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)

Galectin-9 is a member of the galectin family and has been identified as an eosinophil chemoattractant produced by activated T lymphocytes. Vascular endothelial cells play an important role in the initial step of eosinophil recruitment and activation in immune and inflammatory responses. We have addressed the stimulation of galectin-9 expression in endothelial cells. Galectin-9 was detected in membrane and cytosolic fractions of human umbilical vein endothelial cells stimulated with interferon-gamma (IFN-gamma). IFN-gamma also enhanced the adhesion of human eosinophilic leukemia-1 cells to endothelial monolayers, and it was inhibited by the presence of lactose. Interleukin-4, which induces eotaxin expression, did not affect the expression of galectin-9. The in situ endothelium from patients with inflammatory diseases was found to express galectin-9. IFN-gamma-induced production of galectin-9 by endothelial cells may play an important role in immune responses by regulating interactions between the vascular wall and eosinophils.
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PMID:Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. 1222 16

Adult patients with acute leukemia have, in general, a poor prognosis, with long-term, disease-free survival achieved in only approximately one-third of cases. One of the proposed mechanisms for this poor overall response is the inability of the immune system to detect and eliminate residual malignant leukemia cells, which subsequently serve as a source of leukemic relapse. This review discusses the rationale of immunotherapy for acute leukemia and presents in vitro and in vivo model systems that were devised for pre-B acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). New advances in the ex vivo manipulation of acute leukemia cells are presented, which attempt to modify these cells into functional antigen-presenting cells. These cells can then be used as autologous vaccines at the time of minimal residual disease after standard chemotherapy, to stimulate host immune responses against their own leukemia cells. The various approaches toward this aim include incubation of leukemia cells with cytokines or growth factors and gene manipulation of these cells. In particular, ex vivo culture of ALL cells with CD40 ligand, incubation of AML cells with granulocyte-macrophage colony-stimulating factor and interleukin-4 (GM-CSF/IL-4) and lentiviral transduction of ALL and AML cells for expression of immunomodulators (CD80 and GM-CSF) are current approaches under investigation for the development of autologous acute leukemia cell vaccines.
Leukemia 2002 Oct
PMID:Immunotherapy with acute leukemia cells modified into antigen-presenting cells: ex vivo culture and gene transfer methods. 1235 48

The TS/A mouse mammary adenocarcinoma is a poorly immunogenic tumor widely used in preclinical models of cancer immunotherapy. CTLs have often been indicated as important in TS/A tumor destruction, but their generation in this model has been rarely studied, nor have their precise target(s) been identified. We hypothesized that the gp70 Env product of an endogenous murine leukemia virus could be a target antigen for TS/A-specific CTLs and investigated this possibility in four different TS/A cell lines engineered with the genes that encode IFN-alpha, IFN-gamma, interleukin-4, and B7.1, respectively. All tumor cell lines expressed gp70, albeit at different levels, as demonstrated by reverse transcription-PCR analysis. Transfected tumor cells exhibited a delayed growth in vivo, and partial tumor regression. Spleen cells from mice that displayed tumor regression had high percentages of CD8(+) T cells that were specifically stained with L(d) tetramers loaded with gp70(423-431), the antigenic epitope of gp70 protein. Mixed leukocyte-peptide and mixed leukocyte-tumor cultures, set up by stimulating splenocytes with the immunogenic peptide and with transfected TS/A tumor cells, respectively, resulted in similar large increases in tetramer-reactive CD8(+) T cells and showed high lytic activity specific for gp70(423-431). Finally, in a Cold Target Inhibition assay, lytic activity of a mixed leukocyte-tumor culture was inhibited in an overlapping fashion by both the TS/A line used for restimulation and 293L(d) cells loaded with gp70(423-431) peptide, but not by 293L(d) cells pulsed with an irrelevant H-2 L(d) epitope, thus demonstrating that all or most of the cytotoxic activity was directed exclusively against this antigenic epitope.
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PMID:The cytotoxic T-lymphocyte response against a poorly immunogenic mammary adenocarcinoma is focused on a single immunodominant class I epitope derived from the gp70 Env product of an endogenous retrovirus. 1272 34

Immunotherapy for human leukemias has the potential to contribute to the long-term control or cure of these diseases. Our work demonstrates that cells from the majority of adult acute myelogenous leukemia cases can be induced to differentiate into dendritic cells that are effective at antigen presentation. Both interleukin-4 and CD40 ligand are important for optimal dendritic cell differentiation and maturation. Granulocyte-monocyte colony-stimulating factor, interleukin-4, and CD40 ligand in combination are capable of yielding dendritic cells from at least some cases of acute lymphocytic leukemia. Efforts to clone autologous, cytotoxic effector cells will permit the identification of target antigens in the future. With information concerning potential antigens, protocols inducing antileukemic immunity should be possible. Prior to that time, with the availability of suitable reagents for clinical scale differentiation of leukemia-derived dendritic cells, such cells might prove potent as vaccines for the therapy of acute leukemias.
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PMID:Autologous immunotherapy for human leukemias. 1285 Apr 95

Transactivating proteins associated with complex onco-retroviruses including human T-cell leukemia virus-1 (HTLV-1) and bovine leukemia virus (BLV) mediate transformation using poorly understood mechanisms. To gain insight into the processes that govern tumor onset and progression, we have examined the impact of BLV-Tax expression on ovine B-cells, the targets of BLV in experimentally infected sheep, using B-cell clones that are dependent on CD154 and gammac-common cytokines. Tax was capable of mediating progression of B-cells from cytokine dependence to cytokine independence, indicating that the transactivator can over-ride signaling pathways typically controlled by cytokine receptor activation in B-cells. When examined in the presence of both CD154 and interleukin-4, Tax had a clear supportive role on B-cell growth, with an impact on B-cell proliferation, cell cycle phase distribution, and survival. Apoptotic B-cell death mediated by growth factor withdrawal, physical insult, and NF-kappaB inhibition was dramatically reduced in the presence of Tax. Furthermore, the expression of Tax was associated with higher Bcl-2 protein levels, providing rationale for the rescue signals mediated by the transactivator. Finally, Tax expression in B-cells led to a dramatic increase of nuclear RelB/p50 and p50/p50 NF-kappaB dimers, indicating that cellular signaling through NF-kappaB is a major contributory mechanism in the disruption of B-cell homeostasis. Although Tax is involved in aspects of pathogenesis that are unique to complex retroviruses, the viral strategies associated with this transactivating oncoprotein may have wide-ranging effects that are relevant to other B-cell malignancies.
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PMID:Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-kappaB. 1288 10

The late asthmatic reaction is characterised by elevated numbers of interleukin-4/interleukin-5/CD4-positive T-helper cells type 2 in bronchoalveolar lavage fluid (BALF). Cyclosporin A (CsA) is known to inhibit T-cell proliferation, induce apoptosis of CD4-positive T-cells and downregulate cytokine gene expression. It was assessed whether CsA-induced inhibition of the late asthmatic reaction was associated with apoptosis of BALF T-lymphocytes and other cell types, as well as expression of the antiapoptotic protein B-cell leukaemia/lymphoma 2 gene product (Bcl-2). BALF cells were obtained from asthmatics at baseline and 24 h after allergen-inhalation challenge following prior administration of CsA (n=13) or placebo (n=11). The number of apoptotic CD3-positive T-lymphocytes increased in the CsA but not the placebo group. The numbers of Bcl-2-positive cells were significantly reduced in the CsA but not the placebo group. The majority of Bcl-2-positive cells were CD3-positive T-lymphocytes. The beneficial effect of cyclosporin A in asthma may be related to its inhibitory effect on the late asthmatic reaction via induction of T-cell apoptosis and decreased B-cell leukaemia/lymphoma 2 gene product levels.
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PMID:Cyclosporin A, apoptosis of BAL T-cells and expression of Bcl-2 in asthmatics. 1295 49

B-cell chronic lymphocytic leukaemia (B-CLL) is a neoplastic disorder characterized by defective apoptosis, cell accumulation in G0/G1, and high expression of BCL2 oncogene. Intracellular cyclic adenosine monophosphate (cAMP) accumulation increases the chemosensitivity of B-CLL cells in vitro and in vivo. In the present study, we investigated the effects of beta2-adrenergic compounds, well known cAMP-inducing drugs, on the in vitro survival of leukaemia cells. In contrast to the short-acting beta2-mimetic (beta2Mim) salbutamol, a consistent pro-apoptotic effect was observed with the long-acting beta2Mim salmeterol and formoterol. Normal B cells isolated from control donors were totally resistant to the above molecules. These compounds also increased chlorambucil- and fludarabine-induced death of B-CLL cells. Blockade of beta-adrenergic receptor signalling or cAMP did not alter B-CLL apoptosis with beta2 Mimagents. Leukaemia cell apoptosis by beta2Mim correlated with an increase in calcium influx, decreased bcl-2 protein and mRNA levels, increase in BAX gene expression and a marked rise in BCL2/BAX mRNA ratios. Interleukin-4, a cytokine that increases bcl-2 expression in B-CLL cells, rescued leukaemia cell from apoptosis with beta2Mim. These data show that long-acting beta2-adrenergic agents promote apoptotic leukaemia cell death through an adrenoreceptor- and cAMP-independent, Ca2+-dependent mechanism.
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PMID:Long-acting beta2-adrenergic formoterol and salmeterol induce the apoptosis of B-chronic lymphocytic leukaemia cells. 1468 23

Recent studies have shown that human myeloid leukaemia cells can differentiate into dendritic cell (DC)-like cells (leukaemia-DCs) when cultured with a combination of cytokines. In the present study, we examined whether the transduction of leukaemia-DCs with OX40 ligand (OX40L), a member of the tumour necrosis factor (TNF) family, resulted in augmentation of their antigen presenting activity. Bicistronic retroviral vectors expressing both human OX40L and enhanced green fluorescent protein (EGFP) or EGFP alone were generated and used for transduction. Fresh leukaemic cells from five patients with acute myeloid leukaemia (AML) were isolated and retrovirally transduced with OX40L during the culture with a combination of cytokines from stem cell factor, fms-like tyrosine kinase (Flt)-3 ligand, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-4 (IL-4) and TNF-alpha. After 7 d, the majority of cells showed DC-like morphology, and expressed higher levels of CD80, CD86 and HLA-DR than fresh leukaemic cells. The transduction efficiency was 8.5-27.2%. Leukaemia-DCs transduced with OX40L elicited higher proliferative response of allogeneic CD4+ T cells than fresh leukaemic cells, non-transduced, or mock-transduced leukaemia-DCs. Co-culture of allogeneic CD4+ T cells with OX40L-transduced leukaemia-DCs was superior in the generation of interferon (IFN)-gamma producing CD4+ T cells and in production of IFN-gamma. Furthermore, OX40L-transduced leukaemia-DCs could elicit significant proliferative response of human leucocyte antigen-matched T cells from the donor in allogeneic stem cell transplantation. These results indicate that retroviral transduction of leukaemia-DCs with OX40L augments their antigen presenting cell activity and thus renders them more suitable for tumour vaccines or ex vivo stimulation of leukaemia-specific T cells.
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PMID:Retroviral transduction of acute myeloid leukaemia-derived dendritic cells with OX40 ligand augments their antigen presenting activity. 1498 94

Olopatadine hydrochloride (olopatadine) is an anti-allergic drug that functions as a histamine H(1) antagonist and inhibits both mast cell degranulation and the release of arachidonic acid metabolites in various types of cells. In this study, we examined the ability of olopatadine to inhibit the expression of cytokine genes in vitro via high-affinity receptors for immunoglobulin E in mast cells, using a rat basophilic leukemia (RBL-2H3) cell line and an in vivo mouse model. Levels of gene expression in RBL-2H3 cells were determined by semi-quantitative RT-PCR, and serum interleukin-4 (IL-4) level in mice was quantified by ELISA. Olopatadine inhibited significantly the induction of IL-4 expression by mast cells both in vivo and in vitro. Olopatadine inhibited Ca(2+) influx through receptor-operated channels (ROC) without affecting Ca(2+) release from intracellular stores. Comparative analysis of olopatadine with other anti-allergic drugs and the ROC blocker SKF-96365 demonstrated that the potency of inhibition of Ca(2+) influx correlated with the degree of suppression of degranulation and arachidonic acid release. Inhibition of Ca(2+) influx decreased phosphorylation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase, which participate in regulation of cytokine (e.g. IL-4) gene expression. However, the rank order of inhibition of Ca(2+) influx did not correspond to reduction of IL-4 expression, suggesting that an unknown mechanism(s) of action, in addition to inhibition of Ca(2+) influx, is involved in the expression of cytokines in mast cells.
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PMID:Differential regulation of IL-4 expression and degranulation by anti-allergic olopatadine in rat basophilic leukemia (RBL-2H3) cells. 1501 47

Interferon-gamma (IFN-gamma) induces expression of multiple genes in endothelial cells. Retinoic acid-inducible gene-I (RIG-I) encodes a protein belonging to the DExH-box family, but details of its physiological function are not clear. RIG-I is induced in leukemia cells by retinoic acid and in endothelial cells by lipopolysaccharide. In the present study, the authors found that IFN-gamma also induces the expression of RIG-I in human umbilical vein endothelial cells. Induction of RIG-I mRNA by IFN-gamma was not altered by the treatment with cycloheximide or interleukin-4. Fluorescent immunostaining and Western blot analysis revealed cytoplasmic distribution of RIG-I. The in situ endothelium in a normal lung tissue was also found to express RIG-I protein. Although the physiological function of RIG-I is still unknown, induction of RIG-I by IFN-gamma may play an important role in inflammatory or immunological reactions in endothelial cells.
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PMID:Interferon-gamma induces retinoic acid-inducible gene-I in endothelial cells. 1537 Feb 93


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