible candidate for the guinea-pig homologue of the murine Lyt-1 antigen.
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PMID:Characterization of a 75,000 mol. wt glycoprotein synthesized by guinea-pig T-lymphocytes: a possible homologue of Lyt-1 antigen. 698 89

Evidence has previously been presented for an immunomodulatory role of a soluble activity, designated as tumor-derived recognition factor (TDRF), which was produced constitutively by P815 mastocytoma, L 1210 leukemia and other murine tumor targets. TDRF synergized with IFN-gamma and IL-2 to promote TNF-alpha and mRNA synthesis and release by murine macrophages for increased autocrine induction of nitric oxide (NO)-mediated tumor cytotoxicity. We have now further assessed the modulatory role of TDRF on TNF-alpha, TNF receptors (TNF-R) and NOS mRNA synthesis. Macrophages activated by INF-gamma priming and triggering by rTNF-alpha bacterial lipopolysaccharide (LPS) of IL-2 evoked greater NO generation in the presence than in the absence of L1210 targets. TDRF-containing culture fluid from L1210 targets was subsequently confirmed to synergize with IFN-gamma and rTNF-alpha, LPS or IL-2 triggering agents to promote increased TNF-alpha mRNA for autocrine induction of NOS mRNA synthesis with resultant augmentation of NO generation. IFN-gamma selectively upregulated TNF-R1 mRNA expression, whereas either IL-2 or LPS upregulated only TNF-R2 mRNA expression. TDRF combined with IFN-gamma to further upregulate TNF-R1 mRNA and with either IL-2 or LPS to further upregulate TNF-R2, mRNA expression. These findings indicate that TDRF activity synergizes with either IL-2 or LPS triggering agents for enhanced activation of IFN-gamma-primed macrophages by promotion of TNF-alpha and TNF-R mRNA synthesis for autocrine induction of NOS with resultant increased NO-mediated tumor cytotoxicity.
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PMID:Tumor-derived factor synergizes with IFN-gamma and LPS, IL-2 or TNF-alpha to promote macrophage synthesis of TNF-alpha and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity. 754 21

T-cell proliferation is regulated by the autocrine ligand interleukin-2 (IL-2), for which these cells possess dual, low-affinity and high-affinity receptor populations. Proliferation stimulated by IL-2 is dependent upon ligand binding to p75, a component of the high-affinity receptor. As with other cells exhibiting dual receptor systems, a central question is, therefore: what is the role of the low-affinity receptor population? We apply a mathematical modeling approach to examine three alternative mechanisms that have been suggested for the role of low-affinity receptors: a ligand reservoir, a receptor reservoir, and a ligand carrier. Using model parameter values specific to the IL-2/T-cell system, we find that only the ligand carrier mechanism leads to binding of autocrine ligand to high-affinity receptors that is increased over levels found on a single, pre-formed high-affinity receptor population. With the ligand reservoir and the receptor reservoir mechanisms, the presence of the low-affinity receptors actually diminishes high-affinity receptor binding due to competition. In contrast, excess low-affinity receptors can act to enhance the level of high-affinity receptor complexes when membrane transport is included, indicating that should this mechanism be inhibited, cell response could potentially be reduced or eliminated. The ligand carrier effect is especially significant for cells expressing a large number (> 10(5) receptors/cell) low-affinity receptors, and at low cell densities (< 10(4) cells/ml). This may at least partially account for the behavior demonstrated by early phase adult T-cell leukemia cells.
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PMID:The role of low-affinity interleukin-2 receptors in autocrine ligand binding: alternative mechanisms for enhanced binding effect. 803 36

DAB486IL-2 is an IL-2-diphtheria toxin conjugate which was developed to be specifically cytotoxic to cells bearing high affinity IL-2 receptors. The high affinity IL-2 receptor is a heterodimer comprising p55 and p75 subunits. While the p75 subunit appears to be ubiquitously expressed among the common North American leukemias and lymphomas, the p55 subunit is more restricted in its expression. To broaden the therapeutic relevance of the DAB486IL-2 we have sought physiologically feasible inducers of the p55 IL-2 receptor subunit. This report describes that PHA, in vitro, induces the p55 IL-2 receptor subunit on initially p55-negative B-CLL cells and converts toxin-insensitive leukemia cells to a toxin-sensitive state.
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PMID:PHA induces IL-2 receptors on B-CLL cells and is a potential biological response modifier for the LIL-2-diphtheria toxin, DAB486IL-2. 810 88

The cell line described here was established for a 50-year-old male patient with rapidly progressive non-Hodgkin's lymphoma whose marrow was diffusely infiltrated with large granular lymphocytes (LGL). Immunophenotyping of marrow blasts and peripheral lymphocytes was positive for CD56, CD2 and CD7, and negative for CD3. Cytotoxicity of peripheral blood mononuclear cells at an effector: target (E:T) cell ratio of 50:1 was 79% against K562 cells and 48% against Daudi cells. To establish the line, cells from the peripheral blood were placed into enriched alpha medium containing 12.5% fetal calf serum, 12.5% horse serum, 10(-4) M beta-mercaptoethanol and 10(-6) M hydrocortisone. Growth of the line (termed NK-92) is dependent on the presence of recombinant IL-2 and a dose as low as 10 U/ml is sufficient to maintain proliferation. Conversely, cells die within 72 h when deprived of IL-2; IL-7 and IL-12 do not maintain long-term growth, although IL-7 induces short-term proliferation measured by 3H-thymidine incorporation. None of the other cytokines tested (IL-1 alpha, IL-6, TNF-alpha, IFN-alpha, IFN-gamma) supported growth of NK-92 cells which have the following characteristics: surface marker positive for CD2, CD7, CD11a, CD28, CD45, CD54, CD56bright; surface marker negative for CD1, CD3, CD4, CD5, CD8, CD10, CD14, CD16, CD19, CD20, CD23, CD34, HLA-DR. DNA analysis showed germline configuration for T-cell receptor beta and gamma genes. CD25 (p55 IL-2 receptor) is expressed on about 50% of all cells when tested at 100 U/ml of IL-2 and its expression correlates inversely with the IL-2 concentration. The p75 IL-2 receptor is expressed on about half of the cells at low density irrespective of the IL-2 concentration. NK-92 cells kill both K562 and Daudi cells very effectively in a 4 h51-chromium release assay (84 and 86% respectively, at an E:T cell ratio of 5:1). The cell line described here thus displays characteristics of activated NK-cells and could be a valuable tool to study their biology.
Leukemia 1994 Apr
PMID:Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. 815 60

Cell line PER-423 was derived from the cells of a patient with an immature acute T-lymphoblastic leukaemia and the growth of this human cell line is strictly dependent on interleukin-2 (IL-2). PER-423 cells express the p75 (beta) subunit of the IL-2 receptor (IL-2R beta), while the p55 chain (IL-2R alpha) is not detectable by immunofluorescence. The analysis of the IL-2R revealed that it is of intermediate affinity and the median effective IL-2 concentration for PER-423 cells (EC50 value) was determined to be 1.44 +/- 0.29 nM. Chemical crosslinking studies showed that the receptor consists of one polypeptide of approximately 95 kDa as well as a doublet of 70 kDa and 60 kDa and does not include the IL-2R alpha-chain. The steady-state mRNA level for the p75 subunit was similar to that present in a cell line expressing an IL-2R alpha+ beta+, while only traces for the alpha-chain were detectable. PER-423 cells can be induced to express the alpha-chain of the IL-2R on the cell surface, concomitant with a much reduced EC50 level. Since cell line PER-423 is functionally dependent on IL-2, it provides an ideal model for IL-2 signal transduction studies and for investigations focusing on the requirements for ligand binding vs activation.
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PMID:Functional interleukin-2 receptor on a Tac negative human leukaemia T-cell line. 842 80

In the present study, we have investigated the leukemic cells obtained from 16 patients with acute myeloid leukemia (AML) at diagnosis for the membrane expression of p55 (alpha) and p75 (beta) interleukin-2 receptor (IL-2R) chains using specific monoclonal antibodies (mAbs), as well as for the presence of their transcripts using Northern blot analysis. In addition, immunoprecipitation of the p75 membrane molecule with TU27 and Mik-beta 1 mAbs was carried out in selected cases. The p75 IL-2R beta transcripts were detected in all cases, whereas the membrane p75 molecule was demonstrable by flow cytometry in three cases. However, data from the immunoprecipitation analysis suggest that the lack of the p75 IL-2R detection by flow cytometry might be caused by the low density of molecules per cell rather than the fact that the specific mRNA is not translated into the p75 surface molecule. In addition, a consistent membrane positivity with an anti-p55/CD25 mAb, present on fresh uncultured blasts in 37.5% of the cases, became detectable after short-term culture in 75% of cases. In each individual case, a strict correlation was found between membrane CD25 reactivity and the expression of p55 mRNA. Taken together, our data suggest that the expression of both alpha (p55) and beta (p75) IL-2R molecules is a common feature of leukemic cells in AML, and provide new arguments for reassessing the possible role of IL-2 in leukemic growth.
Leukemia 1993 Mar
PMID:Alpha (p55) and beta (p75) chains of the interleukin-2 receptor are expressed by AML blasts. 844 47

Tumour necrosis factor (TNF)-alpha exerts multiple effects on human acute myeloblastic leukaemia (AML) cells in vitro, including (1) synergistic stimulation of proliferation with interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF); (2) inhibition of granulocyte-CSF (G-CSF) and stem cell factor (SCF)-induced growth; (3) suppression of multiplication of clonogenic leukaemic cells; (4) induction of autocrine growth. Recently, two distinct TNF receptors (TNF-Rs), TNF-Rp55 and TNF-Rp75, have been identified. In this study we show that both receptors are expressed on freshly isolated AML blasts, with p75 being the predominant TNF-receptor type. This study investigates the roles of these two receptors in TNF-alpha-driven growth regulation of AML blasts in vitro. Using a receptor-specific antibody, it is shown that both receptor types participate in TNF-alpha-mediated stimulation of GM-CSF/IL-3-induced proliferation and in TNF-alpha-induced autocrine growth. In contrast, the TNF-alpha-triggered growth inhibition (antiproliferation) and the potent suppression of G-CSF- and SCF-induced proliferation exclusively result from activation of TNF-Rp55. Taken together, these results suggest that the proliferative effects of TNF-alpha on AML blasts are mediated through both p55 and p75 TNF receptors, whereas the TNF-alpha-signalled growth inhibition is exclusively transduced via TNF-Rp55.
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PMID:Expression and role in growth regulation of tumour necrosis factor receptors p55 and p75 in acute myeloblastic leukaemia cells. 856 81

NK cells can exert potent anti-leukemia activity after either autologous or allogeneic BMT. However, in autologous blood or marrow transplant patients, NK cell number and/or function could be reduced, and also may vary according to the sampling site. In order to evaluate the hypothesis that blood or marrow grafts from autologous transplant patients exhibit impaired NK cell activity that could contribute to disease recurrence, we evaluated the immunologic characteristics of NK cells in the bone marrow (BM) and peripheral blood (PB) from 27 patients undergoing autologous BMT, and also from 20 normal donors. We measured baseline and interleukin-2 (IL-2)-activated NK cell cytotoxicity, as well as expression of IL-2 receptors (IL-2R) (alpha-chain (p55) and beta-chain (p75)), and adhesion molecules. The cytotoxic activity of PB NK cells was significantly lower in autologous transplant patients than in normal donors (P < 0.0005) and this difference was not mitigated following IL-2 activation. In contrast, BM from autologous patients showed normal NK cell cytotoxicity, but contained higher numbers of NK cells (P < 0.025), with more intense CD56 expression (P < 0.05). Expression of p75 was lower on BM than on PB NK cells in both patients and normal donors. In addition, induction of p55 by IL-2 was abrogated in autologous PB NK cells. Therefore, depending on the site of harvest and the nature of donor cells (pre-BMT vs normal), our results show significant differences in NK cell number, function, and IL-2 receptor expression. This may affect relapse rates following autologous transplants performed with either PB or BM grafts.
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PMID:Phenotypic and functional characterization of peripheral blood and bone marrow natural killer cells prior to autologous transplantation. 870 80

Interferon-gamma (IFN-gamma) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-gamma from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-gamma is unknown. Here we show that the same cytokines that induce human NK cell IFN-gamma production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-alpha (TNF-alpha). Neutralization of TNF-alpha or inhibition of TNF-alpha binding to the p80 TNF-alpha receptor partially inhibited apoptosis. Transforming growth factor-beta, which inhibits cytokine-induced NK cell production of IFN-gamma and TNF-alpha, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3-CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-gamma production, followed by NK cell apoptosis and a decline in IFN-gamma production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.
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PMID:Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response. 902 22


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