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

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

We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) gene therapy with transgene-expressing myeloid progenitor cells (32DTNF-alpha) is effective in inhibiting the progression of leukemia with a lethal dose of murine 32Dp210 myeloid leukemia cells. Because TNF-alpha has been shown to induce the activation and maturation of dendritic cells (DCs), we investigated the effect of TNF-alpha secreted by transduced cells (32DTNF-alpha cells) on the activation of DCs and their role in the production of antileukemic cytotoxic T lymphocytes (CTLs). We demonstrate that administration of 32DTNF-alpha cells to the mice enhances the allo-stimulatory capacity of the splenic (CD11c+) and bone marrow-derived DCs in both mixed leukocyte response and CTL development. The enhanced allo-stimulatory capacity of splenic DCs from mice injected with 32DTNF-alpha cells correlated with increase in the cell-surface expression of the costimulatory molecules CD40, CD80, CD86, and major histocompatibility complex (MHC) class II molecules (I-Ak), and production of interleukin-12 (IL-12). Furthermore, administration of 32DTNF-alpha cells during immunization with irradiated 32Dp210 leukemia cells augmented the capacity of splenic DCs to stimulate antileukemic CTL response in spleen cells. Collectively, these data suggest that in vivo production of TNF-alpha by transduced cells enhances the phenotypic and functional activation of DCs, resulting in induction of a stronger antileukemic cytotoxic T-cell immune response.
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PMID:In vitro analysis of the antileukemic effect of tumor necrosis factor-alpha gene therapy with myeloid progenitor cells: the role of dendritic cells. 1282 12

Acute myeloid leukemia (AML) is a clonal disease of hematopoiesis with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Immunotherapy with dendritic cells (DCs) eliciting specific T cell responses to leukemia-associated antigens (LAAs) might be a therapeutic option. DCs must express HLA class I/II molecules and the costimulatory molecules CD40, CD80 and CD86 to effectively activate T cells for the subsequent lysis of leukemic blasts. The expression of these antigens on DCs generated from 15 AML patients (AML-DCs) and on DCs generated from 15 healthy volunteers (HV-DCs) was analyzed by FACS. All DCs displayed the typical morphology and tested negative for B, T and NK cell markers. The sustained mRNA expression of LAAs such as PRAME, RHAMM or WT-1 proved that the AML-DCs originated from AML blasts. Compared with AML blasts, the expression of CD40, CD80, CD86 and HLA-DR was upregulated during DC culture to a median of 80-98% on AML-DCs. HLA-ABC was preserved on AML-DCs (median 95%). Expression of CD40, CD80 and CD83 remained lower on AML-DCs than on HV-DCs. AML-DCs express at least one LAA and strongly express HLA and costimulatory molecules, the prerequisites for eliciting T cell responses. AML-DCs may play a role in vaccine-based immunotherapies for AML patients.
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PMID:Reconstitution of CD40 and CD80 in dendritic cells generated from blasts of patients with acute myeloid leukemia. 1286 19

Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.
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PMID:Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL. 1290 78

Relapse of pediatric acute lymphoblastic leukemia (ALL) remains a significant clinical problem. The graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation indicates that immune mechanisms may play a role in the control of ALL blasts. In this study, we analyzed primary diagnostic and relapsed pre-B ALL samples for the surface expression of several molecules implicated in immune responses and for the induction of allogeneic T cell responses. There were no significant differences in the expression of CD11a, CD40, CD80 and CD86 or MHC classes I and II molecules between the diagnostic and relapsed samples. We found no significant differences in the overall ability of diagnostic and relapsed pre-B ALL samples to induce T cell proliferation and cytokine production. However, in the case of T cell responses induced by diagnostic ALL samples, there was excellent correlation between proliferation and production of all cytokines analyzed. In the case of relapsed samples, the only correlation obtained was with IL-5. This observation indicates that the nature of the immune response generated by relapsed ALL cells in an allogeneic setting differs from that obtained with diagnostic samples, suggests a biasing towards a Th2 response may contribute to the evasion of effective immune responses by relapsed ALL.
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PMID:Altered patterns of T cell cytokine production induced by relapsed pre-B ALL cells. 1292 52

Dendritic cells (DCs) are potent antigen-presenting cells and play an important role in T-cell-mediated immunity. DCs have been shown to induce strong antitumour immune responses both in vitro and in vivo. One way of providing the DCs with all relevant tumour antigens would be to incubate the DCs with material from dead tumour cells. We have examined the uptake of apoptotic and necrotic K562 leukaemia cells by DCs under different culture conditions. Results from coincubation experiments strongly suggested that uptake of apoptotic K562 cells was dependent upon the addition of autologous serum (AS). Under these conditions, 47-79% of all DCs were shown to ingest apoptotic material. AS also seemed to be important for the expression of functionally important markers, most notably HLA class I, CD86, CCR7 and CD83. The vast majority of DCs were shown to ingest necrotic material from K562 cells, with no additional effect of AS. The results suggest that incubation of DCs with apoptotic material for cell therapeutic purposes may best be performed in the presence of AS.
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PMID:Uptake of Apoptotic K562 Leukaemia Cells by Immature Dendritic Cells is Greatly Facilitated by Serum. 1462 26

The addition of specific cytokines is a mandatory prerequisite for the generation and subsequent function of leukaemia-derived dendritic cells (DC) believed to induce specific T-cell responses. In this study, we report the ability of blasts derived from cytogenetically classified acute myeloid leukaemia (AML) cells with the inversion of chromosome 16 to stimulate allogeneic and autologous T cells without additional cytokines. They displayed a measurable immunogenic effect. Sixteen of 17 established, stable AML cell lines, growing primary tumour cells from patients with a variety of chromosomal abnormalities, altered their surface marker expression pattern in proliferating culture. They lost the progenitor markers CD33, CD13 and CD34 while significantly increasing expression of the co-stimulatory molecules CD80 and CD86. Four cell lines derived from inv(16) positive blasts mounted allogeneic as well as autologous T cell activation with concomitant expression of CD25 and CD69. Moreover, oligoclonal expanded T cells were able to lyse inv(16) AML blasts in a specific major histocompatibility complex class I-restricted and CD80-dependent manner. AML blasts with karyotypes other than inv(16) activated T cells, but without inducing a significant proliferation. We conclude from this study that AML blasts derived from inv(16) positive patients may be preferential targets for AML immunotherapy strategies.
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PMID:Core-binding factor-beta positive acute myeloid leukaemia cells induce T-cell responses. 1463 72

Peptide-pulsed dendritic cells can stimulate T cells showing specific cytotoxicity in chronic myelogenous leukemia. We tried to induce a specific cytotoxic T-cell response stimulated by RNA-pulsed dendritic cells in acute myelogenous leukemia. The total RNA of WEHI-3BD+, a myelomonocytic leukemia cell line derived from BALB/c mice, was transfected into dendritic cells induced from bone marrow nucleated cells of BALB/c mice with granulocyte macrophage colony-stimulating factor (GM-CSF) and lipopolysaccharide (LPS) using liposome. RNA-pulsed dendritic cells were injected into the peritoneal cavity of BALB/c mice, and splenic T cells were isolated for antigen-stimulated proliferation and leukemia-specific cytotoxicity assay. Cultured bone marrow nucleated cells expressed dendritic cell markers including MHC class II antigen, CD80, CD86, and CD11c. T cells stimulated by RNA-pulsed dendritic cells showed enhanced proliferation than those stimulated by unpulsed dendritic cells (P = 0.05) and showed dose-dependent specific cytotoxicity against WEHI-3BD+ cells. We concluded total RNA-pulsed dendritic cells could induce a specific T-cell cytotoxicity in acute myelogenous leukemia.
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PMID:Induction of cytotoxic T lymphocytes by dendritic cells pulsed with murine leukemic cell RNA. 1497 90

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


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