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)

Examination of the interferon gamma (IFN-gamma) amino acid sequence revealed two conserved basic amino acid clusters similar to the prototype nuclear localization signal. We followed the fate of cell surface receptor-bound IFN-gamma in murine leukemia L1210 cells. A time- and temperature-dependent accumulation of murine IFN-gamma in the cell nucleus could be demonstrated by autoradiography and indirect immunofluorescence after the rapid isolation of nuclei. Human IFN-gamma was also internalized and translocated to the nucleus of murine L1210 cells transfected with and expressing the human IFN-gamma receptor, but it appeared to be retained by the nucleus only transiently. IFN-gamma molecules chemically crosslinked to their cell surface receptor remain capable of being translocated to the nucleus even as part of a receptor-ligand complex. Thus, the bipartite nuclear localization signal sequence appears to be functional and suggests that nuclear targeting could participate in IFN-gamma signal transduction.
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PMID:Nuclear accumulation of interferon gamma. 799 44

Numerous cytokines are present in inflammatory foci. Two of them, interleukin-1 (IL-1) and tumour necrosis factor (TNF), play a major role in coordinating mechanisms which command inflammation. Under their action many cells produce lipidic mediators, proteolytic enzymes or free radicals, all factors that are directly responsible for the noxious effects observed. IL-1 and/or TNF exert cytotoxic activities on vascular epithelium, cartilage, bone, muscle or beta cells of pancreatic islets. Such cytokines as interferon gamma (IFN gamma), IL-3 or granulocyte-macrophage colony stimulating factor (GM-CSF) amplify the inflammatory response by increasing the production of IL-1 and TNF by macrophages. GM-CSF also produces other cytokines, such as IL-8 and the macrophage chemoattractant protein 1 (MCP-1), the chemotactic properties of which participate in the recruitment of leucocytes within the focus of inflammation. IL-6 abounds in inflammatory processes and induces the production by hepatocytes of acute inflammation phase proteins. The same applies to IL-1, TNF, IL-11, the leukaemia inhibitory factor (LIF) or the transforming growth factor beta (TGF beta). The latter also possesses a number of anti-inflammatory activities and, like IL-4 and IL-10, can inhibit IL-1 and TNF production. Glucocorticoids have this potential activity, and they may be produced by a cascade of events initiated by IL-1, TNF and IL-6, involving the neuroendocrine system. The concept of "cytokine network", therefore, perfectly illustrates the participation of these mediators in inflammatory mechanisms.
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PMID:[Cytokines and inflammation]. 834 24

Cytokines are now part of the modern armentarium utilized against malignant blood diseases. The essentially lymphocytic haematopoietic growth factors (G-CSF, GM-CSF, IL-3) reduce the infectious morbidity associated with the deep and prolonged neuropoenia induced by the myelo-ablative conditioning for autologous or allogeneic bone marrow transplantations, and widening their indications is tempting. The reluctance expressed about their use in chemotherapy of acute myeloid leukaemia is abating now that controlled studies have shown that they preserve the complete response rate and shorten the duration of leucopoenia. Moreover, they modify the leukaemia biological response, which makes it possible to increase the cytotoxicity of certain drugs and constitutes a new approach to drug-resistant leukaemias. Immuno-modulating cytokines (interferon alpha, interferon gamma, interleukin-2) act through mechanisms that are still ill-defined: antitumoral activity, modification of biological responses, immunoactivation. Nevertheless, interferon alpha has revolutionized the treatment of hairy cell leukaemia and myeloid leukaemia, with a 70% remission rate. The scarcity of complete responses (10% of hairy cell leukaemias) or cytogenetic responses (20% of chronic myeloid leukaemias) justifies a combined treatment (chemotherapy+immunotherapy?) to improve these patients' cure rate. The anti-leukaemic activity of interleukin-2, observed in patients with refractory relapses, produces 33% of responses, including 10% of complete responses, and it is tempting to test the impact of this immunotherapy on the control of residual leukaemia as adjuvant of complete remission using randomized trials.
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PMID:[Cytokines and malignant hemopathies: leukemias and bone marrow graft]. 834 27

Transplantation of bone marrow autografts activated by culture in interleukin-2 (IL-2) followed by administration of IL-2 represents a novel approach in an attempt to combine ex vivo purging and post-transplant in vivo immunotherapy, and initial clinical results have suggested its feasibility. To further characterize the mechanism of the in vitro anti-leukemia effect, fresh bone marrow from normal donors and from patients with acute myelogenous leukemia (AML) in remission was cultured for 6 days in the absence or presence of IL-2 (1000 IU/ml). Proliferation of CD3, CD8, CD14, and CD56 cells was determined by direct immunofluorescence using flow cytometry. Predominantly T-lymphocytes (CD3+) and to a lesser extent CD56+ natural killer (NK) cells proliferate in 6-day marrow cultures in IL-2. Fresh bone marrow cells have no measurable NK activity when tested against K562 and Daudi target cell lines in a 4 h chromium-51 release assay, and it requires at least 6 days of culture in IL-2 to develop optimal cytotoxic activity. Cytokines released in the supernatants of these cultures were measured by immuno- and bioassays. Tumour necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and IL-6 were found to be produced in significant amounts by marrow mononuclear cells during culture in IL-2. Even without IL-2 present, concentrations of these cytokines were increased in 6-day marrow cultures. In contrast, IL-3, IL-7, granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) were below the level of detection of the immunoassay, a result that could be confirmed for GM-CSF and IL-3 by bioassay. The data suggest that culture of marrow from normal donors as well as from patients with AML obtained in remission can generate anti-leukemia effector mechanisms which are non-crossreactive with chemo- and radiotherapy and may contribute to effective ex vivo purging of residual leukemic cells. The transplantation of such IL-2 'primed' marrow may also contribute to an in vivo graft-versus-leukemia effect.
Leukemia 1993 Sep
PMID:Culture of normal and leukemic bone marrow in interleukin-2: analysis of cell activation, cell proliferation, and cytokine production. 837 89

We have used cell surface radioiodination, biosynthetic incorporation of [35S]methionine, and flow cytometry to analyze the effects of interferon gamma (IFN-gamma) and/or phorbol esters (PMA) on the turnover and expression of class I antigens of a human leukemia B cell line. Our results demonstrated that although both IFN-gamma and PMA enhance HLA expression, they act synergistically to increase by eightfold the amount of HLA polypeptides synthesized by the acute lymphoblastic leukemia cells and acted additively to augment the cell surface expression of HLA as quantified by flow cytometry. We observed a cyclic increase or decrease in the expression of class I antigens as a function of time in cell culture. IFN-gamma and/or PMA modulated this effect inducing more cells to express HLA maximally. These results suggest that there is a physiologic limit for the expression of major histocompatibility complex class I antigens.
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PMID:Regulatory effect of interferon-gamma and phorbol esters on the surface expression and biosynthesis of MHC class I antigens by human leukemia cells. 840 45

We studied the regulatory effects of various cytokines on the susceptibility to lymphocyte-mediated lysis of cell lines established from patients with acute T-lymphoblastic leukemia (T-ALL). None of the cytokines tested affected the sensitivity of these targets to natural killer activity. In contrast, specific cytokines, different for each cell line, enhanced the susceptibility to lymphokine-activated killer (LAK) cells, while interferon gamma (IFN)-gamma always induced resistance. The same cytokines that increased LAK susceptibility also induced proliferative responses. The TALL-101 cell line, which responded to granulocyte-macrophage colony-stimulating factor (GM-CSF) with increased susceptibility to lysis, and to IFN-gamma with resistance, was used as a model to analyze the mechanisms underlying these changes. Cold target inhibition and conjugate formation assays both indicated that the changes in LAK susceptibility were not at the level of effector-target (E/T) binding. Furthermore, no significant changes in surface expression of adhesion molecules involved in E/T binding were induced by either GM-CSF or IFN-gamma on TALL-101 cells. Finally, N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl-esterase assays demonstrated no differences in the ability of these cytokines to trigger the secretion of cytolysins in the bound effectors compared to unstimulated cells. Taken together, these results suggest that the cytokine-modulated susceptibility to lysis of these T-ALL lines might occur at a post-binding stage with mechanisms involving an altered responsiveness to lytic factors.
Leukemia 1993 Mar
PMID:Cytokine modulation of the susceptibility of acute T-lymphoblastic leukemia cell lines to LAK activity. 844 46

Natural killer (NK) cells lyse autologous and allogeneic target cells even in the absence of major histocompatibility complex (MHC) class I antigens on the target cells. Recently, however, human allospecific NK cell clones have been generated that recognize at least five distinct specificities inherited recessively and controlled by genes linked to the MHC. Because the genetic specificity of these alloreactive NK cells in vitro appears analogous to that of in vivo NK cell-mediated murine hybrid resistance, i.e., the rejection of parental bone marrow in irradiated F1 animals, we tested the ability of human alloreactive NK clones to recognize allogeneic hematopoietic progenitor cells. NK cells from two specificity 1 alloreactive NK clones, ES9 and ES10, significantly and often completely suppressed colony formation by purified peripheral blood hematopoietic progenitor cells from specificity 1-susceptible donors, but had no significant effect on the cells of specificity 1-resistant donors. Activated polyclonal NK cells were less efficient than the NK clones in inhibiting colony formation and had a similar effect on cells from both specificity 1-susceptible and -resistant donors. The alloreactive NK clones produced cytokines with a suppressive effect on in vitro hematopoiesis, such as interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), when exposed to phytohemagglutinin blasts from specificity 1-susceptible, but not -resistant donors. However, the mechanism by which alloreactive NK cells inhibit colony formation is more consistent with a direct cytotoxic effect than with the production of inhibitory cytokines because antibodies (anti-IFN-gamma, alpha-TNF-alpha, and -lymphotoxin) that completely blocked the inhibition by polyclonal NK cells had only a minimal effect on the inhibition by the alloreactive clones. Moreover, the alloreactive clones were directly cytolytic in a 51Cr release assay against enriched preparations of peripheral blood progenitor cells from specificity 1-susceptible donors. These data indicate that the alloreactive NK cells are likely the human counterpart of the cells mediating murine hybrid resistance and that these cells might play clinically important roles in rejection or in graft-versus-leukemia reactions after allogeneic bone marrow transplantation.
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PMID:Regulation of hematopoiesis in vitro by alloreactive natural killer cell clones. 845 6

Bone marrow (BM) cells from a child with an immature (CD3-) acute T lymphoblastic leukemia (T-ALL) bearing no chromosomal abnormalities failed to grow in long-term culture in the presence or absence of recombinant human (rh) growth factors but could be engrafted in severe combined immunodeficient (SCID) mice and induced leukemia. The leukemic cells recovered from the animal tissues could be adapted to grow in vitro in the presence of rh interleukin-2 (IL-2) and give rise to a growth factor-dependent cell line designated TALL-107. This cell line expresses T-cell-specific mature markers (CD2, CD3/T-cell receptor [TCR] alpha beta, CD8, CD56), and its growth can be inhibited by IL-4 of all the cytokines tested. Similar to the original leukemic blasts, TALL-107 cells are clonal, have rearranged TCR-beta, gamma, and delta loci, and a normal 46 XY karyotype. However, unlike the patient's BM cells, the TALL-107 cell line displays potent tumoricidal activity that is not major histocompatibility complex restricted. The magnitude of mRNA expression of perforin and serine esterases and of lytic activity depends on the doses of IL-2 added. TALL-107 cells can also be triggered by CD3- and CD2-specific monoclonal antibodies (MoAbs) to mediate reverse tumor cell lysis. In addition, this cell line produces high levels of interferon gamma and tumor necrosis factor alpha on stimulation with anti-CD3 and/or anti-CD2 MoAb both in the presence or absence of IL-2. The overall data indicate that the SCID mouse is able to support the functional maturation and expansion of a cytotoxic T-cell subset from some types of T-ALL.
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PMID:Establishment of a karyotypically normal cytotoxic leukemic T-cell line from a T-ALL sample engrafted in SCID mice. 849 Jan 80

We have previously shown that interleukin 4 (IL-4) and interferon gamma (INF-gamma) reciprocally regulate the production of granulocytes and monocytes from mature monopotential hematopoietic progenitor cells, while at the level of the very primitive stem cells IFN-gamma is a selective inhibitor of proliferation and differentiation, and IL-4 has weak stimulatory effects. We investigated the effects of IL-4 and IFN-gamma on the expansion in suspension culture of myeloid colony-forming cells (CFCs) induced by either IL-3 or IL-1+IL-3, using on the one hand more differentiated CD34+HLA-DR strongly positive (HLA-DR++) and on the other hand more primitive Cd34+HLA-DR weakly positive (HLA-DR+/-) human bone marrow cells. It is shown that both IL-4 and IFN-gamma stimulate the IL-3- and IL-3+IL-1-induced expansion of the number of CFCs in the HLA-DR+/- population. In the presence, but not in the absence of IL-1, additive effects of IL-4 and IFN-gamma were seen. We could not demonstrate any IL-3-like effect by IL-4 on early human hematopoietic progenitors. No expansion of CFC number was seen in the HLA-DR++ population. Based on these data and on data which we have published previously, a model for the regulation of myelopoiesis by IL-4 and IFN-gamma is proposed. In this model, IL-4 and IFN-gamma, which are both immune recognition induced inflammatory cytokines, both stimulate the expansion and recruitment of early myeloid progenitors, whereas at the level of their terminal differentiation, the balance between both cytokines determines whether preferentially monocytes/macrophages (IFN-gamma) or granulocytes (IL-4) are being produced. At the level of the most primitive cells, the inhibitory action of IFN-gamma might prevent differentiative exhaustion of the stem cell compartment in situations of hematopoietic stress.
Leukemia 1996 Jan
PMID:Interleukin 4 and interferon gamma costimulate the expansion of early human myeloid colony-forming cells. Proposal of a model for the regulation of myelopoiesis by interleukin 4 and interferon gamma and its integration with the regulation of the immune response. 855 15

T cell clones (CD4+CD8-TCR alpha beta+gamma delta- derived from bone marrow transplant recipients were stimulated with phytohaemagglutinin (PHA) +interleukin-2 (IL-2) in the presence of irradiated (50 Gy) peripheral blood mononuclear cells (PBMC) derived from acute Leukaemia patients (leukaemic PBMC containing more than 95% blast cells). Leukaemic PBMC could function as accessory cells during mitogenic T cell activation resulting in both T cell proliferation and a broad T cell cytokine response [IL-3, IL-4, IL-10, granulocyte/macrophage-colony-stimulating factor (GM-CSF) tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) secretion]. Blockade of IL-1 effects by adding IL-1 receptor antagonist together with PHA + IL-2 + leukaemia blasts increased T cell proliferation, whereas IL-6-neutralizing antibodies did not alter T cell proliferation. A qualitatively similar T cell cytokine response and a similar cytokine profile (highest levels detected for GM-CSF and IFN gamma) were detected when normal polyclonal T cell lines were stimulated with PHA in the presence of non-irradiated leukaemic PBMC. When leukaemic PBMC derived from 18 acute myelogenous leukaemia patients were cultured with PHA and cells from a polyclonal T cell line, increased concentrations of the T cell cytokines IFN gamma and IL-4 were detected for all patients. We conclude that T cell activation resulting in proliferation and a broad cytokine response can take place in the presence of excess acute myelogenous leukaemia blasts.
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PMID:Human T lymphocyte activation in the presence of acute myelogenous leukaemia blasts; studies of normal polyclonal T cells and T lymphocyte clones derived early after allogenic bone marrow transplantation. 864 Aug 41


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