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)

In this paper we review some of the preclinical findings which have led us to believe that immunotherapy with interleukin 2 (IL2)/lymphokine activated killer (LAK) cells may be a feasible approach in the management of acute myeloid leukemia. The main clinical and biological results so far obtained with IL2 treatment, and the currently ongoing protocols and strategies are discussed.
Leukemia 1992
PMID:Interleukin 2 (IL2) in the management of acute myeloid leukemia: clinical and biological findings. 160 6

Unlike many other growth factor receptors, the known subunits of the receptors for the Interleukins IL-2 and IL-3 lack intrinsic tyrosine kinase activity, and yet increases in the phosphorylation of proteins on tyrosines is a rapid event in hematolymphoid cells following stimulation with these lymphokines. Here we show that IL-2 and IL-3 regulate the activity of specific members of the SRC-family of non-receptor protein tyrosine kinases (PTKs). In IL-2-dependent T-cell lines, IL-2 induced rapid and transient increases in the activity of the p56-LCK kinase without influencing the activities of other SRC-like PTKs (p59-FYN, p62-YES) in these T-lymphocytes. In contrast to IL-2's effects on p56-LCK in T-cells, studies of an IL-2-responsive cell line of the B-cell lineage that lacks p56-LCK revealed that IL-2 specifically regulates the activity of the p53/56-LYN kinase. Thus, some flexibility exists in the ability of various SRC-like PTKs to functionally couple to IL-2 signalling pathways. In several IL-3-dependent myeloid-committed leukemic cell lines, IL-3 was found to specifically regulate the activity of the p53/56-LYN kinase without affecting the activities of other SRC-like PTKs (p59/64-HCK, p59-FYN, p62-YES) in these hematopoietic cells. This finding that p53/56-LYN can be regulated by both IL-2 in B-lineage cells and IL-3 in myeloid-committed cells demonstrates that the same SRC-family PTK can participate in signal transduction events mediated via two independent receptor systems. Taken together, our findings imply that the specific combinations of lymphokine receptors and SRC-like PTKs available for coupling with those receptors are coordinately controlled during the differentiation of hematopoietic cells.
Leukemia 1992
PMID:Regulation of SRC-family protein tyrosine kinases by interleukins, IL-2, and IL-3. 160 36

The negative impact of donor marrow T lymphocyte depletion on relapse of chronic myeloid leukaemia (CML) following bone marrow transplantation strongly suggests that the leukaemia is particularly susceptible to immune regulation. The immune response to CML may be mediated by major histocompatibility (MHC) locus unrestricted natural killer and lymphokine activated killer cells, or by MHC-restricted CD4 and CD8 lymphocytes. Interaction with the leukaemia is both by direct cell-contact cytotoxicity, and indirectly via cytokines and growth factors. T4 and T8 lymphocytes recognize a spectrum of minor histocompatibility antigens on the leukaemia cell which may be non-specific, leading to graft-versus-leukaemia and graft-versus-host reactions, or present only on myeloid cells leading to a tissue restricted response. The possibility that the P210 protein derived from the BCR/ABL fusion gene on chromosome 22 leads to the presentation via MHC molecules of leukaemia-specific peptide antigens is currently under investigation. Developments in understanding the immune response to CML open up the possibility of developing leukaemia-specific immunotherapy strategies.
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PMID:Immune responses to chronic myeloid leukaemia. 161 13

Patients suffering from malignant disease will probably develop some metabolic abnormality of electrolytes. Hypernatremia is defined as an elevation of serum natrium over 150 mEq/l and caused by decrease of water intake, low level of ADH secretion and impaired response of kidney to ADH. Hyponatremia below 135 mEq/l of serum natrium is caused by SI-DAH, sick cell syndrome and increased loss of natrium from the kidney. On the other hand, hyperkalemia is defined as an elevation of serum kalium over 5.0 mEq/l and caused by acute tumor cell lysis syndrome, adrenal and renal insufficiency. Hypokalemia is caused by kalium loss from kidney and hypersecretion of mineral corticoid. Hypercalcemia is found in the high frequency among patients with malignant disease. Hypercalcemia is defined as an elevation of serum calcium over 11.0 mg/dl, although the most important aspect is the level of ionized calcium. The excess calcium causes defective urinary concentration with polydipsia, nausea and vomiting leading to volume depletion. At serum calcium levels about 13.8 mg/dl, there may be rapid deterioration or renal function, dehydration, coma and cardiac arrhythmias. Hypercalcemia is rarely the first manifestation of cancer. There are three principle pathogenic causes of malignant hypercalcemia, 1) hypercalcemia is a feature of several hematological cancers, including Burkitt's lymphoma, T cell leukemia, but most commonly with myeloma. The hypercalcemia in these myeloma patients is due to the secretion of an osteoclast activator, a lymphokine by the myeloma cells. 2) all patients with bony metastases have biochemical evidence of increased bone resorption. However, not all patients with bony metastases develop hypercalcemia. Probably the hypercalcemia is due partially to increased renal tubular reabsorption of calcium, mediated by a humoral factor, with activity similar to that of parathormone. 3) hypercalcemia in the patients without bony metastases is due to increased bone resorption caused by the ectopic secretion by the tumor. Mildly symptomatic patients will benefit from modest salt loading. They are dehydrated and replacement of the extracellular fluid is the first line of treatment. This may require 4-10 l normal saline/24 h. In addition, frusemide will increase calcium excretion. Calcitonin may be given subcutaneously or intravenously to refuse the mobilisation of calcium from bone. Glucocorticoids are unhelpful, but will prolong the effect of calcitonin. A diphosphonate is also useful.
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PMID:[Palliative therapy in cancer. 4. Palliation of the symptoms from a malignant tumor. (2)]. 169 56

T cell depletion has decreased the incidence and severity of graft-versus-host disease following transplantation of allogeneic bone marrow. In the treatment of leukemia, decreased GVHD has often been associated with diminished antileukemia or graft-versus-leukemia (GVL) reactivity resulting in higher relapse rates. However, we have not seen a loss of the GVL effect following transplantation of marrow grafts depleted of CD3+ T cells. This suggests that non-T-cell effectors may play a role in preventing leukemic relapse. To study whether natural killer and lymphokine-activated killer (LAK) activity in BM was compromised by T cell depletion, the effect of T-cell-specific monoclonal antibodies against CD3 and CD6 determinants alone, or in combination, on the generation and expansion of NK/LAK cells was examined in vitro and compared to the effect of T depletion on mitogen-driven T cell proliferation. Limiting dilution analysis revealed that T depletion with CD3 and/or CD6 specific antibodies significantly reduced the number of proliferating T lymphocytes but did not significantly affect the frequency of cells able to expand and mediate LAK activity. Bone marrow, depleted of CD3+ or CD6+ T cells, generated levels of LAK activity equivalent to non-T-cell-depleted bone marrow following long-term culture in recombinant interleukin 2. CD3- NKH-1+ cells were the predominant population in rIL-2 expanded marrow cultures prior to transplant and in the peripheral blood of patients who had received a CD3-depleted marrow graft 21-65 days earlier. These studies show that it is possible to selectively reduce GVH-reactive T cells in allogeneic bone marrow while retaining non-T-effector cells with potential to mediate an antileukemia effect in vivo.
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PMID:Preservation of lymphokine-activated killer activity following T cell depletion of human bone marrow. 169 9

Activation of resting T-lymphocytes induces synthesis of interleukin-2 (IL-2) and expression of cell surface receptors for this lymphokine. In contrast to resting normal T-cells that do not express high-affinity IL-2 receptors (IL-2R), abnormal T-cells of patients with leukemia-lymphoma, certain autoimmune disorders, and individuals rejecting allografts express this receptor. Exploiting this difference in receptor expression, antibodies to the IL-2 receptor have been used effectively to treat patients with leukemia and lymphoma. One approach is to use monoclonal antibodies produced in mice; the disadvantage is that they are highly immunogenic. In an effort to reduce the immunogenicity of the mouse monoclonal antibodies, monoclonal-antibody-mediated therapy has been revolutionized by generating humanized antibodies produced by genetic engineering in which the molecule is human except for the antigen-combining regions, which are retained from the mouse. Further, to increase its cytotoxic effectiveness, the monoclonal antibody has been armed with toxins or radionuclides. Alternatively, IL-2 itself has been linked to a toxin to kill IL-2 receptor-bearing cells. Thus, IL-2 receptor-directed therapy provides a new method for treating certain neoplastic diseases and autoimmune disorders and for preventing allograft rejection.
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PMID:The multichain interleukin-2 receptor: a target for immunotherapy. 172 19

Successful generation of adherent lymphokine-activated killer (A-LAK) cells, highly-enriched in CD3-CD56+ antitumour effector cells, from the peripheral blood of ten patients with acute myelogenous leukaemia (AML) is described. The AML patients were either untreated or in remission. In vitro proliferation of A-LAK cells in patients with AML was generally poor, unless the cells were cocultured with irradiated concanavalin A (ConA)--prestimulated allogeneic PBL or selected lymphoblastoid cell lines (LCL) as feeder cells. Using this method, the median fold proliferation was 290 for A-LAK cells cultured with ConA-activated feeders and 291 for those grown with LCL, both significantly higher (both P less than 0.001) than the median of 2-fold expansion observed in cultures without feeders. A-LAK cultures generated in the presence of feeders consistently showed good enrichment (up to 90%) in CD3-CD56+ NK cells. Although NK activity was not significantly increased on a per cell basis in A-LAK cells grown with feeder cells, total lytic activities against both NK-sensitive target, K562, and NK-resistant target, Daudi, were significantly greater (P less than 0.02 for ConA-PBL feeders and P less than 0.005 for LCL feeders) as compared to those in paired cultures without feeders. In the presence of irradiated allogeneic feeder cells, 7/10 AML patients generated A-LAK cultures characterised by good proliferation and increased purity as well as cytotoxic activity.
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PMID:Generation of adherent lymphokine activated killer (A-LAK) cells from patients with acute myelogenous leukaemia. 173 21

In vivo administration of recombinant interleukin 2 (IL2) has been associated, in acute leukaemia as well as in other tumours, with a variable degree of thrombocytopenia. In two patients with acute myeloid leukaemia who showed a progressive and severe fall in platelet count during daily continuous i.v. infusion of IL2, we assessed whether peripheral blood IL2-generated lymphokine activated killer (LAK) lymphocytes could affect growth of the autologous bone marrow megakaryocytic progenitor cell compartment (CFU-MK) in vitro. Following overnight pre-incubation in liquid culture of the marrow cells with autologous LAK effectors, there was an almost complete abrogation of the CFU-MK colony growth (97% and 89% inhibition). Pre-incubation in the presence of a monoclonal antibody to tumour necrosis factor alpha (TNF) completely reversed the inhibitory effect. The role played by TNF was confirmed by the finding that recombinant TNF caused a dose-dependent inhibition of the growth of CFU-MK. IL2 alone was ineffective. These results suggest that the often severe thrombocytopenia observed in patients with acute leukaemia treated with IL2 is at least partly due to autologous LAK cells activated in vivo following the administration of IL2.
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PMID:Thrombocytopenia in acute leukaemia patients treated with IL2: cytolytic effect of LAK cells on megakaryocytic progenitors. 175 72

Interleukin 2 (IL-2) is predominantly produced by T-helper cells (TH1) having the phenotype CD4+, and by subpopulations of thymocytes after antigenic or mitogenic stimulation. IL-2 causes an indefinite growth of T-cells, and its function depends on binding to IL-2 receptors (IL-2R alpha and IL-2R beta). Thus the immune response of T cells is controlled through the expression of the IL-2 receptors and the IL-2 binding. IL-2 receptors are expressed not only by T-cells but also by B-cells, NK cells, monocytes, thymocytes, thymic stroma cells, oligodendrocytes and endothelial cells. This explains the various functions of IL-2, such as increased immunoglobulin production, growth of certain B-cell subpopulations, macrophage-dependent cytotoxicity, growth and differentiation of oligodendrocytes and proliferation of lymphokine activated killer (LAK) cells. Abnormal production of IL-2 may lead to autoimmune diseases, immunodeficiencies and, under certain circumstances, to T-cell leukemia. With antibodies against the IL-2 receptors the binding of IL-2 may be blocked to avoid auto-aggressive destruction in autoimmune diseases. LAK cells increase the growth of NK cells and T-cell cytotoxicity against transformed cells. LAK cells, especially those from tumor infiltrating lymphocytes, in conjunction with IL-2 have already been used with promising initial results in the treatment of distant metastases. In the future LAK cell therapy with IL-2 may be adopted to prevent metastases and second primary tumors in high-risk patients with head and neck cancer.
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PMID:[Interactions and biological mechanisms of action of molecular signal peptides. II. Interleukin 2 (IL-2)]. 183 10

Treatment of splenic B lymphocytes and certain B-lineage cell lines with the mitogen lipopolysaccharide (LPS) and the lymphokine interleukin-4 (IL-4) induces expression of germ line immunoglobulin C epsilon transcripts and class switching to the C epsilon gene. We show that LPS-plus-IL-4 induction of germ line epsilon transcripts (termed I epsilon transcripts) occurs at the transcriptional level in an Abelson murine leukemia virus-transformed pre-B-cell line. A 1.1-kb region of DNA surrounding the I epsilon promoter endows inducible transcription to a heterologous reporter gene stably transfected into these cells; such inducible expression depends on combined treatment with LPS and IL-4. Analyses of constructs transiently introduced into a B-cell lymphoma line demonstrated that LPS-plus-IL-4-inducible expression can be conferred by a 179-bp segment of DNA spanning the I epsilon transcriptional initiation site. Mutational analyses demonstrated that this expression depended on DNA sequences within a conserved region directly upstream from the I epsilon transcriptional initiation region. One nuclear protein that is constitutively expressed in normal B cells binds to the downstream end of the conserved sequence; its binding specificity correlates with the functional effect of several mutations. Two additional proteins, which are induced by IL-4 treatment of splenic B cells, bind to the transcription initiation sites of I epsilon. These proteins are indistinguishable in binding assays from proteins previously shown to bind an enhancer region of the class II major histocompatibility complex gene A alpha.
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PMID:Identification of a conserved lipopolysaccharide-plus-interleukin-4-responsive element located at the promoter of germ line epsilon transcripts. 192 63


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