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)

C57BL/6 (H-2(b)) mice generate type-specific cytolytic T-lymphocyte (CTL) responses to an immunodominant Kb-restricted epitope, KSPWFTTL located in the membrane-spanning domain of p15TM of AKR/Gross murine leukemia viruses (MuLV). AKR.H-2(b) congenic mice, although carrying the responder H-2(b) major histocompatibility complex (MHC) haplotype, are low responders or nonresponders for AKR/Gross MuLV-specific CTL, apparently due to the presence of inhibitory AKR. H-2(b) cells. Despite their expression of viral antigens and Kb, untreated viable AKR.H-2(b) spleen cells cause dramatic inhibition of the C57BL/6 (B6) antiviral CTL response to in vitro stimulation with AKR/Gross MuLV-induced tumor cells. This inhibition is specific (AKR.H-2(b) modulator spleen cells do not inhibit allogeneic MHC or minor histocompatibility antigen-specific CTL production), dependent on direct contact of AKR.H-2(b) cells in a dose-dependent manner with the responder cell population, and not due to soluble factors. Here, the mechanism of inhibition of the antiviral CTL response is shown to depend on Fas/Fas-ligand interactions, implying an apoptotic effect on B6 responder cells. Although B6.gld (FasL-) responders were as sensitive to inhibition by AKR.H-2(b) modulator cells as were B6 responders, B6.lpr (Fas-) responders were largely insensitive to inhibition, indicating that the responder cells needed to express Fas. A Fas-Ig fusion protein, when added to the in vitro CTL stimulation cultures, relieved the inhibition caused by the AKR.H-2(b) cells if the primed responders were from either B6 or B6.gld mice, indicating that the inhibitory AKR.H-2(b) cells express FasL. Because of the antigen specificity of the inhibition, these results collectively implicate a FasL/Fas interaction mechanism: viral antigen-positive AKR.H-2(b) cells expressing FasL inhibit antiviral T cells ("veto" them) when the AKR.H-2(b) cells are recognized. Consistent with this model, inhibition by AKR.H-2(b) modulator cells was MHC restricted, and resulted in approximately a 10- to 70-fold decrease in the in vitro expansion of pCTL/CTL. Both CD8(+) CTL and CD4(+) Th responder cells were susceptible to inhibition by FasL+ AKR.H-2(b) inhibitory cells as the basis for inhibition. The CTL response in the presence of inhibitory cells could be restored by several cytokines or agents that have been shown by others to interfere with activation-induced cell death (e.g. , interleukin-2 [IL-2], IL-15, transforming growth factor beta, lipopolysaccharide, 9-cis-retinoic acid) but not others (e.g., tumor necrosis factor alpha). These results raise the possibility that this type of inhibitory mechanism is generalized as a common strategy for retrovirus infected cells to evade immune T-cell recognition.
 ...
PMID:Antiretroviral cytolytic T-lymphocyte nonresponsiveness: FasL/Fas-mediated inhibition of CD4(+) and CD8(+) antiviral T cells by viral antigen-positive veto cells. 1019 77

In this study, we examined the effects of radiation and ara-C on induction of apoptosis and on the apoptosis-promoting genes p53, Bax and Fas/APO-1, in BV173 human leukemia cells, which harbor the wild-type p53 gene. It has been reported that p53 upregulates Fas/APO-1 and Bax expression. Both irradiation and ara-C treatment resulted in apoptosis and induction of p53 proteins within hours. The Bax gene was activated in irradiated and ara-C-treated BV173 cells, but Fas/APO-1 was induced only in irradiated BV173 cells. Radiation and ara-C treatment did not induce Bax or Fas/APO-1 protein expression in p53-null HL60 cells. Radiation weakly induced Fas/APO-1 expression in KBM-7 cells, which harbor a partially defective p53 gene. Both HL60 and KBM-7 cells are more resistant to radiation- and ara-C-induced apoptosis than BV173 cells. These results suggest that functional p53 is necessary for the activation of Bax and Fas/APO-1 expression. However, elevated p53 protein is not sufficient to activate Fas/APO-1 gene expression in ara-C-treated cells. Using two-dimensional gel electrophoresis, we found that the p53 proteins in irradiated and ara-C-treated BV173 cells have different isoelectric points; they converged to a single isoelectric point after in vitro treatment with phosphatase. These results suggest that different genotoxic treatments cause different phosphorylations of p53, which may account for the different levels of activation of Fas/APO-1 expression.
 ...
PMID:Differential p53 phosphorylation and activation of apoptosis-promoting genes Bax and Fas/APO-1 by irradiation and ara-C treatment. 1020 May 13

Clinical animal models and in vitro data afford evidence for anti-leukaemia immunity. Many reports have underlined the interest of interleukin-7 (IL-7) use in cancer and its pivotal role in immune recognition. This cytokine, initially identified as a B cell growth factor, enhances the anti-tumour properties of immune effector cells via T lymphocyte activation, increased specific cytotoxicity and cytokine secretion. Nonetheless, few data are available regarding the effect of IL-7 on the expression at the leukaemia cell surface of molecules involved in the immune response, which defective expression could induce tolerance or anergy. This prompted us to study the effects of IL-7 on 20 cases of acute myeloid leukaemia (AML) and 9 cases of lymphoid leukaemia (ALL), in comparison with gamma-interferon, a potent inducer of immune regulation molecule expression. In AML and ALL, IL-7 increased MHC class I molecule expression, while class II molecules were weakly modified. The expression of the tumour necrosis factor family members CD40 and Fas/CD95, together with the adhesion molecules ICAM-1/CD54 and CD58/LFA-3, was also increased in both types of leukaemia. The IL-7 was an efficient inducer of B7-2/CD86 expression in AML and ALL, while increased expression of B7-1/CD80 was only observed in AML. In the corresponding, co-cultured T lymphocyte population, IL-7 more particularly increased B7-1/CD80 and CD58/LFA-3 expression. Finally, pre-incubation of leukaemic cells with IL-7 increased the proliferation of responding, normal allogenic T lymphocytes and their secretion of gamma-IFN and IL-2 in mixed the lymphocyte-tumour reaction. We concluded that IL-7 is efficient at increasing the membrane expression of molecules which are central for the development of the immune response, and at improving allogenic immune recognition. The clinical implications of such data require further in vivo investigation.
 ...
PMID:Differential modulation of immune recognition molecules by interleukin-7 in human acute leukaemias. 1021 Jul 78

Interleukin (IL)-12 is a potent immunostimulatory cytokine and inducer of Th1 cell activity and of cytotoxic T lymphocyte and natural killer cell function. This cytokine also has anti-tumor activity. Although IL-12 has been shown to be an important pathogenic cytokine in the induction of graft-versus-host disease (GVHD), injection of exogenous IL-12 to murine allogeneic bone marrow transplantation (BMT) recipients paradoxically leads to a significant delay in the onset of GVHD mortality in fully MHC plus multiple minor antigen-mismatched strain combinations, and to complete inhibition of GVHD in a single haplotype-mismatched murine BMT model. IL-12-induced inhibition of GVHD is associated with reduced donor T cell activation and expansion, in part through an interferon (IFN)-gamma-mediated mechanism. Fas-mediated apoptosis of donor T cells also plays a significant role in IL-12-induced GVHD protection. Importantly, IL-12 preserves the graft-versus-leukemia (GVL) effect of allogeneic CD8 T cells against EL4, a host-type leukemia/lymphoma, while inhibiting GVHD. Like the protective effect against GVHD, the GVL effect in IL-12-treated mice is dependent on IFN-gamma. Thus, treatment with IL-12 leads to separation of GVHD-promoting and GVL effects of allogeneic BMT via an IFN-gamma-dependent mechanism.
 ...
PMID:The role of interleukin-12 in preserving the graft-versus-leukemia effect of allogeneic CD8 T cells independently of GVHD. 1034 69

We constructed an ex vivo gene transfer system to deliver cytokines into the kidney and circulation using genetically modified renal tubular epithelial cells (TEC). TEC were infected with recombinant retroviruses expressing macrophage (Mphi) growth factors using a retroviral Moloney murine leukemia virus-based MFG vector. These infected TEC have the capacity to secrete stable and sustained amounts of cytokines for prolonged periods (>4 months) in vitro and in vivo (>28 days). Implanting genetically modified TEC secreting Mphi growth factors under the kidney capsule initiates severe local renal injury in mice with a deficiency in Fas (Faslpr gene). This system offers a novel and powerful approach to probe for the impact of sustained cytokine expression in the progression of kidney destruction.
 ...
PMID:Application of genetically engineered tubular epithelial cells in kidney disease. 1035 68

Human granulocyte-macrophage colony-stimulating factor fused to truncated diphtheria toxin (DT388-GM-CSF) sensitized wild-type and Bcl2-overexpressing HL60 human leukemia cells to intoxication by Ara-C based on proliferation and clonogenic assays. The toxin/drug combination showed dramatic synergistic toxicity with combination indices of < 0.1. Synergy was not seen with two other protein synthesis inhibiting drugs--ricin and cycloheximide nor with GMCSF alone. No changes in Ara-C incorporation into cellular DNA or cell cycle occupancy were seen. As compared to exposure to DT388-GM-CSF or Ara-C alone, co-treatment produced significant increases in cytosolic accumulation of cytochrome c, a higher percentage of cells with loss of mitochondrial membrane potential and an increase in reactive oxygen species and morphologic changes of apoptosis, and a greater induction of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor 45 (DFF45) cleavage activities of caspase 3. Co-treatment did not significantly alter Bcl2, Bcl-xL, Bax or Fas receptor (FasR), but modestly increased Fas ligand (FasL) protein. These finding suggest that co-treatment with DT388-GM-CSF may lead to a lowered apoptotic threshold and clonogenic survival of human AML blasts due to Ara-C. These observations also suggest that clinical trials of combination therapy may be warranted in patients with AML.
 ...
PMID:Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor and Ara-C exert synergistic toxicity against human AML HL-60 cells. 1037 46

Mouse retrovirus-induced lymphoma/leukemia and immunodeficiency are useful models for analogous human diseases. Both ecotropic (mouse tropic) and recombinant retroviruses, including the polytropic mink cytopathic focus-inducing type, have been studied for disease pathogenesis and as targets for humoral and cellular immunity, particularly cytotoxic T-lymphocyte (CTL) responses. For AKR/Gross murine leukemia viruses (MuLV) we have defined an immunodominant CTL epitope in the p 15E transmembrane anchor envelope protein and three minor/subdominant epitopes. Evidence is presented for retroviral escape from CTL by selection following genetic recombination and point mutation both within and outside CTL epitope sequences, and via endogenous retrovirus-infected cell downregulation of the generation of anti-AKR/Gross MuLV CTL. As demonstrated in vivo in naturally occurring non-responder strains by adoptive transfer, and in vitro by cell-mixing experiments, a central non-responsiveness mechanism appears to be peripheral inhibition mediated by infected cells expressing MHC-presented viral peptides. Such inhibition requires Fas expression by antiviral T cells; occurs upon TCR-mediated recognition of virus-infected, Fas ligand-expressing "veto" cells; and apparently leads to an antigen-specific form of activation-induced cell death of T cells. In the LP-BM5 MuLV isolate that causes murine AIDS (MAIDS) retroviral variation also leads to CTL escape--the BM5-helper virus has altered forms of the immunodominant and two minor/subdominant epitopes. In contrast, a novel immunodominant CTL epitope is recognized by MAIDS resistant, but not MAIDS-susceptible, strains. This epitope is uniquely encoded in an alternative translational reading frame of the viral gag gene. It also appears that the LP-BM5 MuLV have co-opted the cells of the immune system for retroviral pathogenesis--CD40/CD40L (CD154) interactions are required both for the initiation and progression of MAIDS.
 ...
PMID:Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape. 1039 80

It has been postulated that tumor cells expressing Fas ligand (FasL) can evade immune surveillance by inducing apoptosis in T cells expressing Fas. In this study, we investigated FasL expression in 13 human hepatoma cell lines. Strong FasL expression was detected by reverse transcription-polymerase chain reaction or immunofluorescence in Hep G2.2.15, in which the hepatitis-B-virus (HBV) genome was transfected, and in SNU-354, which showed HBx transcripts. To determine the biological activity of FasL, Hep G2.2. 15 was co-cultured with MOLT-4, T-cell-leukemia cells. Hep G2.2.15 induced apoptosis in MOLT-4 and this was inhibited by the antagonistic anti-Fas antibody, ZB4. For further analysis of the role of HBx in the induction of FasL, PLC/PRF/5 cells were transfected transiently with the HBV genome, or HBx, or the frameshift mutant of HBx. In PLC/PRF/5 cells transfected with the HBV genome or HBx but not in cells transfected with the frameshift mutant of HBx, FasL expression was detected. Our data suggest that HBx plays a role in the induction of FasL in hepatoma cells and in the escape from immune surveillance.
 ...
PMID:Expression of fas ligand in human hepatoma cell lines: role of hepatitis-B virus X (HBX) in induction of Fas ligand. 1040 75

Activation-induced cell death is a process by which overactivated T cells are eliminated, thus preventing potential autoimmune attacks. Two known mediators of activation-induced cell death are Fas(CD95) ligand (FasL) and APO2 ligand (APO2L)/TNF-related apoptosis-inducing ligand (TRAIL). We show here that upon mitogenic stimulation, bioactive FasL and APO2L are released from the T cell leukemia Jurkat and from normal human T cell blasts as intact, nonproteolyzed proteins associated with a particulate, ultracentrifugable fraction. We have characterized this fraction as microvesicles of 100-200 nm in diameter. These microvesicles are released from Jurkat and T cell blasts shortly (</=1 h) after PHA stimulation, well before the cell enters apoptosis. FasL- and APO2L-containing vesicles are also present in supernatants from PHA-activated fresh human PBMC. These observations provide the basis for a new and efficient mechanism for the rapid induction of autocrine or paracrine cell death during immune regulation.
 ...
PMID:Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles. 1041 24

Members of the Bcl-2 gene family have been implicated in the regulation of cell death induced by cytostatic drugs. In some malignancies such as B-cell lymphoma, there is evidence that high expression of Bcl-2 is an independent negative prognostic marker and the overexpression of Bcl-2 has been shown to confer resistance to cytotoxic drugs by preventing drug-induced apoptosis. This function of Bcl-2 can be antagonized by apoptosis-promoting members of the Bcl-2 family. We previously showed that overexpression of Bax restores the chemosensitivity of Bax-deficient breast cancer cell lines. Therefore, we investigated whether the death-promoting Bcl-2 homologue Bik/Nbk can enhance cytostatic drug-induced apoptosis. As a model, we used the T-cell leukemia H9 (CD3(+) and CD4(+)CD8(-)), which is resistant to corticosteroid-induced cell death and does not express endogenous Bik/Nbk. Sensitivity for drug-induced apoptosis was increased 10- to 39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In addition, apoptosis induced via CD95/Fas or heat shock was increased to a similar extent. These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete suppression of tumor growth in a severe combined immunodeficient mouse xenotransplant model suggests that, in analogy to Bax, Bik/Nbk may function as a tumor suppressor gene.
 ...
PMID:Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice. 1041 3


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