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:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Host immunity influences clinical manifestations of human T-cell leukemia virus type 1 (HTLV-1) infection. In this study, we demonstrated that HTLV-1-transformed tumors could develop in immunocompetent rats by blocking a costimulatory signal for T-cell immune responses. Four-week-old WKA/HKm rats were treated with monoclonal antibodies (MAbs) to CD80 and CD86 and subcutaneously inoculated with syngeneic HTLV-1-infected TARS-1 cells. During MAb treatment for 14 days, TARS-1 inoculation resulted in the development of solid tumors at the site of inoculation, which metastasized to the lungs. In contrast, rats not treated with MAbs promptly rejected tumor cells. Splenic T cells from MAb-treated rats indicated impairment of proliferative and cytotoxic T-lymphocyte responses against TARS-1 in vitro compared to untreated rats. However, tumors grown in MAb-treated rats regressed following withdrawal of MAb therapy. Recovery of TARS-1-specific T-cell immune responses was associated with tumor regression in these rats. Our results suggest that HTLV-1-specific cell-mediated immunity plays a critical role in immunosurveillance against HTLV-1-transformed tumor development in vivo.
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PMID:Development of human T-cell leukemia virus type 1-transformed tumors in rats following suppression of T-cell immunity by CD80 and CD86 blockade. 1059 Jan 32

Most human myeloid leukemias express both class I and class II HLA and it has been postulated that leukemia-associated peptides are presented by those molecules. It is possible, however, that leukemia cells escape the immune surveillance by lacking expression of "costimulatory" molecules required for activating the immune response. Human erythroleukemia line (HEL) has been the subject of previous detailed studies demonstrating surface expression of bona fide HLA molecules but inability to stimulate allogeneic response of proliferative or cytolytic T cells. We found that an HLA-DR+ subclone (HEL-DR+) expresses LFA-1, LFA-3, ICAM-1, ICAM-3, but neither CD80 nor CD86 on the surface. Transfection of CD80 cDNA into HEL-DR+ cells induced the allogeneic response of purified T cells from both cord blood and peripheral blood of adult donors, demonstrating that CD80 expression could lead to accessory cell-independent activation of naive T cells. Priming allogeneic peripheral blood T cells by HEL-DR+/CD80+ also lead to generation of cytotoxic T lymphocytes that lysed both HEL-DR+/CD80+ and wild type HEL-DR+ equally well, confirming CD80 expression is required only in the CTL induction phase but not in the CTL effector phase. We established and maintained alloproliferative T cell clones from adult blood by stimulation with the HEL-DR+/CD80+ line. The clones could respond not only to HEL-DR+/CD80+ line but also to the HEL-DR+ line; however, the proliferative response to HEL-DR+/CD80+ was amplified and sustained compared to the short-lived response to wild type HEL-DR+ cells. Therefore, expression of CD80 by HEL-DR+ cells was determinant both to initiate and sustain the T cell response. These experiments support the hypothesis that lack of expression of "costimulatory" molecules for T cells contributes to leukemia escape from immune surveillance, and provide preliminary data for the use of CD80 transfection in the immunotherapy of human leukemia.
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PMID:The role of T cell costimulation by CD80 in the initiation and maintenance of the immune response to human leukemia. 1060 80

Acute myeloid leukemia (AML) cells are malignant counterparts of normal myeloid pathway progenitors. Myeloid progenitors differentiate into professional antigen presenting cells (APC) under the essential influence of GM-CSF along with additional cytokines. Twelve cases of human AML were tested for ability to be differentiated toward a professional APC phenotype in short-term culture with addition of GM-CSF and the following recombinant proteins: TNFalpha, IL-4, CD40 ligand, Flt3 ligand and SCF. Significant upregulation of CD80 (B7-1) and enhancement of alloantigen presentation was seen with the addition of GM-CSF and TNFalpha alone or with additional cytokines. The combination of GM-CSF and TNFalpha, either alone or in combination with an additional cytokine, resulted in enhancing alloantigen presentation by at least two-fold over the media control group in 10/12 patients studied, and resulted in CD80 expression of greater than 15% in 11/12 patients studied. In AML cultures with GM-CSF and TNFalpha, coexpression of CD80 and either CD34 or an aberrant surface marker (CD56) was seen. In one case, sorted CD80, cells retained a characteristic cytogenetic marker and CD34 expression, proving their derivation from an AML precursor. These studies verify other reports of in vitro differentiation of human AML precursors into enhanced APC, suggesting that this phenomenon could be utilized for immunotherapy strategies aimed at enhancing presentation of leukemia antigens to T cells.
Leukemia 2000 Mar
PMID:Cytokine upregulation of the antigen presenting function of acute myeloid leukemia cells. 1072 Jan 35

Gene transfer of various cytokines and co-stimulatory molecules has been reported to induce a potent antileukemic immunity in murine models, however, the relative efficiency and possible synergistic effects between candidate genes have not been extensively investigated. We analyzed in a murine model of BCR/ABL acute leukemia whether gene transfer of CD154, CD80 or GM-CSF as a single agent or combination of CD154 + GM-CSF, CD80 + CD154 and GM-CSF + CD80 in leukemic cells could enhance survival. We observed that CD154 gene transfer induced a marked inhibition of leukemogenicity, and also that CD154 and combination of GM-CSF and CD80 gene transfer protected mice against subsequent challenge with leukemic cells and had a therapeutic effect for a pre-established leukemia disease. We also found minimal residual leukemic disease by RT-PCR for 6 to 12 months in 0 to 25% of animals injected with transduced leukemic cells and surviving the challenge without evidence of disease, except in the control empty plasmid group where very few mice survived the challenge but all of those were positive by RT-PCR. These findings suggest that leukemic cell vaccination by gene transfer can induce a tumor dormancy phenomenon compatible with long-term survival.
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PMID:Gene transfer of GM-CSF, CD80 and CD154 cDNA enhances survival in a murine model of acute leukemia with persistence of a minimal residual disease. 1091 2

Cell vaccines engineered to express immunomodulators have shown feasibility in eliminating leukemia in murine models. Vectors for efficient gene delivery to primary human leukemia cells are required to translate this approach to clinical trials. In this study, second-generation lentiviral vectors derived from human immunodeficiency virus 1 were evaluated, with the cytomegalovirus (CMV) promoter driving expression of granulocyte-macrophage-colony-stimulating factor (GM-CSF) and CD80 in separate vectors or in a bicistronic vector. The vectors were pseudotyped with vesicular stomatitis virus G glycoprotein and concentrated to high titers (10(8)-10(9) infective particles/mL). Human acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia cell lines transduced with the monocistronic pHR-CD80 vector or the bicistronic pHR-GM/CD vector became 75% to 95% CD80 positive (CD80(+)). More important, transduction of primary human ALL and AML blasts with high-titer lentiviral vectors was consistently successful (40%-95% CD80(+)). The average amount of GM-CSF secretion by the leukemia cell lines transduced with the pHR-GM-CSF monocistronic vector was 2182.9 pg/10(6) cells per 24 hours. Secretion was markedly lower with the bicistronic pHR-GM/CD vector (average, 225.7 pg/10(6) cells per 24 hours). Lower amounts of CMV-driven messenger RNA were detected with the bicistronic vector, which may account for its poor expression of GM-CSF. Primary ALL cells transduced to express CD80 stimulated T-cell proliferation in an autologous mixed lymphocyte reaction. This stimulation was specifically blocked with monoclonal antibodies reactive against CD80 or by recombinant cytotoxic T-lymphocyte antigen 4-immunoglobulin fusion protein. These results show the feasibility of efficiently transducing primary leukemia cells with lentiviral vectors to express immunomodulators to elicit antileukemic immune responses. (Blood. 2000;96:1317-1326)
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PMID:Lentiviral vectors for efficient delivery of CD80 and granulocyte-macrophage- colony-stimulating factor in human acute lymphoblastic leukemia and acute myeloid leukemia cells to induce antileukemic immune responses. 1094 73

Peripheral blood mononuclear cells (PBMCs) from 15 newly diagnosed acute myeloid leukemia (AML) patients were cultured in fetal calf serum-free media supplemented with either granulocyte/macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-4 and tumor necrosis factor alpha (TNFalpha), or GM-CSF, stem cell factor (SCF), TNFalpha and transforming growth factor beta (TGFbeta) in order to generate leukemia-derived dendritic cells (DCs). Cultured cells were analyzed by flow cytometry with respect to DC-associated surface molecules (CD1a, CD83, CD40, CD80, CD86, HLA-DR) when they showed significant DC morphology in culture (14 cases). After cultivation, neo-expression or upregulation of CD1a antigen was found in 8 samples, CD83 in 2, CD40 in 14, CD80 in 7, and CD86 in 9. Twelve of 14 AMLs, in which DC morphology could be induced upon cultivation, showed upregulation of at least 2 DC-associated molecules. For induction of DC differentiation. GM-CSF, IL-4 plus TNFalpha was superior in 11 cases, and better results were obtained with GM-CSF, SCF, TNFalpha plus TGFbeta in 3 cases. In 7 of 14 samples tested, a marked increase of the T-cell stimulatory capacity could be demonstrated in the allogeneic mixed lymphocyte reaction. The leukemic origin of in vitro-generated DCs was demonstrated by fluorescence in situ hybridization in a patient with translocation t(15;17). Our results suggest that the use of different culture conditions may extend the number of AML patients in which a differentiation towards the DC lineage can be induced in vitro.
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PMID:Culture requirements for induction of dendritic cell differentiation in acute myeloid leukemia. 1096 83

The ability of acute myelogenous leukemia (AML) blasts to mediate costimulatory signals during T lymphocyte activation was investigated in an experimental model where monoclonal T cell populations were stimulated with standardized activation signals (anti-CD3, anti-CD2, and anti-CD28 monoclonal antibodies and phytohemagglutinin). Proliferative T cell responses were detected for all AML patients (n = 16) when irradiated leukemia blasts were used as accessory cells during activation. T cell cytokine release was also observed for all patients when nonirradiated AML accessory cells were used, and for most patients a broad cytokine response (interleukin (IL) 2, IL4, IL10, IL13, and interferon-gamma) was detected. However, both T cell proliferation and cytokine release showed a wide variation among AML patients, and T cell responsiveness was in addition dependent both on the nature of the activation signal and on differences between individual T cell clones. The accessory cell function of AML blasts showed no correlation with the release of any single immunomodulatory soluble mediator (IL1beta, IL6, TNF-alpha, soluble IL2 receptors) or the expression of any particular adhesion/costimulatory membrane molecule (CD54, CD58, CD80, and CD86) by the blasts. However, blocking studies with anti-CD58 and anti-CD80/86 monoclonal antibodies demonstrated that both pathways can be involved when AML blasts are used as accessory cells, but the relative importance and the final effects of signaling through these pathways differ between AML populations. Although there is a wide interpatient variation, we conclude that for a majority of patients the native AML blasts can mediate adequate costimulatory signals needed for accessory cell-dependent T cell activation.
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PMID:Acute myelogenous leukemia blasts as accessory cells during in vitro T lymphocyte activation. 1116 36

The ability of leukemic cells to differentiate to mature dendritic cells (DCs) was investigated in six acute myelomonocytic or monocytic leukemia cases. It was found that CD14 positive cells were more efficiently changed to CD83 positive mature typed DCs with granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin-4 (IL-4) and tumor necrosis factor alpha (TNF-alpha) compared with CD14 negative cells. Such leukemia derived DCs expressed a sufficient level of costimulatory molecules (CD80 and CD86), and were shown to be monoclonal based on an the X-inactivation analysis. They also stimulated not only allo- but auto-T lymphocytes, which thereafter became cytotoxic T lymphocytes (CTLs).
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PMID:The efficient generation of CD83 positive immunocompetent dendritic cells from CD14 positive acute myelomonocytic or monocytic leukemia cells in vitro. 1122 22

Herpes simplex virus (HSV)-based vectors have favorable biologic features for gene therapy of leukemia and lymphoma. These include high transduction efficiency, ability to infect postmitotic cells, and large packaging capacity. The usefulness of HSV amplicon vectors for the transduction of primary human B-cell chronic lymphocytic leukemia (CLL) was explored. Vectors were constructed encoding beta-galactosidase (LacZ), CD80 (B7.1), or CD154 (CD40L) and were packaged using either a standard helper virus (HSVlac, HSVB7.1, and HSVCD40L) or a helper virus-free method (hf-HSVlac, hf-HSVB7.1, and hf-HSVCD40L). Both helper-containing and helper-free vector stocks were studied for their ability to transduce CLL cells, up-regulate costimulatory molecules, stimulate allogeneic T-cell proliferation in a mixed lymphocyte tumor reaction, and generate autologous cytotoxic T lymphocytes (CTLs). Although helper-containing and helper-free amplicon stocks were equivalent in their ability to transduce CLL cells, a vigorous T-cell proliferative response was obtained using cells transduced with hf-HSVB7.1 but not with HSVB7.1. CLL cells transduced with either HSVCD40L or hf-HSVCD40L were compared for their ability to up-regulate resident B7.1 and to function as T-cell stimulators. Significantly enhanced B7.1 expression in response to CD40L was observed using hf-HSVCD40L but not with HSVCD40L. CLL cells transduced with hf-HSVCD40L were also more effective at stimulating T-cell proliferation than those transduced with HSVCD40L stocks and were successful in stimulating autologous CTL activity. It is concluded that HSV amplicons are efficient vectors for gene therapy of hematologic malignancies and that helper virus-free HSV amplicon preparations are better suited for immunotherapy.
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PMID:Development of herpes simplex virus-1 amplicon-based immunotherapy for chronic lymphocytic leukemia. 1143 95

Blood monocytes and CD34(+) haemopoietic progenitor cells, as well as certain leukaemic cell lines, acquire characteristics of mature dendritic cells (DC) after stimulation with calcium ionophore (CI). We studied whether the in vitro treatment of primary human acute myelogenous leukaemia (AML) cells with CI leads to differentiation towards DC. Blast cells derived from nine AML patients were cultured in the presence of either CI or an established differentiation cocktail consisting of granulocyte-macrophage colony-stimulating factor plus interleukin 4 and tumour necrosis factor-alpha for 5-7 d. Microscopic examination revealed that under both conditions, AML cells were shifted along the DC pathway. In seven out of nine cases, CI-cultivation led to a higher proportion of cells with dendritic morphology. The percentage of CD40 and CD86 expressing cells was significantly increased upon CI treatment compared with cytokine-cultured cells. DC molecules as CD80 and CD83 were up-regulated upon calcium mobilization of AML cells in four out of nine samples. In four cases, CI-treated stimulator cells induced an enhanced proliferative allogeneic T-cell response compared with cytokine-treated stimulator cells. In conclusion, these data demonstrate that CI treatment is an alternative in vitro strategy to differentiate human AML cells into DC.
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PMID:Calcium ionophore: a single reagent for the differentiation of primary human acute myelogenous leukaemia cells towards dendritic cells. 1152 71


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