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)

In a murine tumor model, complete tumor remission is achievable at even advanced metastasized stages by transfer of immune T cells from donor B10.D2 (H-2d, Mls(b)) into tumor-bearing DBA/2 (H-2d, Mls(a)) mice. We showed previously that this graft-versus-leukemia (GvL) effect is dependent on synergistic interactions of transferred CD4+ and CD8+ T cells with host sialoadhesin (SER)-positive macrophages. We now show that the CD40-CD40L (CD154) interaction is involved in the induction of inducible nitric oxide synthase (iNOS) expression during adoptive immunotherapy (ADI). We demonstrate that during ADI, the level of CD40 expression in the liver becomes significantly augmented in comparison to livers of tumor-bearing, untreated animals. CD40 expression is found mostly on SER+ macrophages and to a lesser extent on dendritic cells (DCs). In GvL animals, more SER+ macrophages express iNOS than untreated animals. iNOS expressing cells are found in close proximity to apoptotic cells, at early time points of the therapy in areas of metastasis, and at late stages around portal veins, where CD4+ and CD8+ T lymphocytes form clusters with SER+ macrophages. Blocking of CD40L in vivo at days 5 and 20, when all iNOS+ cells express CD40, leads to significantly reduced CD40 and iNOS expression as well as to a marked inhibition of the therapeutic effect. These data provide functional and in situ evidence that the increased CD40 and iNOS expression observed during ADI contribute to the eradication of liver metastases and to the clearance of donor lymphocytes from the liver.
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PMID:Functional and in situ evidence for nitric oxide production driven by CD40-CD40L interactions in graft-versus-leukemia reactivity. 1081 24

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma, characterized by a poor response to therapy and short survival. To assess the proliferative capacity, we cultured MCL cells, using irradiated 3T6 mouse fibroblasts transfected with human CD40L ('CD40 system') in the presence of different cytokines. Proliferation was measured by 3H-thymidine incorporation and by CFSE fluorescence. Thirteen out of 16 MCL cases proliferated well in the CD40 system. In 10 cases a strong response upon further addition of IL-10 was seen, whereas IL-4 had an additional effect in only four cases. CFSE staining of cells before and after culture showed an increased number of cell divisions in the IL-10/CD40L stimulated cells. The MCL cells remained CD5+CD19+. Neither plasma cell differentiation nor isotype switching was seen. The light chain expression was strictly monoclonal. IL-1beta, IL-2, IL-6, G-CSF and GM-CSF did not stimulate MCL proliferation. IL-10 receptor expression correlated with the response to IL-10 in the culture system and the effect of added IL-10 could be blocked by antibodies directed against IL-10 and the IL-10 receptor. Autocrine IL-10 production by the MCL cells was detected in eight of 10 cases tested. IL-10 receptor blocking decreased proliferation when no exogenous IL-10 was used in four of seven cases tested. EBV assessed by EBER in situ hybridization was not detected in six cases tested. In conclusion, MCL can successfully be cultured upon CD40 stimulation if 3T6 CD40L+ cells are used. In this context IL-10 is a costimulatory factor. IL-10 receptor expression seems to correlate with response to CD40 crosslinking and IL-10. Autocrine IL-10 production might play a role in the proliferation of this lymphoma. This culture system may be useful to test new treatment strategies for this, thus far, therapy-resistant lymphoma.
Leukemia 2000 Aug
PMID:Mantle cell lymphoma proliferates upon IL-10 in the CD40 system. 1094 46

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

Proper gene expression and cell growth are critical for the survival of all organisms. Nuclear factor-kappa B (NF-kappa B)-dependent gene expression and apoptosis play crucial roles in numerous cellular processes, and defects in their regulation may contribute to a variety of diseases including inflammation and cancer. Although there has recently been tremendous progress in our understanding of the signaling pathways that lead to NF-kappa B activation and apoptosis, signaling mechanisms that negatively regulate these processes are only partially understood. This review deals with the zinc finger protein A20, which has been characterized as a dual inhibitor of NF-kappa B activation and apoptosis. Its inducible expression by a wide variety of stimuli, including cytokines such as tumor necrosis factor, interleukin-1, and CD40, as well as bacterial and viral products such as lipopolysaccharide, Epstein-Barr virus latent membrane protein 1, and human T-cell leukemia virus type I Tax, suggests that it is involved in the negative feedback regulation of signaling. We will discuss the possible underlying mechanisms, placing emphasis on the role of several A20-binding proteins that have recently been described. Moreover, evidence is presented that A20 and A20-binding proteins are potential novel therapeutic tools in the treatment of a variety of diseases.
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PMID:A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. 1100 52

Gene therapy offers many new and exciting treatment strategies for patients with hematologic malignancies. Through the transfer of genes into hematopoietic stem cells, one can reduce the sensitivity of myeloid cells to chemotherapy. Donor T cells can be modified to become sensitive to otherwise nontoxic prodrugs, allowing for their safer use as effectors in graft-versus-leukemia immune reactions following allogeneic transplantation. Neoplastic cells also may be modified to enhance their sensitivity to various drugs. Finally, neoplastic cells can be modified to enhance their immunogenicity using genes that encode immune stimulatory cytokines or cell surface proteins. Recent studies, for example, indicate that the stealth-like phenotype of leukemia cells can be reversed through transfer of genes such as the one encoding CD154, the ligand for CD40. A phase I clinical trial using autologous CD154-transduced leukemia cells as a cellular vaccine has provided encouraging results. Indeed, we may soon enter an era of effective gene therapy for hematologic malignancies.
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PMID:Gene therapy of hematologic malignancies. 1104 18

Chronic lymphocytic leukemia (CLL) cells can be made to express recombinant CD40-ligand (CD154) by transduction with a replication-defective adenovirus vector (Ad-CD154). Ad-CD154-transduced and bystander leukemia cells become highly effective antigen-presenting cells that can induce CLL-specific autologous cytotoxic T lymphocytes in vitro. This study investigated the immunologic and clinical responses to infusion of autologous Ad-CD154-CLL cells in patients with CLL. After a one-time bolus infusion of autologous Ad-CD154-transduced leukemia cells, there was increased or de novo expression of immune accessory molecules on bystander, noninfected CLL cells in vivo. Treated patients also developed high plasma levels of interleukin-12 and interferon-gamma, the magnitudes of which corresponded to absolute blood CD4(+) T-cell counts before therapy. On average, patients experienced a greater than 240% increase in absolute blood T-cell counts within 1 to 4 weeks of treatment. Moreover, treatment increased the numbers of leukemia-specific T cells, demonstrated by autologous ELISPOT assay and mixed lymphocyte reactions. These biologic effects were associated with reductions in leukemia cell counts and lymph node size. Treatment did not induce autoimmune thrombocytopenia or hemolytic anemia and no dose-limiting toxicity was observed. This approach may provide a novel and effective form of gene therapy for patients with this disease.
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PMID:CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. 1179 65

Relapse of childhood acute lymphoblastic leukaemia (ALL) comprises a leading challenge of investigation. Characterization of leukaemic cells regarding their potency to express growth factors and surface molecules can provide insight into their aberrant biology. Thus, we analyzed bone marrow blasts from 10 children with relapsed B cell precursor ALL. The gene and protein expression of essential haematopoietic growth factors (IL-2, IL-4, IL-7, IL-10, IL-15, IFN-gamma, G-CSFR), their corresponding receptors as well as the expression pattern of adhesion molecules (ICAM-1, CD58) and costimulatory proteins (CD40, CD40L, B7.1, B7.2, CD28, MHC-I and II) was analyzed by RT-PCR and flow cytometry. Constitutive gene expression was found for IL-7, IL-10, IL-15 and IFN-gamma and their corresponding receptors. Flow-cytometric analysis showed that IL-10R, IL-7Ralpha, IL-4Ralpha and the gamma(c)chain are constitutively expressed, and that some cells bear the G-CSFR. IL-10 and IL-15 protein-producing leukaemic cells were easily detectable. The neoplastic cells mainly lack B7.1, and ICAM-1 is mostly decreased. Furthermore, high CD40, and, surprisingly, CD40L expression could be found. These studies show that ALL cells are likely to be sensitive to many growth factors and some factors are produced by the neoplastic cell itself. The secretion of IL-10 by leukaemic cells, and the absence or downregulation of conventional adhesion and costimulatory molecules might represent an effective mechanism of escape of immune surveillance in relapsed ALL.
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PMID:Characterization of cytokine, growth factor receptor, costimulatory and adhesion molecule expression patterns of bone marrow blasts in relapsed childhood B cell precursor all. 1114 41

Chronic lymphocytic leukemia (CLL) is associated with impaired immunoglobulin (Ig) class-switching from IgM to IgG and IgA, a defect that leads to recurrent infections. When activated in the presence of leukemic CLL B cells, T cells rapidly up-regulate CD30 through an OX40 ligand and interleukin 4 (IL-4)-dependent mechanism. These leukemia-induced CD30+ T cells inhibit CD40 ligand (CD40L)-mediated S mu-->S gamma and S mu-->S alpha class-switch DNA recombination (CSR) by engaging CD30 ligand (CD30L), a molecule that interferes with the assembly of the CD40-tumor necrosis factor receptor-associated factor (TRAF) complex in nonmalignant IgD+ B cells. In addition, engagement of T cell CD30 by CD30L on neoplastic CLL B cells down-regulates the CD3-induced expression of CD40L. These findings indicate that, in CLL, abnormal CD30-CD30L interaction impairs IgG and IgA production by interfering with the CD40-mediated differentiation of nonmalignant B cells.
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PMID:Dysregulation of CD30+ T cells by leukemia impairs isotype switching in normal B cells. 1117 13

Dendritic cells (DC) play a key role in the initiation of primary immune response, and pilot clinical studies have demonstrated their ability to induce efficient antitumor immunity. However, the DC used in these clinical trials were generated with various serum sources and were poorly characterized. Obtaining fully characterized DC in controlled and reproducible culture conditions is thus of major interest. We demonstrate that X-VIVO 15 medium supplemented with 2% human albumin can be used to obtain DC. The phenotypic and functional characteristics of these clinical-grade DC were analyzed according to their differentiation stages. CD83 immature DC, obtained in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, were able to endocyte soluble antigens and internalize apoptotic tumor cells, and also expressed receptors for inflammatory chemokines. Tumor necrosis factor-alpha (TNF-alpha) induced irreversible DC maturation in association with a decreased ability to uptake antigens and an increased allostimulatory capacity. CD83+ mature DC became responsive to EBI1 ligand chemokine (ELC), a chemokine specifically expressed in secondary lymphoid organs. In addition, mature DC obtained with TNF-alpha produced IL-12 and some IL-10 in response to CD40 stimulation. In conclusion, we present well-defined culture conditions allowing the control of DC maturation for clinical or fundamental studies.
Leukemia 2000 Dec
PMID:Extensive characterization of dendritic cells generated in serum-free conditions: regulation of soluble antigen uptake, apoptotic tumor cell phagocytosis, chemotaxis and T cell activation during maturation in vitro. 1118 9

Neoplastic B cells are stealthlike in their ability to evade immune detection, even by allogeneic T cells of normal healthy donors. This stealthlike phenotype can be reversed by activating neoplastic B cells through ligation of CD40, a cell surface molecule that can interact with a ligand expressed on activated T cells. The gene encoding this ligand, CD154, can be transferred into neoplastic B cells ex vivo through infection with a modified adenovirus vector called Ad-CD154. This results in a dramatic change in the phenotype and function of the neoplastic B cells. Infected malignant B cells can stimulate T cells reactive with potential tumor antigens and induce autologous cytotoxic T cells capable of destroying the neoplastic B cells in vitro. This formed the basis for an immune gene therapy protocol in which patients were infused with Ad-CD154-transduced leukemic B cells. Treatment was well tolerated, without apparent long-term toxicity, and without a maximum tolerated dose. Biologic and clinical responses were observed, including significant reductions in leukemia cell counts and lymph node sizes after a single one-time infusion. Furthermore, preliminary data suggest that this approach can enhance antibody-dependent cellular cytotoxicity and thereby augment the activity of antitumor monoclonal antibody therapy. Development of such strategies may allow for effective immunogenetic therapy for B-cell malignancies.
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PMID:Immunogenetic therapy for B-cell malignancies. 1122 94


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