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)

Relapse is more frequent after autologous than allogeneic bone marrow transplantation (BMT), due in part to lack of T-lymphocyte mediated allogeneic graft-versus-leukemia (GVL) effects. Infusions of leukemia-reactive T cells to patients after autologous BMT may be a means for providing a GVL effect. Costimulation of T cells by binding of the CD28 receptor on T cells with B7-counter receptors on antigen presenting cells amplifies antigen-specific T-cell responses. To enhance generation of leukemia reactive cytotoxic T lymphocytes (CTL), the murine B7-1- and B7-2-costimulatory molecule cDNAs were introduced into the MHC class I+, class II-, murine meyloid leukemia cell line C1498. B7-1 expression greatly enhanced the ability of the leukemia cells to generate and expand leukemia reactive CTL in vitro. A highly cytolytic and C1498 specific CD8+ CTL line was generated by B7-1 costimulation. This CTL line proliferated autonomously and produced interleukin-2 when provided B7-1 or B7-2 costimulation by C1498 leukemia cells. To test the in vivo antileukemia properties of this CTL line, irradiated syngeneic BMT recipients were given graded doses of leukemia cells on day 0, followed by CTL infusions beginning on day 1 post-BMT. Recipients of 10(7) CTL had a 3 log reduction in leukemia burden such that 100% of mice were protected from a supralethal leukemic cell dose. Sustained immune responses were detectable up to 3 months postinfusion of the CTL line. B7-1 or B7-2 costimulation in vivo did not augment antileukemia effects of infused CTL post BMT. These results suggest that B7 costimulation of leukemia reactive CTL may be important for their ex vivo generation and expansion for use in human adoptive immunotherapy of leukemia.
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PMID:The role of B7 costimulation by murine acute myeloid leukemia in the generation and function of a CD8+ T-cell line with potent in vivo graft-versus-leukemia properties. 912 56

T cells require at least two signals to be fully activated: one is generated by interactions between antigen-specific receptor on T cell and peptide-MHC complexes on tumor cells and second signal is delivered by costimulatory molecules on antigen presenting cells to their counter-receptor on T cells. We demonstrated previously that expression of T cell costimulatory molecule B7-1, a counterreceptor for CD28, on tumors led to tumor regression in syngeneic mice. We have used retrovirus to transfer B7-1 into a variety of murine tumor lines to examine their ability to stimulate CTL in vivo and in vitro. Expression of B7 results in increased immunogenicity in immunogenic, but not poorly-immunogenic tumors, suggesting a deficiency of tumor cells on antigen presentation. We analyze tumor epitopes associated with MHC molecules by HPLC combining with specific CTL clones and the results indicate that many non-immunodominant epitopes do not normally induce a response unless B7 costimulation is provided. Furthermore, increased T cell receptor signaling, such as co-expression of CD2 ligand with B7-1, can convert some poorly-immunogenic tumours to become immunogenic. Our results indicate that deficiency on antigenic signaling in many tumors could be a quantitative phenomenon. Induction of T cell immunity by targeting on both antigen receptor and costimulatory pathway thus may be useful for cancer treatment.
Leukemia 1997 Apr
PMID:Manipulation of T cell response to tumors by targeting on costimulatory pathway. 920 56

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare FAB subtype (2-3% of AMLs) of poor prognosis. The aim of our study was to characterize AML-M0 expression and regulation of adhesion/costimulatory molecule involved in immune recognition, to test blast in vitro immunogenicity, and to determine the percentage of leukemia progenitor cells. Here, we demonstrate that alloimmune recognition of AML-M0 in primary mixed lymphocyte reaction, as evaluated by IL-2 secretion of responding T cells, is reduced in comparison with more differentiated subtypes (128 +/- 95 pg/ml vs304 +/- 159 pg/ml, P < 0.05). These data are in line with low blast cell expression of major histocompatibility complex (MHC) class II DR molecules, and of the CD28 ligand B7-2, which plays an important role in AML immune recognition. Adhesion/costimulatory molecules were up-regulated by leukemic cell stimulation via CD40, and, although less efficiently, by gamma-IFN; both stimuli improved blast cell immunogenicity. We also demonstrate that AML-M0 have a very high percentage (40% +/- 30) of CD34+/CD38- leukemic clonogenic precursors in comparison with more differentiated AMLs (2.5% +/- 2) or non-leukemic CD34+hematopoietic precursors (1.8% +/- 0.8). Since the presence of a leukemic cell population at an early differentiation stage has been identified as a poor prognostic factor, we conclude that the high frequency of CD34+/CD38- blasts in AML-M0 may converge with already identified poor prognosis factors such as chemotherapy resistance and cytogenetic abnormalities. The clinical implications of AML-M0 impaired in vitroimmunogenicity and a high percentage of CD34+/CD38- blasts will require comparative analysis of additional patients. The increased immunogenicity of blast cells after CD40 triggering provide interesting clues for AML-M0 immunotherapy, that have to be confirmed with an in vivo leukemia model in mice.
Leukemia 1999 Oct
PMID:The immunophenotype of minimally differentiated acute myeloid leukemia (AML-M0): reduced immunogenicity and high frequency of CD34+/CD38- leukemic progenitors. 1051 51

Gene transfer into early hematopoietic cells has been problematic due to the quiescent nature of primitive cells and the lack of gene transfer vehicles with high efficiency for hematopoietic cell types. Previously, we have shown that adenoviral vectors can be used for the transduction of normal human progenitors with gene transfer efficiencies of approximately 30%. However, this approach is limited by relatively slow uptake kinetics (24-48 h) and a strong dependence on the presence of exogenous cytokines. Thus, we have modified this approach by combining adenoviral vectors with polycations to generate a virus-polycation complex, or VPC. Vehicles of this nature, when composed of conventional adenoviral vectors and polyamidoamine dendrimers, are a highly efficient means of transducing both normal and acute myelogenous leukemia (AML) cells. Moreover, the kinetics of gene transfer are markedly increased using the VPC strategy, with approximately 70% of transduction complete within 2 h. In this study, using viruses that encode green fluorescence protein (GFP), or the T cell costimulatory molecule B7.1 (CD80), we show that VPC-mediated gene transfer is an effective means of transducing normal and AML cells, including those with a highly primitive phenotype. Our data suggest that transient genetic manipulation of primitive hematopoietic cells can readily be achieved and should therefore permit a variety of research and clinical endeavors.
Leukemia 1999 Oct
PMID:Genetic manipulation of primitive leukemic and normal hematopoietic cells using a novel method of adenovirus-mediated gene transfer. 1051 63

Costimulatory signals supplied by genetically modified tumor cells can enable T-cell recognition of tumor-associated antigens that were previously silent when presented by unmodified tumor cells. Although the mechanism of the CD80/CD28 costimulation has been studied extensively in the normal T-cell/antigen-presenting cell (APC) interactions, it is unclear how expression of CD80 by tumor cells mediates its effect. We demonstrate here that optimal CD80 expression on a leukemic cell enhances T-cell recognition of alloantigen primarily by lowering the level of T-cell receptor (TCR) stimulation required for activation. CD80 expression by leukemic cells leads to increased survival of activated T cells by inducing upregulation of the antiapoptotic protein BCL-2, but not BCL-X(L). The cytokine microenvironment in which T cells are activated is crucial in determining their differentiation and consequently the nature of the immune response generated. Many tumor cells produce immunosuppressive cytokines that may not favor the induction of cell-mediated immunity. In this study, the presence of CD80 on leukemic cells increased T-cell activation in vitro, but this did not result in the production of Th1 cytokines. We show that this is due to a leukemia-derived soluble factor that inhibits the production of Th1 cytokines. Optimal expression of a costimulatory molecule, therefore, enhances the ability of leukemic cells to present antigen by amplifying TCR signals, but the microenvironment generated by leukemic cells may suppress the immune response required for their eradication. Thus, strategies aimed at inducing antileukemic immunity by providing leukemic cells with costimulatory functions must ensure the presence of an appropriate microenvironment.
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PMID:Effect of costimulation and the microenvironment on antigen presentation by leukemic cells. 1055 58

OX40 is a member of the tumor necrosis factor (TNF) receptor superfamily and known to be an important costimulatory molecule expressed on activated T cells. To investigate the role of costimulation of OX40 in human immunodeficiency virus type 1 (HIV-1) infection by its natural ligand, gp34, the OX40-transfected ACH-2 cell line, ACH-2/OX40, chronically infected with HIV-1, was cocultured with paraformaldehyde (PFA)-fixed gp34-transfected mouse cell line, SV-T2/gp34. The results showed that HIV-1 production was strongly induced. This was followed by apparent apoptosis, and both processes were specifically inhibited by the gp34-specific neutralizing monoclonal antibody 5A8. Endogenous TNF alpha (TNF-alpha) and TNF-beta production were not involved in the enhanced HIV-1 production. Furthermore, enhanced HIV-1 transcription in gp34-stimulated ACH-2/OX40 cells was dependent on the kappa B site of the HIV-1 long terminal repeat, and the OX40-gp34 interaction activated NF-kappa B consisting of p50 and p65 subunits. When primary activated CD4(+) T cells acutely infected with HIV-1(NL4-3) (CXCR4-using T-cell-line-tropic) were cocultured with PFA-fixed gp34(+) human T-cell leukemia virus type 1-bearing MT-2 cells or SV-T2/gp34 cells, HIV-1 production was also markedly enhanced. The enhancement was again significantly inhibited by 5A8. The present study first shows that OX40-gp34 interaction stimulates HIV-1 expression and suggests that OX40 triggering by gp34 may play an important role in enhancing HIV-1 production in both acutely and latently infected CD4(+) T cells in vivo.
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PMID:OX40 stimulation by gp34/OX40 ligand enhances productive human immunodeficiency virus type 1 infection. 1143 53

B cells of chronic lymphocytic leukemia (B-CLL) are resistant to transduction with most currently available vector systems. Using an optimized adenovirus-free packaging system, recombinant adeno-associated virus (rAAV) vectors coding for the enhanced green fluorescent protein (AAV/EGFP) and CD40 ligand (AAV/CD40L) were packaged and highly purified resulting in genomic titers up to 3 x 10(11)/mL. Cells obtained from 24 patients with B-CLL were infected with AAV/EGFP or AAV/CD40L at a multiplicity of infection (MOI) of 100 resulting in transgene expression in up to 97% of cells as detected by flow cytometry 48 hours after infection. Viral transduction could be specifically blocked by heparin. Transduction with AAV/CD40L resulted in up-regulation of the costimulatory molecule CD80 not only on infected CLL cells but also on noninfected bystander leukemia B cells, whereas this effect induced specific proliferation of HLA-matched allogeneic T cells. Vaccination strategies for patients with B-CLL using leukemia cells infected ex vivo by rAAV vectors now seems possible in the near future.
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PMID:Efficient gene transfer of CD40 ligand into primary B-CLL cells using recombinant adeno-associated virus (rAAV) vectors. 1217 85

Evidence from allogeneic hematopoietic stem cell transplantation indicates a possible immune response against leukemia-associated antigens in patients with either acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). However, autologous immune responses are less evident. We have developed a method using sequential modulation of growth factors (SMGF) to generate specific anti-AML T-cells from primary cultures of mononuclear cells (MNCs) from patients with AML. This culture method induces greater degrees of antigen presentation by inducing dendritic cell (DC) differentiation of AML in the presence of autologous lymphocytes, which are then expanded by interleukin (IL)-2 and costimulatory molecule ligation. MNCs consisting of 92.3% +/- 5.1% AML blasts and 3.4% +/- 3.2% CD3+ T-cells were obtained from AML patients (n = 12) and cultured in AIM-V medium with IL-4 and recombinant granulocyte-monocyte colony-stimulating factor. Recombinant IL-2 was added on day 8. On day 21, culture conditions were changed to anti-CD3/anti-CD28 monoclonal antibodies and IL-2. By day 42, 354 +/- 182-fold CD3+ T-cell expansion had occurred. Cytotoxic T-lymphocyte assays demonstrated that these T-cells caused significant lysis of autologous leukemia cells and AML cell lines, but not of cells of other lineages, in an HLA class I-dependent manner. Specific Vbeta subgroups (Vbeta3, -7, and -12a), possibly representing T-cell clones specific to AML-specific antigens, were expanded in the cultures of cells from 3 AML patients. SMGF can be used to induce and expand autologous T-cells with HLA class I-dependent antileukemia potential from the peripheral blood of AML patients. Adoptive transfer of these expanded T-cells to patients is a possible therapeutic approach for further study.
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PMID:Sequential modulation of growth factors: a novel strategy for adoptive immunotherapy of acute myeloid leukemia. 1243 51

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.
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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

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


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