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)

CD20 is a B-cell differentiation antigen and known to induce apoptosis in Burkitt's lymphoma/leukemia (BL) cells upon antibody-mediated crosslinking. We examined the biological effect of CD20 crosslinking on BL cell lines and observed that apoptosis induction is accompanied by activation of multiple caspases, including caspase-8, -9, -3, -2, and -7. Further investigation revealed a clear synergism between apoptosis mediated by CD20 and by B-cell antigen receptor (BCR). Examination of the effect of simultaneous crosslinking of other cell surface molecules with crosslinking of CD20 or BCR on apoptosis induction showed that these molecules had either a synergistic or inhibitory effect on induction of apoptosis. It is worth noting that some molecules had a different effect on CD20- and BCR-mediated apoptosis. Simultaneous crosslinking of the molecules CD10, CD22, CD72, and CD80 inhibited BCR-mediated apoptosis, but enhanced CD20-mediated apoptosis. Further studies revealed that regulation of CD20-induced apoptosis by other costimulatory molecules is achieved by modification of caspase activation. CD20-mediated apoptosis in BL cells may provide not only a model for understanding the mechanism regulating clonal selection of B cells but a new therapeutic strategy for BL patients.
Leukemia 2003 Jun
PMID:Costimulatory signals distinctively affect CD20- and B-cell-antigen-receptor-mediated apoptosis in Burkitt's lymphoma/leukemia cells. 1276 85

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.
 ...
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

Our goal is to develop cell vaccines against leukemia cells, genetically modified to express molecules with potent immune-stimulatory capacities. Pre-clinical evaluation of this approach in murine models has demonstrated efficient anti-leukemic responses with the expression of immunomodulators, in particular GM-CSF and CD80, in irradiated cell vaccines. We have previously shown efficient insertion of GM-CSF and CD80 genes into primary human leukemia cells with the use of second and third generation self-inactivating (SIN) lentiviral vectors (Blood 96 (2000), 1317; Leukemia 16 (2002), 1645). The advantages of lentiviral vectors for development of autologous leukemia cell vaccines include: (1) efficient and consistent gene delivery; (2) high levels of transgene expression; (3) persistent expression of the transduced gene; (4) no viral proteins, as only the transduced gene is expressed; (5) no undesirable cytotoxic effects, and; (6) simplicity of use [leukemia cells are exposed to vector(s) only once]. In this work, we evaluated the insertion of the central polypurine tract and the central termination sequence into a SIN lentiviral vector encoding for GM-CSF and CD80, which significantly enhanced the transduction efficiency of primary leukemia cells and provided higher levels of GM-CSF and CD80 co-expression. We also demonstrate a methodology to deliver simultaneously a combination of immunomodulatory molecules (GM-CSF, CD80, IL-4, and CD40L) to activate different pathways of immune stimulation. Therefore, lentiviral vectors offer a simple, versatile, and reliable approach for engineering leukemic cells for use as cell vaccines.
 ...
PMID:The use of lentiviral vectors in gene therapy of leukemia: combinatorial gene delivery of immunomodulators into leukemia cells by state-of-the-art vectors. 1285 Apr 80

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.
 ...
PMID:Reconstitution of CD40 and CD80 in dendritic cells generated from blasts of patients with acute myeloid leukemia. 1286 19

Chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by a profound dysregulation of the host immune system that has a marked impact on the clinical course of the disease. To date, the competence of the circulating dendritic cell (DC) compartment in CLL patients has not been investigated. To address this issue, we sorted DC precursors from the peripheral blood of CLL patients and found a profoundly altered compartment as compared with normal donors. CLL DCs proved a morphologically and phenotypically immature population, lacking the maturation antigen CD83 and the costimulatory molecule CD80, unable to induce a significant proliferative response in allo-mixed lymphocyte reaction, with a reduced ability to release interleukin 12 and to drive a type 1 T-cell response. To investigate whether these defects could be ascribed to inhibiting soluble factors released by the leukemic clone, DCs were generated in vitro from normal monocytes in the presence of allogeneic CLL cells. The addition of CLL cells induced similar markers of abnormal maturation and functional impairment with an inhibition in the expression of costimulatory molecules and a reduction of their allo-stimulatory ability. The blocking of interleukin 6 activity was able to revert the inhibition in a proportion of patients. Taken together, these findings indicate that mechanisms of tumor-induced DC inhibition are operational in CLL patients, resulting in both maturative and functional defects in the circulating DC compartment, with a potential functional impact in the regulation of in vivo T-cell immune responses.
 ...
PMID:The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response. 1290 23

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.
 ...
PMID:Altered patterns of T cell cytokine production induced by relapsed pre-B ALL cells. 1292 52

The existence of an immune based graft-versus-leukaemia (GvL) effect highlighted the prospect of managing relapsed leukaemias with T cell-based adoptive immunotherapy. Thus, various strategies have been explored for the in vitro expansion of acute myeloid leukaemia (AML)-specific T cells. In a popular approach, AML blasts have been genetically modified to express co-stimulatory molecules essential for effective T cell priming. One such tactic has been the modification of AML cells to express the B7/CD80 co-stimulatory molecule that binds to CD28 on T cells initiating events that culminate in enhanced cytokine production, proliferation and development of effector functions by T cells. The success of these strategies has been limited by difficulties in attaining sufficient transduction efficiencies and associated high levels of CD80 expression. We demonstrate that these problems can be circumvented by using anti-CD28 monoclonal antibody. Furthermore, we show that the synergistic relationship between CD80/CD28 pathway and interleukin 12 cytokine (IL-12), documented in the generation of cytotoxic T lymphocytes (CTL) for solid tumours, also applies to AML. CD28/IL-12 synergy facilitated the proliferation of allogeneic T cells in response to stimulation with primary AML blasts. The synergy also favoured generation of a Th1-type immune response, evidenced by gamma interferon (IFN-gamma) secretion and facilitated naive and memory T cell proliferation. Unlike some methods of in vitro T cell expansion, use of CD28/IL-12 synergy left T cells in the physiologically appropriate CD45RA-/CCR7- subsets known to be associated with immediate cytotoxic functions.
 ...
PMID:In vitro co-stimulation with anti-CD28 synergizes with IL-12 in the generation of T cell immune responses to leukaemic cells; a strategy for ex-vivo generation of CTL for immunotherapy. 1293 Mar 76

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.
 ...
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.
 ...
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.
 ...
PMID:Retroviral transduction of acute myeloid leukaemia-derived dendritic cells with OX40 ligand augments their antigen presenting activity. 1498 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>