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)

The endogenous viral superantigen 7 in DBA/2 mice serves as a target antigen on syngeneic ESb-MP lymphoma cells for allogeneic graft-vs-leukaemia reactive cells. Allogeneic viral superantigen 7 reactive Vbeta6+ T cells are able to transfer graft-vs-leukaemia reactivity and to kill specifically viral superantigen 7+ ESb-MP tumour cells in vitro. Here we elucidate the mechanism of this superantigen specific cell lysis. Already 10 min after co-incubation with in vitro stimulated Vbeta6+ T cells, viral superantigen 7+ ESb-MP tumour cells show an apoptotic phenotype (Annexin V-positivity, DNA-fragmentation). This extremely rapid type of cell death is not mediated by the death inducing ligands CD95L, TRAIL and TNF but by perforin and granzyme B. Surprisingly, neither mitochondria nor any of the known caspases appear to be involved in this type of tumour cell killing. In contrast, nitric oxide, released by activated macrophages and endothelial cells, induces in the same tumour cells another type of apoptosis which is much slower and involves mitochondria and caspase activation. A synergistic effect between the two different effector mechanisms of superantigen reactive donor cytotoxic T lymphocytes and nitric oxide releasing host macrophages and endothelial cells might explain the effective immune rejection of even advanced metastasised cancer in this graft-vs-leukaemia animal model.
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PMID:Superantigen reactive Vbeta6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells. 1187 49

Wilms tumor gene product WT1 and proteinase 3 are overexpressed antigens in acute myeloid leukemia (AML), against which cytotoxic T lymphocytes can be elicited in vitro and in murine models. We performed this study to investigate whether WT1- and proteinase 3-specific CD8 T cells spontaneously occur in AML patients. T cells recognizing HLA-A2.1-binding epitopes from WT1 or proteinase 3 could be detected ex vivo in 5 of 15 HLA-A2-positive AML patients by interferon-gamma (IFN-gamma) ELISPOT assay and flow cytometry for intracellular IFN-gamma and in 3 additional patients by flow cytometry only. T cells producing IFN-gamma in response to proteinase 3 were further characterized in one patient by 4-color flow cytometry, identifying them as CD3(+)CD8(+)CD45RA(+) CCR7(-) T cells, resembling cytotoxic effector T cells. In line with this phenotype, most of the WT1- and proteinase-reactive T cells were granzyme B(+). These results provide for the first time evidence for spontaneous T-cell reactivity against defined antigens in AML patients. These data therefore support the immunogenicity of WT1 and proteinase 3 in acute leukemia patients and the potential usefulness of these antigens for leukemia vaccines.
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PMID:CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. 1220 Mar 77

The diagnosis of granular lymphocytic leukaemia (GLL) requires the presence of an immunophenotypically distinct T-cell (T-GLL) or natural killer-cell (NK-GLL) population. Flow cytometric immunophenotyping was performed on 21 T-GLL patients, 11 NK-GLL patients and 20 normal control subjects using antibodies to T and NK cell-associated antigens in order to accurately identify the distinguishing features of T-GLL and NK-GLL. The NK antigens evaluated included: CD16, CD57, CD94, CD161, and the killing inhibitory receptors (KIRs) CD158a, CD158b and CD158e (p70). Abnormal T-antigen expression was present in all T-GLL patients. CD57 was frequently expressed in T-GLL, however, one-third of patients showed partial CD57 expression similar to that seen in T cells from normal control subjects. Ten T-GLL were KIR positive; all expressed a single KIR isoform. All NK-GLL showed a distinctive, abnormal immunophenotype. Four NK-GLL expressed a single KIR isoform; the remaining seven patients lacked all tested KIRs, which is also a distinct, abnormal finding. Immunoperoxidase staining of bone marrow biopsy specimens from NK-GLL patients with antibodies to CD8, TIA-1 and granzyme B revealed the disease-specific distinctive staining patterns previously found in T-GLL. These studies delineate the unique immunophenotypic features diagnostic of T-GLL and provide strong evidence that NK-GLL, like T-GLL, represents a clonal lymphoproliferative disorder.
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PMID:Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia. 1264 73

Apoptosis in response to granzyme B involves activation of caspase-dependent target cell death pathways. Herein, we show that granzyme B initiates caspase processing but cannot fully process procaspase-3 in intact Jurkat T leukemia or NT2 neuronal cells. Rather, the release from mitochondria of proapoptotic mediators cytochrome c, Smac/Diablo, and HtrA2/Omi facilitates full activation of caspases that results from autoprocessing. Bcl-2 overexpression in mitochondria suppresses the release of these proapoptotic molecules, resulting in cell survival despite partial procaspase processing by granzyme B. We propose that binding of inhibitor of apoptosis (IAP) proteins to partially processed procaspases inhibits cell death unless mitochondrial disruption also occurs in response to granzyme B or activated BH3-domain proteins such as truncated Bid.
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PMID:Caspase activation by granzyme B is indirect, and caspase autoprocessing requires the release of proapoptotic mitochondrial factors. 1264 50

Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8(+) or less frequently natural killer cells; in contrast, monoclonal expansions of CD4(+) T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4(+) T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4(+) T cells of a series of 34 consecutive cases. Like CD8(+) T-LGL leukemias, CD4(+) T-LGL leukemia patients have an indolent disease; however, in contrast to CD8(+) T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4(+) T-LGLshowed expression of TCRalphabeta, variable levels of CD8 (CD8(-/+dim)) and a homogeneous typical cytotoxic (granzyme B(+), CD56(+), CD57(+), CD11b(+/-)) and activated/memory T cell (CD2(+bright), CD7(-/+dim), CD11a(+bright), CD28(-), CD62L(-) HLA-DR(+)) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-gamma(++), tumor necrosis factor-alpha(++), interleukin (IL-2)(-/+), IL-4(-), IL-10(-), IL-13(-)]. Phenotypic analysis of the TCR-Vbeta repertoire revealed large monoclonal TCR-Vbeta expansions; only a restricted number of TCR-Vbeta families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRalphabeta(+)/CD4(+)/NKa(+)/CD8(-/+dim) T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8(+) T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder.
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PMID:TCRalphabeta+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder. 1287 95

We report a case of an Epstein-Barr virus (EBV)-associated nasal-type natural killer cell lymphoma (NKCL) preceded by benign panniculitis, which arose in a 48-year-old woman with an asymptomatic human T-cell leukemia/lymphoma virus type-1 (HTLV-1) infection. A biopsy of the initial panniculitis lesion demonstrated lobular panniculitis with a germinal center composed of benign mononuclear cells with a phenotype of CD4+CD45RO+CD5sCD3+ cCD3 epsilon + T-cell intracellular antigen-1 (TIA-1)- and granzyme B-. One year after oral prednisolone therapy, the patient developed subcutaneous nodules composed of atypical lymphoid cells with a phenotype of CD4-CD45RO+CD56+sCD3-cCD3 epsilon + (TIA-1)+ and granzyme B+. In the initial panniculitis lesion, neither EBV-encoded RNA (EBER-1) nor clonal proliferation of EBV-infected cells was identified. In later lesions, however, a large number of atypical cells were positive for EBER-1, and a clonal expansion of EBV-infected cells was detected. No clonal rearrangement of T-cell receptor-alpha, -beta, or -gamma genes was found in either specimen. This patient was an asymptomatic carrier of human T-cell leukemia/lymphoma virus type-1 (HTLV-1) without clonal integration of proviral HTLV-1 in neither the peripheral blood nor the skin lesions. These observations suggest that EBV-associated NKCL occurred subsequently in the clinical course of benign panniculitis under the influence of immunosuppression caused by prednisolone treatment and HTLV-1 infection.
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PMID:Nasal-type natural killer cell lymphoma preceded by benign panniculitis arising in an asymptomatic HTLV-1 carrier. 1295 85

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the Western world. It is currently an incurable disease, making new treatment options such as immunotherapy desirable. Monoclonal antibodies (Mabs) to surface antigens of the tumor cell is one option. Administration of cytotoxic cells such as natural killer (NK) and natural killer-like T (NKT) cells expanded in vitro might be a useful treatment modality alone or in combination with MAbs. A limiting step in the development of successful cellular immunotherapy has been the availability of appropriate cytotoxic cells. Here, we report the feasibility of expanding populations of the human killer cells, CD3-CD56+ NK and CD3+CD56+ NKT cells, from peripheral blood mononuclear cells (PBMCs) of B-CLL patients. The influence of tumor B cells on the in vitro expansion of killer cells was assessed by depleting B cells from PBMCs by microbead separation before culture. The 21-day cultures from both B-cell- and non-B-cell-depleted PBMC showed a marked expansion of NK cells, and also of T cells, among which almost half had the NKT phenotype. Depletion of B cells before culture did not change the expansion rates of NK and NKT cells significantly. In patients with progressive B-CLL, NK cell expansion capacity was improved after fludarabine treatment when compared to samples obtained before treatment. Repeated samples of PBMCs from individual untreated patients with both indolent and progressive disease cultured under identical conditions gave similar NK cell expansion rates. Expanded killer cell populations had cytotoxic function against the NK-sensitive target K562 cell line and expressed high levels of Granzyme B. From our studies, we conclude that NK cells as well as NKT cells from the peripheral blood of B-CLL patients can be expanded, and that these cells have cytotoxic capacity.
Leukemia 2003 Oct
PMID:Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy. 1451 43

Clinical outcome in diffuse large B-cell lymphoma (DLBCL) remains unpredictable, despite the identification of clinical prognostic parameters. Here, we investigated in pretreatment biopsies of 70 patients with DLBCL whether numbers of activated cytotoxic T-lymphocytes (CTLs), as determined by the percentage of CD3-positive lymphocytes with granzyme B (GrB) expression, have similar prognostic value as found earlier in Hodgkin's lymphoma and anaplastic large-cell lymphoma and whether loss of major histocompatibility complex (MHC)-I molecules or expression of the GrB antagonist protease inhibitor 9 (PI9) may explain immune escape from CTL-mediated cell death. Independent of the International Prognostic Index (IPI), the presence of >/=15% activated CTLs was strongly associated with failure to reach complete remission, with a poor progression-free and overall survival time. Downregulation of MHC-I light- and/or heavy-chain expression was found in 41% of interpretable cases and in 19 of 56 interpretable cases PI9 expression was detected. We conclude that a high percentage of activated CTLs is a strong, IPI independent, indicator for an unfavorable clinical outcome in patients with primary nodal DLBCL. Although in part of DLBCL expression of PI9 and loss of MHC-I expression was found, providing a possible immune-escape mechanism in these cases, no correlation with clinical outcome was found.
Leukemia 2004 Mar
PMID:Prognostic significance of activated cytotoxic T-lymphocytes in primary nodal diffuse large B-cell lymphomas. 1471 86

In order to monitor the immunological status of patients after allogeneic hematopoietic stem cell transplantation(HSCT), granzyme B(GrB), perforin(PRF) and Fas ligand(L) antigens and mRNAs were measured by flow cytometry and real time RT-PCR, respectively. Cytoplasmic antigens were detected in whole blood after fixation and pretreatment with saponin. Real time PCR was carried out using extracted RNA from buffy coat. We measured these substances in a cytotoxic T cell clone, a natural killer cell line, and peripheral blood collected from 11 patients after HSCT. Although changes in antigen levels were not detected, increased levels of GrB and Fas L mRNAs were quantitatively measured in CTLs and NK cells stimulated by IL-2 combined with IL-12. Increased levels of GrB and/or PRF antigens were detected in four of five patients with chronic GVHD. Increased mRNA levels were also observed in one or more of GrB, PRF or Fas L in four of five patients with cGVHD, although there was a discrepancy between antigen and mRNA positivity. Four of six patients without cGVHD were positive for apoptosis-inducing factors, either by antigen detection or RT-PCR. One of these four had relapsing leukemia, and another had herpes zoster infection, while the reasons for positive results in the other two patients are not clear. Although changes in antigen levels did not parallel those in mRNA, measurement of these parameters may assist in predicting GVHD, GVL and infections following HSCT.
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PMID:[Levels of granzyme B, perforin and Fas ligand antigens and mRNAs in patients following allogeneic hematopoietic stem cell transplantation]. 1474 38

Chronic lymphocytic leukemia (CLL) is associated with increased risk of malignancy, but the occurrence of other lymphomas, in particular T-cell lymphomas, is rare. We identified 7 cases of peripheral T-cell malignancy associated with B-cell-derived CLL from the files of two institutions over a 20-year period. The presence of both B and T lymphoproliferative disorders was confirmed in all cases by immunophenotype and in 6 cases by gene rearrangements. Six patients developed peripheral T-cell lymphoma (PTCL), unspecified, during the course of CLL (10-168 months). In all 5 evaluable cases, the cells had a cytotoxic T-cell phenotype; the sixth case was CD56+, but TIA-1 and Granzyme B could not be studied. A seventh patient with CLL developed mycosis fungoides, and an aggressive NK cell leukemia. To investigate possible risk factors for the development of PTCL, we screened 100 unselected peripheral blood samples from newly diagnosed CLL patients by PCR for the presence of clonal T cell populations. We found evidence of clonal T-cell expansion in 8 patients and increased lymphocytes with large granular lymphocyte morphology in 7 of 8 cases. The immunophenotype was assessed by multicolor flow cytometry and in 4 cases the T-cell expansion was composed of either CD3+/CD8+ or CD3+/CD4-/CD8- cells. The cytotoxic nature of the clonal T-cell expansions in the peripheral blood correlates with the cytotoxic nature of the PTCLs, but their role in the subsequent development of T-cell lymphomas is still unclear. PTCL following CLL should be distinguished from typical Richter syndrome, which it can mimic clinically.
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PMID:Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. 1522 53


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