Variable expression of CD3‐zeta and associated protein tyrosine kinases in lymphocytes from patients with myeloid malignancies

Buggins,; Hirst,; Pagliuca, Antonio; Mufti,

doi:10.1046/j.1365-2141.1998.00654.x

Cited by 57 publications

(35 citation statements)

References 43 publications

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“…1 Immune activity has been implicated in the clonal evolution of childhood leukaemia, 2 yet host immune inactivity, or immunoparesis, [3][4][5][6] as well as tumour evasion of immune recognition 7,8 have been emphasised in studies of AML pathogenesis. Experimental studies of the mechanisms of immune tolerance to AML have led to novel therapies designed to modulate the immune response, including antibody, 9 cytokine 10 and dendritic cell-based treatments.…”

Section: Introductionmentioning

confidence: 99%

Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia

2003

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A simple assay was developed to assess the potential of patients with acute myelogenous leukaemia (AML) to respond to immunotherapy. Lymphocytes, monocytes and leukaemic blasts with their corresponding intracellular cytokine profiles were evaluated by four-colour flow cytometry. In 50 ll samples of whole blood, surface labelling for CD45, CD8 and CD3 was used for cell identification prior to intracellular staining for interleukin (IL)-4, IL-10, IL-12 and interferon (IFN)-c. Absolute numbers of CD8 + and CD8 À (putative CD4 + ) T-cells, NK cells (CD8 + /CD3 À ) and monocytes were determined by reference to a fixed number of added fluorescent beads. The absolute numbers of CD8 À and CD8 + T-cells in the blood of patients with AML were similar to those of normal controls. More of the lymphocytes in the blood of leukaemic patients spontaneously produced cytokines compared with those of controls. Furthermore, primary AML blasts secreted predominantly IFN-c. After recovery from chemotherapy, lymphocyte counts tended to be lower than in normals and reduction of NK cells reached significance after the second chemotherapy (P ¼ 0.01). A prominent CD8 lo /CD3 lo-int lymphocyte subset appeared after recovery in some patients. This laboratory application of the study of cell subsets and intracellular cytokines in patients undergoing treatment may be helpful in monitoring immunological responses in AML.

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Section: Introductionmentioning

confidence: 99%

Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia

2003

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“…94 Defective effector functions of T cells, which were associated with diminished expression of the CD3-and CD3-⑀ chains, have also been described. 95,96 Decreased expression of CD3-and CD3-⑀ was more likely on lymphocytes of patients with advanced disease. Diminished expression of CD3-and CD28 was also observed in patients with advanced malignancies, chronic viral infections, or autoimmune diseases, occurring as a consequence of chronic lymphocyte stimulation.…”

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confidence: 97%

Graft-versus-leukemia reactions in allogeneic chimeras

Kolb

Schmid

Barrett

et al. 2004

Blood

359

256

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There is a strong graft-versus-leukemia (GVL) effect of allogeneic stem cell transplantation (SCT) due to elimination of tumor cells by alloimmune effector lymphocytes. When leukemia relapses after allogeneic SCT, donor lymphocyte transfusions (DLTs) can induce sustained remissions in some patients. This review summarizes the current status on clinical use of DLT, the basis of GVL reactions, problems associated with this therapy, and new strategies to improve DLT. Several multicenter surveys demonstrated that the GVL effect of DLT is most effective in chronic myelogenous leukemia (CML), whereas it is less pronounced in acute leukemia and myeloma. Cytokine stimulation to induce differentiation of myeloid progenitor cells or to up-regulate costimulatory molecules on tumor cells may improve the efficacy of DLT. Infections and graft-versus-host disease (GVHD) are major complications of DLT. Control of GVHD may be improved using suicide gene-modified T cells for DLT, allowing T-cell elimination if severe GVHD develops. Hopefully, in the future, GVL effect can be separated from GVHD through adoptive transfer of selected T cells that recognize leukemia-specific antigens or minor histocompatibility antigens, which are expressed predominantly on hematopoietic cells, thereby precluding attack of normal tissues. In patients with leukemia and lymphomas with fast progression, tumor growth may outpace development of effector T cells. Here it may be preferable to select stem cell transplant donors with HLA-mismatches that allow alloreactive natural killer cells, which appear early after transplantation, to retain their cytolytic function. New approaches for adoptive immune therapy of leukemia, which promise a better prognosis for these patients, are being developed. IntroductionAllogeneic stem cell transplantation (SCT) is an established form of treatment for leukemia and is now being explored as a treatment for a variety of other hematologic and nonhematologic malignancies. In the last decade, the paradigm for treatment of leukemia by SCT has changed. The initial focus was to use myeloablative doses of radiation and chemotherapy to eliminate the leukemia, and SCT was performed to prevent death from marrow failure. Increasingly today, the emphasis has shifted to eradicating leukemia with alloimmune effector cells, while limiting radiation and chemotherapy to those doses sufficient to permit donor stem cell engraftment as a platform for adoptive immune therapy and reducing the conditioning toxicity for SCT.The antileukemia effect of the graft-versus-host (GVH) reaction was recognized early in murine models 1 and soon applied to human patients. 2 A systematic analysis by the Seattle team showed that patients surviving acute graft-versus-host disease (GVHD) benefited from a reduced tumor relapse rate. 3 The important role of T cells in eliminating chronic myelogenous leukemia (CML) was suggested by a retrospective study of the International Bone Marrow Transplant Registry (IBMTR), 4 which found an increased leukemia relapse rate...

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“…23,24 These changes have been reported in patients with renal carcinoma, colon cancer, melanoma, follicular lymphoma, as well as CML and AML. 25 Importantly, remission induction (either by surgical debulking for solid tumors or chemotherapy for leukemia) appears to lead to reversal of these alterations and restoration of immune responsiveness.…”

Section: Issues Of Tumor Burden Tolerance Andmentioning

confidence: 99%

New Developments in the Therapy of Acute Myelocytic Leukemia

Gorin¹

2000

Hematology

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In Section IV, Dr. Slavin reviews the concept of delivering non-myeloablative stem cell transplantation (NST) and delayed lymphocyte infusion (DLI) to increase tolerance in particular in high risk and older patients, and take advantage of the graftversus-leukemia (GVL) effect.All these approaches hold promise in reducing morbidity and mortality and differ from the older concepts aiming at delivering the highest possible doses of chemotherapy and/or total body irradiation to reach maximum leukemia cell kill, whatever the toxicity to the patient.

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Variable expression of CD3‐zeta and associated protein tyrosine kinases in lymphocytes from patients with myeloid malignancies

Cited by 57 publications

References 43 publications

Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia

Quantification and cytokine production of circulating lymphoid and myeloid cells in acute myelogenous leukaemia

Graft-versus-leukemia reactions in allogeneic chimeras

New Developments in the Therapy of Acute Myelocytic Leukemia

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