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)

Vaccination with dendritic cells (DCs) as professional antigen presenting cells generated from autologous leukemic blasts might elicit anti-leukemic T cell responses in patients with acute myeloid leukemia (AML). To test this hypothesis, autologous AML-DC were generated under good manufacturing practice (GMP) conditions and injected s.c. into five AML patients up to four times at a biweekly interval. No severe adverse side effects were observed. Three patients remained in a stable condition for 5.5-13 months and two patients died from rapidly progressive AML. Compared to the initial T cell frequency, enzyme linked immunosorbent spot (ELISPOT) assays revealed a significant increase of granzyme B releasing CD8+ T cells specifically recognizing the PRAME derived peptide (ALYVDSLFFL), a leukemia associated antigen expressed by AML blasts. The cytokine levels in the serum of vaccination AML patients as assessed by cytokine bead assay changed over the period of vaccination to an elevated type 1 T helper cell pattern. Interferon gamma production by CD4+ T helper cells increased during vaccination. In summary, we demonstrated that autologous AML-DC vaccination is well tolerated and can result in an enhanced and specific response of cytotoxic T cells in AML patients.
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PMID:Immunotherapy for patients with acute myeloid leukemia using autologous dendritic cells generated from leukemic blasts. 1652 34

Target cell resistance against natural killer (NK) cell-mediated cytotoxicity obstructs NK cell-based immunotherapy of leukaemia. Several mechanisms of resistance have been described. Because of lack of simple assays for analysing these mechanisms, their relative impact on a given effector-target pair is mostly unknown. We here analysed the combination of the Granzyme B (GrB) enzyme-linked immunospot assay (ELISPOT) for the assessment of NK cell reactivity and cytotoxicity assays to estimate target cell escape mechanisms. Target cell recognition failure leads to negative GrB ELISPOT results, whereas target cell resistance shows positive GrB ELISPOT results in the absence of cytotoxicity. We confronted NK cells with the sensitive target cell line K562, and with the resistant cell lines ML2, SupB15 and Raji. ML2 cells sufficiently activated GrB-release whilst being resistant against cytotoxic granules of NK cells. Partial resistance of Raji results from the interaction of HLA class I with inhibitory killer immunglobulin-like receptors (KIR) on the NK cells. Failure of target recognition by HLA class I-KIR interaction, lacking ligands to stimulatory NK cell receptors and partial resistance to cytotoxic granules all contributed to resistance of SupB15. In conclusion, revealing the mechanisms of resistance against NK cell-mediated cytotoxicity may allow improving the results of NK-based immunotherapy.
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PMID:Resistance against natural killer cell cytotoxicity: analysis of mechanisms. 1697 Jun 88

The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate is highly effective in the front-line treatment of chronic myeloid leukemia (CML) and is increasingly used in patients with residual disease or relapse after allogeneic stem cell transplantation (allo-SCT). Since an impairment of anti-viral CD8+ T-lymphocyte function by imatinib has been described, we question whether imatinib also affects specific anti-leukemic CD8+ T lymphocytes generated from the peripheral blood of healthy donors, and of CML patients after allo-SCT. Here, we assessed CD8+ T-cell expansion and function from healthy donors and patients with CML. The release of IFN-gamma and granzyme B by CD8+ T-lymphocytes specific for R3, a recently described T-cell epitope peptide derived from a leukemia-associated antigen designated RHAMM/CD168 (receptor for hyaluronic acid mediated motility), was inhibited by imatinib in a dose-dependent fashion (range: 1-25 microM). These T cells were able to lyse cognate peptide labeled T2 cells and CD34+ CML progenitor cells. This lysis was inhibited by imatinib. The inhibitory effect was not associated with an increased rate of apoptosis of T cells and reversible after removal of imatinib. In the light of these findings, clinical administration of imatinib might result in the reduction of efficacy of the graft-versus-leukemia effect or other T-cell-based immunotherapies.
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PMID:Imatinib impairs CD8+ T lymphocytes specifically directed against the leukemia-associated antigen RHAMM/CD168 in vitro. 1700 43

Recently, we described the receptor for hyaluronic acid-mediated motility (RHAMM) as a leukemia-associated antigen and characterized the RHAMM-derived peptide R3 (pos. 165-173: ILSLELMKL) as a CD8+ T cell epitope. Directing CD8+ T lymphocytes specifically to R3 might help to shape the graft-versus-leukemia effect observed after allogeneic stem cell transplantation (allo-SCT). To detect the potential induction of R3-specific cytotoxic T lymphocytes in chronic myeloid leukemia (CML) patients after allo-SCT and healthy donors, we used mixed lymphocyte peptide culture, enzyme-linked immunospot (ELISPOT) release assays for interferon (IFN)-gamma and granzyme B, tetramer staining and 51Cr release cytotoxicity assays. The R3 peptide showed the capacity to elicit specific CD8+ T cell responses characterized by the release of IFN-gamma and granzyme B upon stimulation with R3-pulsed T2 cells. Responses to R3 peptide were detected in 67% (6/9) of the CML patients after allo-SCT and 24% (8/34) of healthy donors in ELISPOT assays for IFN-gamma and granzyme B. These R3-specific CD8+ T cells comprised predominantly effector cells (CCR7-CD45RA+ or CD27-CD45RA+) in patients with CML after allo-SCT or healthy donors respectively. Cytotoxicity assays demonstrated effective lysis of CML progenitor cells by R3-primed CD8+ T lymphocytes. Imatinib inhibited the functional activation of R3-specific CD8+ T lymphocytes. In summary, we demonstrated R3-specific CD8+ effector T lymphocytes after allo-SCT in CML patients which might have been augumented by R3 peptide vaccination and hampered at least partially by imatinib in this particular patient cohort.
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PMID:The receptor for hyaluronic acid-mediated motility induces specific CD8+ T cell response in healthy donors and patients with chronic myeloid leukemia after allogeneic stem cell transplantation. 1739 13

A 66-year-old female was referred to our hospital with bone pain and progressive pancytopenia with granular lymphocyte infiltration only in the bone marrow (BM). Flow cytometric and histological analyses revealed that these cells were positive for CD3, TCRalphabeta, granzyme B, and the diagnosis of T-cell granular lymphocyte leukemia (T-GLL) with myelofibrosis was made. These BM granular lymphocytes were greatly ruffled and showed the CD3/CD20 double positive phenotype, which was not detected in the peripheral blood. The patient was treated with a single course of fludarabine followed by a favorable clinical course for 3 months. Many of the BM lymphocytes displayed almost normal appearance after treatment, however, the number of lymphocytes in the BM did not decrease and these were still CD3/CD20 double positive. This is an overlap case of T-GLL and peripheral T-cell lymphoma, unspecified (PTCLu).
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PMID:[Bone marrow-restricted involvement of T-cell granular lymphocyte leukemia]. 1769 8

A novel nude mice model of human extranodal nasal type NK/T-cell lymphoma was established by subcutaneously implanting the sample taken from the patient with secondary extranodal nasal type NK/T-cell lymphoma of the stomach into the right axillary region of a BALB/c (nu/nu) nude mouse. This model had been successfully transplanted in vivo for thirty-two generations with a stable growth cycle. The survival rates of both resuscitation and transplantation were 100%. Histologically, the tumor cells were medium to large size and arranged in sheets, with a little mesenchyma, and disseminated almost in all passages of the lymphoma-bearing nude mice. Immunologically, the tumor cells were positive for CD56, cytoplasmic CD3, granzyme B or TIA-1 and LMP1, sometimes for CD8 but negative for surface CD3, CD7, CD20 and CD1a. EBER1/2 was found. No T-cell receptor gamma gene rearrangement was detected in the transplanted tumors. Furthermore, both human sequencing-tagged sites SY14 and Y chromosome were detected by PCR or fluorescent in situ hybridization, respectively, in the transplanted tumor. The transplanted tumor in this novel nude mice model maintained the essential features of human extranodal nasal type NK/T-cell lymphoma, and it would be an ideal tool in vivo for further research of the tumor.
Leukemia 2008 Jan
PMID:A novel nude mice model of human extranodal nasal type NK/T-cell lymphoma. 1785 53

The tyrosine kinase inhibitor imatinib has been reported to inhibit CD8+ T lymphocytes. Little is known about its effects on CD4+CD25+ regulatory T cells (T(reg) cells) which might regulate the graft-vs.-leukemia (GVL) reaction after allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion (DLI). This is of particular interest in patients with relapse of chronic myeloid leukemia (CML) after allo-SCT, as the two therapeutical options DLI and imatinib might interact reversely. Here, we demonstrate that the proliferation of CD4+CD25+ T(reg) cells and their production of IL-10, TGF-beta1 and granzyme B as markers of activation were significantly down-regulated by imatinib in a dose-dependent manner. In addition, the expression of surface CD69, both surface and intracellular GITR, FoxP3, CD152 (CTLA) of activated CD4+CD25+ T(reg) cells were inhibited by imatinib in a dose-dependent manner. In light of these findings, clinical administration of imatinib might not result in a reduction of the GVL effect on CML patients receiving imatinib after allo-SCT and/or DLI or other CD8+ T lymphocyte based immunotherapies as the function of CD8+ cytotoxic T lymphocytes and CD4+CD25(hi) Treg cells is hampered in a similar way by imatinib.
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PMID:Imatinib impairs the proliferation and function of CD4+CD25+ regulatory T cells in a dose-dependent manner. 1791 40

Human umbilical cord blood (CB) has recently been used as a source of stem cells in transplantation. NK cells derived from CB are the key effector cells involved in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). It was reported that the activity of CB NK cells was lower than that of adult peripheral blood (PB) NK cells. In this study, we analyzed the expression of some NK cell receptors and cytotoxicity-related molecules in CB and PB NK cells. The expressions of activating NK receptors, CD16, NKG2D and NKp46, did not show significant difference between CB and PB NK cells. But the expression of inhibitory receptor NKG2A/CD94 was significantly higher on CB NK cells. As to the effector function molecules, granzyme B was expressed significantly lower in CB NK cells, but the expressions of intracellular perforin, IFN-gamma, TNF-alpha and cell surface FasL and TRAIL did not show difference between CB and PB NK cells. The results indicated that the high expression of NKG2A/CD94 and low expression of granzyme B may be related with the reduced activity of CB NK cells.
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PMID:High expression of NKG2A/CD94 and low expression of granzyme B are associated with reduced cord blood NK cell activity. 1797 18

Cyclopentenyl cytosine (CPEC) has been shown to induce apoptosis in human T lymphoblastic cell lines and T cells from leukaemia patients. In this study we have addressed the question of whether CPEC is able to decrease proliferation and effector functions of human alloresponsive T lymphocytes and induce T cell anergy. The proliferative capacity of human peripheral blood mononuclear cells in response to allogeneic stimulation was measured by 5,6-carboxy-succinimidyl-diacetate-fluorescein-ester staining. Flow cytometric analysis was performed using surface CD4, CD8, CD25, CD103 and intracellular perforin, granzyme A, granzyme B, caspase-3 and forkhead box P3 (FoxP3) markers. The in vivo immunosuppressive capacity was tested in a murine skin graft model. Addition of CPEC at a concentration of 20 nM strongly decreased the expansion and cytotoxicity of alloreactive T cells. Specific restimulation in the absence of CPEC showed that the cells became anergic. The drug induced caspase-dependent apoptosis of alloreactive T lymphocytes. Finally, CPEC increased the percentage of CD25(high) FoxP3+ CD4+ and CD103+ CD8+ T cells, and potentiated the effect of rapamycin in increasing the numbers of alloreactive regulatory T cells. Treatment with CPEC of CBA/CA mice transplanted with B10/Br skin grafts significantly prolonged graft survival. We conclude that CPEC inhibits proliferation and cytotoxicity of human alloreactive T cells and induces alloantigen non-responsiveness in vitro.
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PMID:The pyrimidin analogue cyclopentenyl cytosine induces alloantigen-specific non-responsiveness of human T lymphocytes. 1806 97

The novel selective BCR-ABL Breakpoint cluster region--Abelson murine leukemia viral oncogene homolog 1 (BCR-AML) inhibitor nilotinib (AMN107) is a tyrosine kinase inhibitor that is more potent against leukaemia cells in vitro than imatinib. As nilotinib might be used in the context of allogeneic stem cell transplantation where CD8+ T lymphocytes play a pivotal role in the graft-versus-leukaemia (GVL) effect, we investigated effects of nilotinib on this lymphocyte subpopulation. Nilotinib inhibits phytohemagglutinin (PHA)-induced proliferation of CD8+T lymphocytes in vitro at therapeutically relevant concentrations (0.5-4 microM). The inhibition of CD8+ T lymphocytes specific for leukaemia or viral antigens through nilotinib was associated with a reduced expansion of antigen peptide specific CD8+ T lymphocytes and with a decreased release of interferon-gamma and granzyme B by these cells as analysed by flow cytometry and enzyme-linked immunospot (ELISPOT) assays. The inhibitory effect caused by nilotinib was two times stronger than by imatinib. These effects were mediated through the inhibition of the phosphorylation of ZAP-70, Lck and ERK 1/2 and the NF-kappaB signalling transduction pathway. Taken together, we observed a strong suppressive impact of nilotinib on the CD8+ T lymphocyte function which should be considered carefully in the framework of allogeneic stem cell transplantation or other T cell based immunotherapies.
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PMID:Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling. 1937 87


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