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)

Cytotoxic T lymphocytes (CTLs) specific for hematopoietic-restricted minor histocompatibility antigens (mHags) are important reagents for adoptive immunotherapy of relapsed leukemia after allogeneic stem cell transplantation. However, expansion of these CTLs to therapeutic numbers is often hampered by the limited supply of antigen-presenting cells (APCs). Therefore, we evaluated whether cell-sized latex beads coated with HLA/mHag complexes HLA-A2/HA-1 or HLA-A2/HA-2 and recombinant CD80 and CD54 molecules can replace professional APCs. The artificial antigen-presenting constructs (aAPCs) effectively stimulated HA-1- and HA-2-specific CTL clones as shown by ligand-specific expansion, cytokine production, and maintenance of cytotoxic activity, without alteration of CTL phenotype. Furthermore, HA-1-specific polyclonal CTL lines were enriched as efficiently by aAPCs as by autologous HA-1 peptide-pulsed dendritic cells. Thus, aAPCs coated with HLA/mHag complexes, CD80, and CD54 may serve as tools for in vitro enrichment of immunotherapeutic mHag-specific CTL lines.
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PMID:Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen-specific cytotoxic T lymphocytes. 1503 Dec 3

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Although the viral transactivation factor, Tax, has been known to have apparent transforming ability, the exact function of Tax in ATL development is still not clear. To understand the role of Tax in ATL development, we introduced short-interfering RNAs (siRNAs) against Tax in a rat HTLV-1-infected T-cell line. Our results demonstrated that expression of siRNA targeting Tax successfully downregulated Tax expression. Repression of Tax expression was associated with resistance of the HTLV-1-infected T cells to Tax-specific cytotoxic-T-lymphocyte killing. This may be due to the direct effect of decreased Tax expression, because the Tax siRNA did not alter the expression of MHC-I, CD80, or CD86. Furthermore, T cells with Tax downregulation appeared to lose the ability to develop tumors in T-cell-deficient nude rats, in which the parental HTLV-1-infected cells induce ATL-like lymphoproliferative disease. These results indicated the importance of Tax both for activating host immune response against the virus and for maintaining the growth ability of infected cells in vivo. Our results provide insights into the mechanisms how the host immune system can survey and inhibit the growth of HTLV-1-infected cells during the long latent period before the onset of ATL.
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PMID:Repression of tax expression is associated both with resistance of human T-cell leukemia virus type 1-infected T cells to killing by tax-specific cytotoxic T lymphocytes and with impaired tumorigenicity in a rat model. 1504 98

To treat leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the possibility of immunotherapy using donor CD8+ T cells that were generated by stimulating leukemic cell-derived dendritic cells (leukemic-DCs) or leukemic cell lysate pulsed donor cell-derived DCs (donor-DCs). Leukemic- and donor-DCs were generated from mononuclear cells of patients and CD14+ cells of HLA-matched donors, respectively. The expression of CD80, CD83, CD86, CD1a, and CD40 on leukemic-DCs was significantly lower than that on donor-DCs. Donor-DCs exhibited a higher capacity to stimulate allogeneic T cells compared with leukemic-DCs. Donor CD8+ T cells stimulated by leukemic- or donor-DCs were more cytotoxic than unprimed CD8+ T cells, and slightly higher cytotoxicity was observed with donor-DCs compared to leukemic-DCs. This study indicates that leukemic- or donor-DCs pulsed with leukemic cell lysates can effectively prime donor cytotoxic T cells in vitro, and that they may be used as a potential alternative tool for treating leukemic patients who relapse after allogeneic HSCT.
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PMID:Generation of cytotoxic donor CD8+ T cells against relapsing leukemic cells following allogeneic transplantation by stimulation with leukemic cell- or leukemic lysate pulsed donor cell-derived dendritic cells. 1506 5

Chemotherapeutic drugs kill cancer cells mainly by direct cytotoxicity, but they might also induce a stronger host immune response by causing the tumor to produce costimulatory cell surface molecules like CD80. We previously reported that in myeloid leukemic cells, gamma-irradiation induced CD80 expression. In this study, we show that cytosine arabinoside (Ara-C), even at low doses, induced CD80 expression in vitro in mouse DA1-3b leukemic cells, by a mechanism that involved reactive oxygen species. In vivo experiments in the mouse DA1-3b/C3H whole-animal acute myeloid leukemia (AML) model showed that injection of Ara-C induced expression of CD80 and CD86, and decreased expression of B7-H1, indicating that chemotherapy can modify costimulatory molecule expression in vivo, in a way not necessarily observed in vitro. Mouse leukemic cells exposed in vivo to Ara-C were more susceptible to specific cytotoxic lymphocyte (CTL)-mediated killing. Ara-C also induced CD80 or CD86 expression in 14 of 21 primary cultured human AML samples. In humans being treated for AML, induction chemotherapy increased CD86 expression in the leukemic cells. These findings indicate possible synergistic strategies between CTL-based immunotherapy and chemotherapy for treatment. They also suggest an additional mechanism by which chemotherapy can eradicate AML blasts.
Leukemia 2004 Jul
PMID:Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells. 1515 66

To develop an effective antitumor immunotherapy for B-lineage non-Hodgkin's lymphoma, we constructed a tetravalent tandem diabody (tanDb) specific for both human CD19 (B-cell marker) and CD3 (T-cell antigen). Here, we report the effective killing of malignant primary B cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) by autologous T cells induced by tanDb at very low E:T ratios. Mononuclear cells from patients with B-CLL were cultured with bispecific antibody fragments in either the presence or absence of monospecific anti-CD28 antibody. Use of tetravalent tanDbs caused almost quantitative elimination of malignant B cells from the blood samples of 19 patients and some cytotoxic activity in 3 of 23 analyzed cases. In contrast, the structurally similar but bivalent diabody and single-chain diabody demonstrated nearly no antitumor activity in an autologous system. tanDb-induced activation and proliferation of T cells occurred only in the presence of CD19+ target cells. Expression of the B7-1 (CD80) and B7-2 (CD86) molecules on the surface of leukemia cells made unnecessary the additional CD28-costimulation of T cells. When only a few tanDb molecules were present, the effect of CD28 costimulation on T-cell activation was more pronounced. Depending on the patient sample, we observed a 10- to 1,000-fold decrease of the half-maximal concentrations of tanDb for cell lysis. Upon CD28 crosslinking by agonistic MAb, specific tumor cell lysis was found at tanDb concentrations as low as 0.5 pM. These data demonstrate that the tetravalent CD19xCD3 tanDb might be a promising tool for the immunotherapy of human B-cell leukemias and lymphomas.
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PMID:Effect of tetravalent bispecific CD19xCD3 recombinant antibody construct and CD28 costimulation on lysis of malignant B cells from patients with chronic lymphocytic leukemia by autologous T cells. 1538 79

Dendritic cells (DC) play a pivotal role in linking innate and adaptive immunity. Only mature DC are able to initiate adaptive immune responses by sensitising naive antigen-specific T cells. For clinical immunotherapeutic applications, safe and efficient clinical grade maturation factors of DC are required. Here, we investigated the impact of OM-197-MP-AC (OM-197), a synthetic lipid A analogue pseudo-dipeptide derived from amino acids linked to three fatty acid chains, on the maturation of human monocyte-derived-DC (Mo-DC) and leukemia-derived DC generated in serum-free conditions. After culture with clinical grade GM-CSF and IL-13, OM-197 at 20 microg/ml efficiently induced CD83+ Mo-DC. In comparison to immature Mo-DC that were derived by culture with GM-CSF and IL-13 only, CD40, CD80, CD86, HLA-ABC and HLA-DR molecules were up-regulated upon OM-197 or LPS treatment similarly. In MLR, OM-197-matured Mo-DC were found to be as potent stimulators as LPS-matured Mo-DC for CD4+ T cell proliferation. No significant difference in IFN-gamma quantification was shown between naive CD4+ T cells stimulated by LPS- or OM-197-Mo-DC suggesting that OM-197-Mo-DC can drive naive T cells towards a Th1 response profile that was mainly independent of IL-12 secretion. Similarly, CD8+ T cells could be efficiently polarized into IFN-gamma-secreting-cells by OM-197-Mo-DC, and activated polyclonal pp65-cytomegalovirus-specific CD8+ T lymphocytes. Finally, myeloid leukemic blasts were able to differentiate in vitro into mature functional DC-like cells upon OM-197 treatment in our culture model. Overall, the in vitro effects of clinical grade adjuvant OM-197, showed that it represents a potent inducer of both normal and leukemic-DC maturation, and is likely a good candidate for adjuvant immunotherapy in DC-based vaccines.
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PMID:OM-197-MP-AC adjuvant properties: the in vitro maturation of normal and leukemic dendritic cells in a serum-free culture model. 1548 Nov 42

To investigate the induction method and function of dendritic cells (DC) derived from acute myelogenous leukemia (AML) blasts in vitro, cytokine-supplemented suspension cultures of leukemia blasts in 25 AML patients were performed. Mononuclear cells were cultured for 8 to 12 days using recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF), recombinant human interleukin-4 (rhIL-4) and recombinant human tumor necrosis factor-alpha (rhTNF-alpha). Morphology, phenotype, cytogenetics, and function of induced cells were studied. The results showed that after culture for 3 days, cells in 20/25 AML cases demonstrated an increase in size with dendritic morphology. After culture for 8 - 9 days, the percentage of such cells reached peak. When cultured for 12 days, the total number of cells and the number of cells with DC morphology decreased greatly. Phenotypic analyses of cells (11/20 cases) were measured by flow cytometry before and after culture. Before culture, cells did not express CD1a, CD80 and CD83, while expressed CD54, CD86 and HLA-DR with low frequency. After culture, cells upregulated CD1a, CD80, CD83, CD54, CD86 and HLA-DR significantly. A marked increase of the T-cell stimulatory capacity could be generated in Allo-MLRs. FISH confirmed the leukemic origin of generated cells. In conclusion, leukemia-derived DC can be generated from AML blasts using cytokine combination (GM-CSF, IL-4, and TNF-alpha) in vitro.
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PMID:The induction and function study on dendritic cells derived from blasts from patients with acute myelogenous leukemia. 1549 23

Recently, the focus is on new specific immunotherapies for AML such as cellular therapies employing dendritic cells (DCs) generated from AML blasts. AML-DCs express constitutionally leukemia-associated antigens (LAAs) present in AML blasts they are generated from. Here we investigated whether the generation of AML-DCs would alter the expression level of LAAs. Moreover, we evaluated the presence of HLA and costimulatory molecules on AML blasts versus AML-DCs. Quantitative real-time polymerase chain reaction (PCR) was performed for the following LAAs: preferentially expressed antigen in melanoma (PRAME), the receptor for hyaluronic acid mediated motility (RHAMM/CD168), Wilms' tumor gene 1 (WT-1) and proteinase 3. The expression of HLA-ABC, HLA-DR, CD40, CD80, CD83 and CD86 was evaluated by flow cytometry. RHAMM protein expression was evaluated by immunocytochemistry, recognition of AML-DCs by PRAME epitope-specific T cells was evaluated in a chromium-release assay. Quantitative real-time PCR for AML-DCs versus AML blasts showed an alteration in mRNA expression of LAAs. An elevated PCR signal for PRAME was detected in 7/12 AML-DC preparations. 6/12 AML-DC preparations showed a significant upregulation of the PCR signal for RHAMM. A stronger WT-1 and proteinase-3 signal was observed in PCR for only 2/12 and 1/12 AML-DCs , respectively. All preparations showed a strong expression of at least one of the LAAs examined. As demonstrated by flow cytometry, AML-DCs strongly upregulated costimulatory molecules like CD40 and CD80 in comparison with AML blasts. AML-DCs tested positive for RHAMM protein. PRAME positive AML-DCs were recognized by specific T cells. AML-DCs might constitute a powerful tool in immunotherapy for AML. Real-time PCR allows a quick and quantitative assessment of immunologically relevant LAA expression with only 10(5) DCs and might be helpful for the decision whether the AML-DC vaccination strategy is favourable or not.
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PMID:Dendritic cells generated from acute myeloid leukemia (AML) blasts maintain the expression of immunogenic leukemia associated antigens. 1562 12

The initiation of graft-vs-host disease (GVHD) after stem cell transplantation is dependent on direct Ag presentation by host APCs, whereas the effect of donor APC populations is unclear. We studied the role of indirect Ag presentation in allogenic T cell responses by adding populations of cytokine-expanded donor APC to hemopoietic grafts that would otherwise induce lethal GVHD. Progenipoietin-1 (a synthetic G-CSF/Flt-3 ligand molecule) and G-CSF expanded myeloid dendritic cells (DC), plasmacytoid DC, and a novel granulocyte-monocyte precursor population (GM) that differentiate into class II+,CD80/CD86+,CD40- APC during GVHD. Whereas addition of plasmacytoid and myeloid donor DC augmented GVHD, GM cells promoted transplant tolerance by MHC class II-restricted generation of IL-10-secreting, Ag-specific regulatory T cells. Importantly, although GM cells abrogated GVHD, graft-vs-leukemia effects were preserved. Thus, a population of cytokine-expanded GM precursors function as regulatory APCs, suggesting that G-CSF derivatives may have application in disorders characterized by a loss of self-tolerance.
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PMID:Cytokine expanded myeloid precursors function as regulatory antigen-presenting cells and promote tolerance through IL-10-producing regulatory T cells. 1569 10

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of both adult T-cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the genesis of HAM/TSP likely involves several steps, the generation of a highly specific and effective population of Tax-specific CD8+ cytotoxic T lymphocytes (CTLs) that migrate to the central nervous system (CNS) is of pivotal importance in this neuropathologic process. Presentation of Tax peptides by activated dendritic cells (DCs) to naive CD8+ T cells likely plays an important role in the induction of a Tax-specific CTL response and the eventual neurologic dysfunction observed in HAM/TSP. The immune response mounted during HTLV-I infection is primarily targeted against Tax with both Tax-specific antibodies and CTLs found in HTLV-I-infected individuals, indicating that Tax is available for immune recognition. Studies have suggested that Tax may be secreted from HTLV-I-infected cells and act as an extracellular cytokine, be internalized and processed for presentation, or be transported to the nucleus where it may act as a transcriptional activator. The authors report in this article that purified Tax induces DC activation involving an increase in the production of CD80 and CD86 mRNA in the absence of corresponding protein synthesis. Furthermore, intracellular Tax down-regulates the protein expression of molecules involved in antigen presentation. This implies a difference in the mechanism of Tax activity depending upon its location. Additionally, treatment of JAWS II DCs with extracellular Tax decreases the ability of DCs to present a major histocompatibility complex (MHC) class I-restricted peptide, indicating that Tax likely matures the DCs to the point where presentation of a secondary antigen is restricted. The implication of the experimental results with respect to the generation of a Tax-specific CTL compartment that participates in the genesis of HAM/TSP is discussed.
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PMID:Human T-cell leukemia virus type I Tax induces the expression of dendritic cell markers associated with maturation and activation. 1576 7


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