Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated that unstimulated highly-enriched NK cells have the capability to inhibit the growth of fresh clonogenic leukemic cells from AML, CML and preleukemic patients. The NK-cell population mediating antileukemic reactivity exhibited LGL morphology and NKH1 and CD16 phenotype. The inhibition of leukemic growth could be mediated by cell-to-cell contact or by soluble factor produced by NK cells. Antileukemia activity was only detectable when enriched population of LGL was utilized; NW-filtered lymphocyte population did not exhibit leukemia-inhibitory effect. However, such activity could be generated after culture of the latter effector cells with IL-2. The leukemia directed IL-2 activated effector cells were characterized as NK cells. The data reported here provide new insight into host factors which may control leukemia growth and indicate the possible future application of NK cells for therapy of leukemia.
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PMID:Inhibition of clonogenic growth of fresh leukemia cells by unstimulated and IL-2 stimulated NK cells of normal donors. 350 Oct 42

Recombinant human IL-2, secreted by yeast harboring a plasmid containing a synthetic IL-2 gene, is biologically active in augmenting human natural killer (NK) cell activity. A dose-dependent linear stimulation of NK activity was obtained against the chronic myelogenous leukemia cell line K562 over the range 3 to 300 units/ml of IL-2. Enhancement of NK activity was similarly demonstrable against the less NK-sensitive carcinoma cell lines LoVo and SKOSC. IL-2 could also be demonstrated to augment antibody-dependent cellular cytotoxicity (ADCC) against SKOSC targets. IL-2 responsiveness segregated with a non-E-rosetting fraction comprising 11% of postfractionation lymphocytes and containing 94% of the recoverable NK activity, suggesting that IL-2 might operate directly upon the NK cell rather than through an accessory cell. This is believed to be the first demonstration of NK stimulatory activity by the product of a totally synthetic human IL-2 gene. The availability, purity, and NK-enhancing properties of the recombinant IL-2 make it a potentially important agent for clinical trial.
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PMID:Modulation of human natural killer cell activity by recombinant human interleukin 2. 387 64

Recombinant human IL-2, secreted by yeast harboring a plasmid containing a synthetic IL-2 gene, is biologically active in augmenting human natural killer (NK) cell activity. A dose-dependent linear stimulation of NK activity was obtained against the chronic myelogenous leukemia cell line K562 over the range of 3 to 300 units/ml of IL-2. Enhancement of NK activity was similarly demonstrable against the less NK-sensitive carcinoma cell lines LoVo and SKOSC. IL-2 could also be demonstrated to augment antibody-dependent cellular cytotoxicity (ADCC) against SKOSC targets. IL-2 responsiveness segregated with a non-E-rosetting fraction comprising 11% of postfractionation lymphocytes, and containing 94% of the recoverable NK activity, suggesting that IL-2 might operate directly upon the NK cell rather than through an accessory cell. This is believed to be the first demonstration of NK stimulatory activity by the product of a totally synthetic human IL-2 gene. The availability, purity, and NK-enhancing properties of the recombinant IL-2 make it a potentially important agent for clinical trial.
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PMID:Modulation of human natural killer cell activity by recombinant human interleukin 2. 388 Nov 92

The requirements for allogeneic T-cell activation have been studied in experiments with T and/or B cells as stimulator. Although target determinants (TDs, defined by CTL effectors in CML) are present on B and T cells used as target cells, this study indicates that TDs are functionally different when expressed on B and T cells used as stimulator cells, as only B cells can activate CTL precursors. Further, the study confirms that inducing TDs and strong lymphocyte-activating determinants (LADs, defined by proliferation in MLC) can be distinct structures found on two different stimulator B cells. The study suggests that binding of cytotoxic precursor T cells to TDs per se does not allow any detectable activation or start of proliferation and differentiation but requires another function of the stimulator cells in the non-T-cell compartment. The nature of this function is unknown, but it is the background for the first signal received by the TD-specific clones of CTL precursors, resulting in the expression of growth receptors for T-cell growth factor or interleukin 2 which is the second signal necessary for clonal expansion and differentiation.
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PMID:Activation of human alloreactive cytotoxic precursor T lymphocytes. 618 Oct 39

K-76 COONa is a derivative of a fungal product which blocks complement (C)-mediated lysis by combining with C5 and preventing its activation to C5b. K-76 COONa can also combine with Factor I and inhibit its ability to hydrolyze C3b to iC3b. The inclusion of K-76 COONa at concentrations similar to those which inhibit C lysis blocked both murine cytotoxic-T-lymphocyte (CTL)-mediated lysis (CML) and the lectin-stimulated proliferative response of murine and human T lymphocytes. A modified cation pulse procedure has been used to determine which phases of CML were most sensitive to the drug. K-76 COONa was inhibitory when it was added to CML prior to the early Mg+2-dependent binding phase, but was much less effective when it was added at any time after the formation of CTL-target conjugates. The principal effect of the drug on the proliferative response was also exerted during an early phase of the response. K-76 COONa did not appreciably decrease the production of T-cell growth factor (TCGF), but it did inhibit the induction of TCGF receptor expression by both functional criteria, i.e., induction of responsiveness to TCGF, and by morphological criteria, i.e., the expression of the Tac antigen. Later events, such as the TCGF-dependent proliferation of cycling T cells, were less sensitive to the drug. Evidence is discussed suggesting that molecules similar to Factor I and to C3 may be involved both in the early events of CML and of T-lymphocyte activation.
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PMID:The mechanism of cell-mediated cytotoxicity. IV. K-76 COONa, which inhibits the activity of Factor I and of C5, inhibits early events in cytotoxic T-lymphocyte-mediated cytolysis and in T-lymphocyte activation. 623 82

Impairment in T cell proliferation in response to E. coli and in CML to unrelated alloantigens was usually observed in patients early after marrow grafting and persisted in long-term patients with chronic GVHD but not in those without chronic GVHD. We analyzed various cellular functions in the pathway of T cell activation and found that in patients with immunodeficiency, (1) their M phi usually could process and present antigens to normal T cells, (2) their T cells did not proliferate even in the presence of normal antigen-pulsed M phi, (3) IL-2 production by T cells was deficient, and (4) exogenous IL-2 restored CML activity in cells of most patients early after grafting but not in cells of most patients with chronic GVHD. Therefore, failure to induce proliferation and cytotoxicity in T cells of marrow recipients is not likely due to M phi defects but because of ineffective communication among T cell subsets, probably related to impaired IL-2 production and/or unresponsiveness to IL-2.
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PMID:Ineffective cellular interaction and interleukin 2 deficiency causing T cell defects in human allogeneic marrow recipients early after grafting and in those with chronic graft-versus-host disease. 639 Aug 48

The mechanism whereby Cyclosporin A (CsA) inhibits secondary mixed lymphocyte responses was assessed. CsA added to secondary MLR cultures inhibited proliferation and induction of cytolytic lymphocyte activity. This inhibition was found to be associated with the inhibition of T lymphocyte stimulating growth factor(s) (TCGF) production in the supernatants of secondary MLR cultures. As little as 1.0 micrograms/ml of CsA added to secondary MLR cultures resulted in no measurable TCGF activity. In contrast, moderate doses of CsA (1.0, 2.5 micrograms/ml), which completely inhibited the secondary MLR response to alloantigen, did not inhibit the proliferative and CML response of alloantigen-primed lymphocytes to these stimulating growth factors. Even at high doses of CsA (20 micrograms/ml), substantial levels of proliferation (50% of control response) and CML induction (60% of control response) were observed when the primed cells were exposed to secondary MLR supernatants containing TCGF activity. It was concluded that inhibition of secondary mixed lymphocyte responses by CsA may be due in part to the inhibition of TCGF production rather than the inhibition of the effect of TCGF on mature cytotoxic T lymphocytes.
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PMID:Effect of cyclosporin A on human lymphocyte responses in vitro. III. CsA inhibits the production of T lymphocyte growth factors in secondary mixed lymphocyte responses but does not inhibit the response of primed lymphocytes to TCGF. 645 74

The present study investigated the peripheral blood mononuclear cells (PBMC) blastic responses to PHA, PHA plus recombinant IL-2 (rIL-2) and rIL-2 alone; the expression of membrane-bound IL-2R on PHA-stimulated PBMC; and the levels of IL-1 alpha, IL-2, IL-6, and sIL-2R in serum and in culture supernatants from PHA-stimulated PBMC in 17 patients with with non-Hodgkin's lymphoma (NHL), 4 with Hodgkin's lymphoma (HL), 5 with Hairy cell leukemia, 1 with chronic myelogenous leukemia, and 1 with chronic lymphocytic leukemia. The patients with HL and NHL with active disease (AD) were separated from those in clinical remission. The patients with AD were studied at diagnosis (obviously before therapy) and the patients in clinical remission were out of therapy since at least 6 mo. The lymphocyte blastogenic response to PHA was significantly lower in patients with HL and NHL with AD than in the control group. The response to rIL-2 alone was in the same range in the control group and in HL and NHL AD patients. By adding rIL-2 to PHA there was an increase of the blastogenic response of the same patients. The percentage of CD25 expressed on PHA-stimulated lymphocytes from patients with HL and NHL AD and from normal subjects is in the same range. Serum levels of IL-2, IL-6, and sIL-2R were significantly higher in HL and NHL AD patients than in controls as well as in all other hematological malignancies. Supernatants derived from PHA-stimulated PBMC were assessed for the presence of cytokines and sIL-2R by ELISA. The levels of IL-2, IL-6, and sIL-2R were significantly lower in HL and NHL AD patients than in controls as well as in all other hematological malignancies.
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PMID:Membrane-bound/soluble IL-2 receptor (IL-2R) and levels of IL-1 alpha, IL-2, and IL-6 in the serum and in the PBMC culture supernatants from 17 patients with hematological malignancies. 749 95

The expression of the ectoenzyme gamma-glutamyl transpeptidase (EC2.3.2.2., gamma GT) was investigated by flow cytometry on populations of peripheral blood mononuclear cells (PBMC) from healthy subjects and patients suffering from several types of leukemia before and under chemotherapy. In unstimulated PBMC, 28% of these cells were found to be gamma GT positive. The highest expression was measured on monocytes (CD14/gamma GT+ cells: 60%). Within the subsets of T lymphocytes (CD3/gamma GT+ cells: 18%) we saw no clear differences between CD4+ and CD8+ cells. B lymphocytes, NK cells, and activated cells showed low expressions (up to 10%). Treatment of PBMC with mitogens, alpha-IFN, IL-2, and GM-CSF did not affect the enzyme expression on normal mononuclear cells (MNC). However, a rapid increase of gamma GT+ cells was found in the presence of glutathione (GSH) and n-acetyl cysteine (nAC), particularly on monocytes, B cells, and NK cells. Comparing 40 healthy subjects and untreated patients suffering from leukemias, a significantly higher expression of gamma GT+ cells in the total MNC populations (B-CLL: 57%, CML: 62% gamma GT+ cells) was observed in B-chronic lymphocytic leukemia (B-CLL) and chronic myelogenous leukemia (CML), whereas other leukemias did not show clear differences. Most interestingly, the gamma GT expression was diminished in all populations of CML cells after 5 h of incubation in the presence of 10 units/ml IFN-alpha. These data suggest a possible protective role of gamma GT in MNC and a regulatory function of this enzyme in the development of CML.
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PMID:gamma-Glutamyl transpeptidase-cellular expression in populations of normal human mononuclear cells and patients suffering from leukemias. 759 85

It has been suggested that cord blood T cells may be less able to mediate GVHD than marrow-derived T cells due to their naive status. A decreased potential for GVHD may be advantageous for allogeneic transplant, but this benefit might be counteracted by loss of the GVHD associated graft-versus-leukemia (GVL) effect. The GVL potential of cord blood could be doubly compromised since cord blood NK cell activity is also decreased. To assess these issues we have performed extensive comparative functional and immunophenotypic evaluations of cord and adult mononuclear cells. We found a somewhat reduced alloproliferative, allostimulatory and allocytolytic capacity of cord blood mononuclear cells in bulk assays but not by limiting dilution assays. Immunophenotyping revealed no significant differences in the proportion of major lymphocyte subsets with the exception of the previously recognized predominance of CD45RA+ cells in both CD4 and CD8 cord blood T cells. Cord blood T cells expressed normal percentages of the cellular adhesion molecules, CD11a, CD18 and LFA-3; however, the antigen density of each of these molecules was less than that found on adult T cells. Fewer resting cord blood T cells expressed CD54, the ligand for LFA-1. Cord blood B cells and monocytes expressed normal levels of HLA-class I and HLA class II DR, DP and DQ antigens, suggesting that the decreased expression of cellular adhesion molecules or their receptors rather than a decrease in expression of HLA might have contributed to the lower alloreactivity of cord blood. Although the percentages of NK cells and NK cell subsets in adult and cord blood were similar our data confirmed that cord blood has very low NK lytic activity. In contrast, LAK activity was much more readily induced in cord blood compared with adult PBMC, a finding which could be explained in part by a higher frequency of LAK precursors and a more rapid expansion of NK cells in response to culture with medium containing of NK cells in response to culture with medium containing IL-2. Cord blood LAK cells were readily able to lyse fresh leukemia targets from patients with ALL, AML and CML. The data indicate that although the alloreactive potential of cord blood cells may be somewhat decreased, it is not absent and must be considered a factor in cord blood transplants. LAKp with the potential to lyse leukemia are present in increased numbers in cord blood and might contribute to the GVL effect of a cord blood transplant.
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PMID:Characterization of the alloreactivity and anti-leukemia reactivity of cord blood mononuclear cells. 759 66


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