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)

The factors determining the growth and survival of cells in B chronic lymphocytic leukemia (CLL) have remained poorly understood. We investigated the effects of optimal mitogen combinations (OMCs) on the expression of 26 surface membrane antigens among 33 CLL patients. The seven OMCs used were selected after pre-testing 14 combinations of (1) S. aureus Cowan I (SAC), (2) interleukin-2 (IL-2), (3) tumor necrosis factor alpha (TNF-alpha) and (4) 12-O-tetradecanoylphorbol 13-acetate (TPA; also known as phorbol 12-myristate 13-acetate or PMA). In flow cytometry we revealed that OMCs induced statistically highly significant upregulation of the expression of CD5, CD11c, CD19, CD22, CD23, CD25, CD38, CD40, CD45, CD45RO, CD95, CD126, CD130 and FMC7, and downregulation of CD20 and CD124 expression. Interestingly, the expression of CD27, CD45RA, CD79b, CD80, CD122 and that of the immunoglobulin gene superfamily members CD21, Ig-kappa, Ig-lambda, Ig-delta and Ig-micro were not significantly affected under similar conditions. The expression of several antigens was co-regulated, suggesting common regulatory pathways. These antigens include CD11c/CD5, CD11c/CD22, CD11c/CD126, CD11c/FMC7 as well as CD27/CD45, CD27/CD45RA and CD27/CD79b. Upregulation of surface antigen expression, induced by OMCs, should be applicable in antibody therapy in vitro and in vivo, and in negative stem cell selection for autotransplantation. Furthermore, the current strategy to enhance cell surface antigen expression may be a versatile tool to raise humoral and cell-mediated host defense against CLL cells. Upregulation of proteins mediating positive growth signals (eg CD25, CD40) and negative signals or apoptosis (eg CD95) may be used to sensitize cells to chemotherapy and programmed cell death.
Leukemia 2002 Sep
PMID:Surface membrane antigen expression changes induced in vitro by exogenous growth factors in chronic lymphocytic leukemia cells. 1220 Jun 83

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

Childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells, collected from bone marrow (BM) at diagnosis, were cultured, after thawing, on allogeneic human bone marrow stroma (HBMS) for 48 h in the presence of a soluble trimeric CD40 ligand (stCD40L) molecule. HBMS maintained leukemic cells viability in all tested cases (mean viability 85%). Under these culture conditions we noticed upregulation or de novo expression of costimulatory molecules CD40, CD80 (B7-1) and CD86 (B7-2) in 22/22, 15/23 and 21/23 cases, respectively. Upregulation, in terms of fluorescence intensity, was also observed in the expression of MHC I, MHC II, CD54 (ICAM 1) and CD58 (LFA 3) molecules. HBMS alone, although to a lesser extent, was able to induce modulation of these molecules, but not CD80, in a similar proportion of cases. Neither stCD40L nor HBMS induced modulation of CD10 and CD34 molecules. Moreover, in 4/4 tested cases, stCD40L-stimulated ALL cells were able to induce allogeneic T cells proliferation. To evaluate whether leukemia-reactive T cells were detectable in the BM of ALL patients at diagnosis, stCD40L-stimulated ALL cells were co-cultured with autologous T cells (ratio 1:1), isolated from BM at diagnosis, for 4 days and a 24 h ELISPOT assay was applied to detect the presence of interferon-gamma (IFN-gamma)-producing cells. In four of seven cases IFN-gamma-producing cells were detected with frequencies of 1/900, 1/1560, 1/2150 and 1/1575 autologous T cells. These data confirm that stCD40L exposure can activate the antigen-presenting cell (APC) capacity of BCP-ALL cells cultured on HBMS and that ELISPOT assay can be used to measure the frequency of leukemia-reactive autologous T cells in the BM of ALL patients even after short-term culture with stCD40L-stimulated ALL cells.
Leukemia 2002 Oct
PMID:CD40 ligand-stimulated B cell precursor leukemic cells elicit interferon-gamma production by autologous bone marrow T cells in childhood acute lymphoblastic leukemia. 1235 56

We have previously reported that stressed apoptotic tumor cells are more immunogenic in vivo than nonstressed ones. Using confocal microscopy we have confirmed our previous observation that heat-stressed apoptotic 12B1-D1 leukemia cells (BCR-ABL(+)) express HSP60 and HSP72 on their surface. To explore how the immune system distinguishes stressed from nonstressed apoptotic tumor cells, we analyzed the responses of dendritic cells to these 2 types of apoptotic cells. We found that nonstressed and heat-stressed apoptotic 12B1-D1 cells were taken up by dendritic cells in a comparable fashion. However, when stressed apoptotic 12B1-D1 cells were coincubated with immature dendritic cells for 24 hours, this resulted in greater up-regulation of costimulatory molecules (CD40, CD80, and CD86) on the surface of dendritic cells. Moreover, stressed apoptotic 12B1-D1 cells were more effective in stimulating dendritic cells to secrete interleukin-12 (IL-12) and in enhancing their immunostimulatory functions in mixed leukocyte reactions. Furthermore, we demonstrated that immunization of mice with stressed apoptotic 12B1-D1 cells induced the secretion of T helper-1 (T(H)1) profile of cytokines by spleen cells. Splenocytes from mice immunized with stressed apoptotic cells, but not nonstressed ones, were capable of lysing 12B1-D1 and the parental 12B1 line, but not a B-cell leukemia line, A20. Our data indicate that stressed apoptotic tumor cells are capable of providing the necessary danger signals, likely through increased surface expression of heat shock proteins (HSPs), resulting in activation/maturation of dendritic cells and, ultimately, the generation of potent antitumor T-cell responses.
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PMID:Stressed apoptotic tumor cells stimulate dendritic cells and induce specific cytotoxic T cells. 1239 1

To observe the proliferation of T lymphocytes stimulated by CML and AML cells which were induced by rhGM-CSF and rhIL-4, and the secretion of IFN-gamma from proliferated T lymphocytes, the expression of CD80, CD86 and HLA-DR on CML and AML cells induced by GM-CSF and IL-4 was assayed by flow cytometry in vitro. Then one-way mixed lymphocyte reaction was carried out, with induced leukemia cells as stimulating cells and auto-T lymphocytes as reactive cells. The secretion of IFN-gamma from T lymphocytes was determined by double antibody sandwich ELISA. The results showed that GM-CSF and IL-4 significantly upregulated the expression of CD80, CD86 and HLA-DR on CML cells and CD80 and CD86 on AML cells, which could stimulate the T lymphocyte proliferation and high secretion of IFN-gamma (in CML group) of autologous T lymphocytes. It is concluded that the CML and AML cells induced by GM-CSF and IL-4 have the ability to present tumor specific antigen to auto-T lymphocyte.
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PMID:[Proliferation and IFN-gamma secretion of autologous T lymphocytes stimulated by myeloid leukemia cells induced with rhGM-CSF and rhIL-4]. 1251 7

Dendritic cell (DC) plays a key role in antitumor immune response. However, there is a deficiency of DC function in the majority of leukemia patients. It is a novel idea that expanding DC in vitro and enhancing their antitumor immune function and DC-based tumor vaccines may be used as an efficient immune therapy for leukemia. In the project, the condition to induce DC from myeloid leukemia cell lines and its anti-leukemia response were investigated. HL-60, K562 and THP-1 cells were cultured with various combinations of cytokines for inducing DC. The morphologic features were analyzed with optical and electron microscopy. The phenotype of DC was detected by FCM with CD1a, CD40, CD80, CD86, HLA-A, B, C and HLA-DR monoclonal antibodies. The ability of DC stimulating lymphocyte proliferation was observed by allo-mixed lymphocyte reaction using (3)H-TdR incorporation. Cytotoxicity assay was measured by (51)Cr-release method. The level of IL-12 and IFN-gamma in supernatant of DC culture was measured by ELISA. It was proved that the DCs derived from K562, HL-60 and THP-1 cells showed a typical morphology of dendritic cell. The induced cells expressed the surface differentiation antigens of DC. A high expression of phenotypes was found in HL-60-DC and THP-1-DC stimulated by GM-CSF + IL-4 + TNF-gamma and K562-DC with GM-CSF + IL-4 + IL-12. The DCs from the 3 leukemia cell lines stimulated allo-MLR and CTL reaction strongly. Different contents of IL-12 were detected in the supernatants of DC culture and IFN-gamma in the coculture of DC and blood mononuclear cells. It is concluded that the myeloid leukemia cells are able to be induced DCs by cytokines in vitro. The different leukemia cells need different cytokines and cultural conditions. DCs derived from leukemia cells express phenotype of antigen-presenting cells. They have the ability of stimulating T lymphocyte proliferation and inducing CTL reaction to clear leukemia cells, and the DCs secrete IL-12 and increase secretion of IFN-gamma by T cells.
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PMID:[Study on induction of dendritic cells from myeloid leukemia cell lines and their antitumor immune function]. 1251 92

The ability of acute myeloid leukaemia (AML) cells to acquire dendritic cell (DC)-like characteristics in vitro with a rapid culture method based either on the phorbol ester PMA or calcium ionophores has been studied in comparison to conventional AML-DC cultures with the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor-alpha (TNF-alpha), interleukin-3 (IL-3), SCF, FLT3-L and IL-4. In all AML patients, antigen-presenting cells (APC) could be generated from leukaemic cells in 2 days by incubation with PMA or calcium ionophore (A23187 or ionomycin) in the presence as well as in the absence of IL-4. In 30 out of 36 patients APC could be generated after 2 weeks of culture in cytokine-enriched medium. AML-APC cultured with PMA or calcium ionophores immunophenotypically and functionally were at a more mature stage than those cultured in cytokine-enriched medium. The most mature APC were generated by calcium ionophore A23187 plus IL-4, as evidenced by the higher expression of CD40, CD80, CD86 and HLA-DR. Autologous T cell mediated cytotoxicity towards AML blast cells in vitro was observed in 2 cases tested. The persistence of cytogenetic abnormalities confirmed the leukaemic origin of the AML-APC. The generation of AML-APC was possible from freshly isolated as well as cryopreserved material. Our data show that generation of sufficient AML-APC by A23187 plus IL-4 is feasible, for vaccination purposes, in approximately 70% of AML specimens, offering a time-saving and cost-effective approach in preparing anti-leukaemia vaccines.
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PMID:Rapid generation of antigen-presenting cells from leukaemic blasts in acute myeloid leukaemia. 1253 36

The purpose of this study was to investigate the function of dendritic cells derived from chronic myeloid leukemia (CML-DC). Mononuclear cells were prepared from bone marrow and peripheral blood of 24 patients with CML, and the DCs were obtained by incubation of MNCs with media containing GM-CSF, IL-4 and TNF-alpha. The phenotype of CML-DCs was identified by flow cytometry. FITC-dextran uptake, (3)H-TdR incorporation or MTT assay and lactate dehydrogenase release assay were used to detect uptake of exogenous antigen in immature DCs, the antigen presenting ability in mature DCs and specific cytotoxicity of CTL to leukemic cells, respectively. The DCs with high expression of CD1a, CD86, CD80, HLA-DR, CD54 and CD4 were obtained from marrow and blood of patients with CML. The uptake of FITC-DX was observed in early DCs. There was a potent stimulation to allo-MLR in DCs cultured for 7 - 10 days, and a lightly lower stimulation to auto-MLR. CML-DCs can induce the generation of specific cytotoxic T cells. These results suggest that CML-DCs are functional DCs with the ability to induce anti-leukemia effect.
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PMID:[The Function of Dendritic Cells Derived from Chronic Myeloid Leukemia] 1257 75

Recently, leukaemia-associated antigens (LAA) recognized by T lymphocytes, such as Wilm's tumour-1 (WT-1) or pathogenesis-related protein-1 (PR-1), have been identified. For immunotherapies that employ antigen peptides, either alone or pulsed on dendritic cells (DC), the expression of human leucocyte antigen (HLA) molecules on the targeted leukaemic blasts (LB) is crucial. The co-stimulatory molecules CD80 and CD86 give the secondary signal to T lymphocytes that is necessary for the lysis of leukaemia cells, and CD40 enhances the efficacy of antigen presentation. Here, the expression of HLA-ABC, HLA-A2, HLA-DR, CD40, CD80 and CD86 was flow cytometrically examined in blood samples from 24 healthy volunteers (HV), 24 patients with newly diagnosed acute myeloid leukaemia (AML) and five patients with relapsed AML. The expression of HLA-ABC, CD40, CD80 and CD86 was significantly reduced on LB in comparison with monocytes of HV. HLA-A2 and HLA-DR expression was similar on LB and on monocytes of HV. In AML patients, the expression of HLA and CD86 molecules was significantly higher on LB than on CD33/CD34-negative monocytes. CD40 and CD80 molecules were deficient on AML blasts. The preservation of HLA molecules and CD86 on LB of the majority of AML patients at the time of diagnosis and even at relapse of the disease are prerequisites for LAA-targeted immunotherapies in these patients.
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PMID:Expression of human leucocyte antigens and co-stimulatory molecules on blasts of patients with acute myeloid leukaemia. 1264 70

The ability of acute lymphoblastic leukemia (ALL) blasts to mediate costimulatory signals during T-lymphocyte activation was investigated in an experimental model in which monoclonal T-cell populations were stimulated with standardized activation signals (anti-CD3 and anti-CD28 monoclonal antibodies; phytohemagglutinin, PHA). Leukemia cells from 12 consecutive ALL patients with high peripheral blood blast counts were studied. Proliferative T-cell responses were detected for a majority of these patients when irradiated leukemia blasts were used as accessory cells during activation. T-cell cytokine release was also observed for most patients when using nonirradiated ALL accessory cells. Low or undetectable cytokine levels were usually observed for CD8+ clones, whereas the CD4+ clones often showed a broad cytokine response with release of interleukin-2 (IL-2), IL-4, IL-10, IL-13 and interferon gamma(IFN-gamma) in the presence of the ALL accessory cells. ALL blasts were also able to function as allostimulatory cells for normal peripheral blood mononuclear responder cells. However, both T-cell proliferation and cytokine release showed a wide variation between ALL patients. The accessory cell function of ALL blasts showed no correlation with the release of immunomodulatory mediators (IL-2, IL-10, IL-15) or the expression of any single adhesion/costimulatory membrane molecule (CD54, CD58, CD80, CD86) by the blasts. We conclude that for a majority of patients, native ALL blasts can mediate costimulatory signals needed for accessory cell-dependent T-cell activation, but differences in costimulatory capacity between ALL patients affects both the proliferative responsiveness and cytokine release by activated T cells.
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PMID:Human acute lymphoblastic leukemia (ALL) blasts as accessory cells during T-cell activation: differences between patients in costimulatory capacity affect proliferative responsiveness and cytokine release by activated T cells. 1266 46


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