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 study we have demonstrated that natural killer (NK) cells adhere to elements of the bone marrow stroma (BMS) including fibroblasts, fibronectin and laminin but not to collagen type I, vitronectin and hyaluronic acid. NK cells bind to fibronectin and laminin using the beta 1 integrins VLA-4 and VLA-5, and VLA-6 respectively. The mechanism of adhesion to bone marrow fibroblasts is more complicated with beta 1 and beta 2 integrins being partially responsible but the majority of adhesion remaining unexplained. IL-2 stimulation of NK cells resulted in an increase in the expression of adhesion molecules involved in binding of NK cells to bone marrow fibroblasts (BMF) and extracellular matrix (ECM) proteins including the beta 1 chain CD29, alpha chains of VLA-4 and 5, beta 2 chain CD18 and alpha L chain CD11a. A marked increase in expression of beta 7 was also observed. There was a significant increase in the adhesion of NK cells to fibronectin in response to IL-2 treatment. NK cells also bound more strongly to BMF following IL-2 treatment although the development of cytotoxicity appeared to interfere with the adhesion assay. NK cells competitively inhibit the binding of AML blasts but not ALL blasts to BMF. Mechanisms underlying the inhibition of leukemic growth by NK and LAK cells may include direct and cytokine mediated cytotoxicity and perturbation of the interaction of leukemic blasts with the bone marrow stroma which is essential for blast cell survival.
Leukemia 1995 Jun
PMID:Natural killer cells adhere to bone marrow fibroblasts and inhibit adhesion of acute myeloid leukemia cells. 759 92

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

The B-lymphoblastoid cell line Eskol, which is composed of differentiated cells resembling hairy-cell leukemia, has been used to study the effects of type I interferon in vitro. In order to study the mechanism of delayed interferon therapy resistance, a hairy-cell leukemia-like clonal cell line (IREs-4) was isolated from Eskol after 4 months of exposure to r-metIFN-con1. When compared to Eskol cells, the IREs-4 cells were resistant to the antiproliferative effect of type I interferons as well as interferon induced protection against LAK cells. Treatment of IREs-4 with type I interferon did not induce MHC antigens, although both MHC class I and II antigens were induced in Eskol. Binding studies indicated the presence of equal numbers of high affinity binding sites with similar affinities on both cell lines. The resistant phenotype appears to result from an intracellular event which is essential to interferon signal transduction. It is hypothesized that this variant may reflect heterogeneity in the normal population of hairy-cell leukemia cells, and may explain the partial resistance of HCL patients to IFN therapy.
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PMID:An interferon resistant variant of the hairy-cell leukemic cell line, Eskol: biochemical and immunological characterization. 769 2

In patients with primary immunodeficiencies the role of natural killer (NK)- and lymphokine (IL-2)-activated killer (LAK)-cells is not yet satisfactorily established. Using a clonogenic assay with K562 leukemia target cells, we studied their NK- and LAK-cell activity in vitro. Moreover, the effect of thymosin alpha 1 (T alpha 1) on LAK-cell activity was studied in 11 patients with different immunodeficiencies. The results were compared with data of healthy controls (n = 11) and cord blood samples (n = 6). Common variable immunodeficiency patients demonstrated a mean LAK-cell activity of about 65% of normal controls and cord blood samples. The moderately reduced LAK-cell activity was not affected by T alpha 1. In the immunodeficient other patients, low levels of LAK-cell activity with a mean value of 10% of normal controls were seen. The mean LAK-cell activity could be improved by T alpha 1: three patients showed an improvement of their LAK-cell activity up to 25-30% after T alpha 1 administration in vitro, but in one case T alpha 1 was without any effect. Analysis of the expression of the surface markers CD8, CD16, CD57 and CD8/CD57 revealed that only CD16 positive lymphocytes were significantly less in immunodeficient patients. We found a linear correlation between LAK-cell activity and CD8/CD57 double positive lymphocytes in all patients. Our results demonstrate that suppressed LAK-cell activity from immunodeficient patients can be individually improved by T alpha 1. Further in vivo studies should evaluate thymic peptide immunotherapy for individual immunodeficient patients.
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PMID:Thymosin alpha 1 effects, in vitro, on lymphokine-activated killer cells from patients with primary immunodeficiencies: preliminary results. 770 63

The characteristics of rhuIL-4 induced cytotoxicity was detected in vitro by using 51Cr release assay and the anti-tumor activity of rhuIL-4 induced killer cell was evaluated in vivo by using a human tumor model in nude mice. huIL-4 can induce LAK activity from peripheral blood lymphocytes (PBMC) stimulated with phytohemagglutinin (PHA). Compared with the LAK activity induced by rhuIL-2, the cytotoxicity of the killer cells induced by rhuIL-4 to K562 and Raji cells was lower, but that to TBL-E, a human lymphoid leukemia cell line established in our laboratory, and PHA-activated blast cells (PHA-blasts) was of similar magnitude. In the cytotoxicity assay using PHA-blasts, the addition of PHA increased the IL-4-induced killer cell cytotoxicity by 131%, but had no effect on IL-2-induced killer cell cytotoxicity. This implies that IL-4 mainly induces CTL-like activity, while IL-2 mainly induces NK-like activity. An experimental human tumor model in nude mice was established by injection of TBL-E human leukemia cells. The anti-tumor activity of rhuIL-4 was evaluated by injection of human LAK cells induced from PHA-blasts by rhuIL-2+rhuIL-4 and human cytokines into tumor-bearing nude mice. The results showed that human LAK cells effectively inhibit the tumorigenicity of TBL-E cells in nude mice with an inhibition rate of 61%. The antitumor effect of rhuIL-2 was better than that of rIL-4, and the antitumor effect of rhuIL-2+rhuIL-4 was similar to that of rhuIL-2, though the former delayed the occurrence of tumors. Our data imply the potential application of human IL-4 in clinic, and provide an animal model to evaluate the anti-tumor activity of human cytokine(s) with species specificity.
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PMID:Evaluation of the antitumor activity of human IL-4 by in vitro and in vivo assays. 771 66

Changes in LAK susceptibility of tumor cells in which MHC class I antigen expression was undergoing regeneration following treatment at pH 3.0, were studied. P815 (murine mastocytoma) and RAJI (human B-cell leukemia) cell lines were briefly exposed to pH 3.0 buffer which brought down the MHC class I expression on these cells by 70-80% and resulted in a 3-fold increase in their susceptibility to murine and human LAK cells, respectively. During the MHC class I regeneration phase, LAK susceptibility fell and reached normal levels at a time point when MHC class I antigens had regenerated to a level which was 60-70% of the normal. Highly significant inverse correlations were obtained between LAK susceptibility and the log of MHC class I antigen expression, for both P815 and RAJI cell lines. These results indicate that during the MHC class I regeneration phase, there is an inverse correlation between MHC class I antigen levels and LAK susceptibility. Moreover, these results also suggest that the extent of change in LAK susceptibility may depend upon the levels of basal MHC class I expression on the tumor cells.
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PMID:Changes in LAK susceptibility of tumor cells as their MHC class I antigen expression levels regenerate after treatment at pH 3.0. 772 47

Allogeneic bone marrow transplantation (BMT) frequently is accompanied by the occurrence of graft-versus-host disease (GVHD). GVHD is thought to mediate a beneficial graft-versus-leukemia (GVL) effect believed to be important for disease-free survival in cancer patients. However, it is uncertain if GVHD and GVL are mediated by unique effector cell populations in the graft. The lack of bone marrow donors for individuals needing HLA-matched, unrelated BMT has recently led to the use of cord blood for transplantation. Cord blood transplantation has generated much enthusiasm because of its very low incidence of GVHD, even in HLA-mismatched situations, owing to intrinsic defects in mature T cell functions. Concerns have arisen, however, as to whether cord blood would mediate a significant GVL activity in vivo in the absence of GVHD, and thus prevent relapse in patients treated for malignancies. In this study in vitro and in vivo assessments have been made of the ability of cord blood to mediate GVL activity, focusing on non-specific effector cell mechanisms. Although minimal non-specific cytotoxic activity is found in freshly isolated cord blood (both NK and LAK cell activity), it is rapidly induced and displays a spectrum of lytic activity similar to adult peripheral blood. The kinetics of LAK cell induction in cord blood as well as the responsiveness to IL-2 stimulation was identical to adult peripheral blood.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro and in vivo assessment of the graft-versus-leukemia activity of cord blood. 774 53

The immune response to leukemia is poorly understood. We postulated that nonmalignant T lymphocytes remaining within bone marrow from children with newly diagnosed ALL could be involved in this immune response. T lymphocytes which expressed gamma delta TCR comprised less than 1% of ALL marrow cells. A preferential outgrowth of gamma delta T cells within the CD3 population was observed when marrow cells were cultured with IL-2 alone or with stimulating feeder cells. These results, obtained in a series of 14 patients with precursor B-ALL, were significantly different when compared with expansions from normal marrow cells. In one patient, the clones established from the expanded population displayed different patterns of cytotoxicity against tumoral targets of the B cell lineage. Some clones expressing the TCR V delta 1 segment showed cytotoxic activity against a cell line derived from a pre-B ALL without activity against a LAK-sensitive B cell line. Using PCR amplification, one such clone was detected at high frequency, in the primary expansion of ALL marrow cells. These results suggest a prior activation in vivo of some gamma delta T cells by leukemic cells and provide some evidence on the role of these subsets in the immune response to leukemia.
Leukemia 1995 May
PMID:Potential antileukemic effect of gamma delta T cells in acute lymphoblastic leukemia. 776 50

The overall unfavourable prognosis of adult acute leukaemia patients has prompted the search for alternative therapeutic strategies. Probably the most sought challenge, which over the years has been met by consistent disillusion, has been immunotherapy. With little doubt the goal of stimulating the immune system of the host in the hope of controlling or eradicating residual disease following more conventional ablative regimens, remains conceptually a highly desirable approach. During the last few years an innovative strategy, based on the in vitro demonstration that IL2 is capable of inducing a previously unrecognized cytotoxic function directed against primary tumours and named LAK, has been applied with some success in solid tumour patients. Here, we shall review the pre-clinical data which indicate that IL2-based immunotherapy may be employed also in the management of patients with acute leukaemia. Clinical data which support a possible in vivo antileukaemic effect of IL2 are presented. The clinicohaematological modifications, as well as the biological modulations induced in the patients following the administration of IL2 are also discussed. In view of the recent demonstration that the IL2 gene can be successfully transduced into human neoplastic cells, we finally discuss the rationale of gene transfer approaches in an attempt to overcome some of the limitations associated with the administration of high doses of exogenous IL2.
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PMID:Interleukin-2 and gene therapy in the management of acute lymphoblastic leukaemia. 780 10

AKR/J mice, highly susceptible to spontaneous T cell leukemogenesis, were protected from developing the disease by H-2-compatible allogenic bone marrow transplantation (BMT) and intermittent treatment with interleukin-2(IL-2). Allogeneic BMT from C3H/HeJ mice and treatment with PBS yielded T cell leukemia in chimeras after the same latent period as that observed in normal AKR/J mice. In contrast, IL-2-treated chimeras caused an incidence of only 40% T cell leukemia. The preventing effect of IL-2 on leukemia development was not observed in one-year-treated chimeras, probably due to a lack of continuous antileukemic effects over the long term. Both LAK and NK activities in spleen cells were significantly increased in IL-2-treated chimeras. The cytotoxicity against T cell lymphoma cell line derived from AKR/J also increased in the IL-2-treated chimeras. Similarly, LPS-, PWM-, and IL-2-induced responses were increased in the IL-2-treated chimeras. TNF-alpha secretion from spleen cells also rose after IL-2-administration. IL-1 beta, IFN-gamma, and TNF-alpha mRNA became detectable in spleen cells using the PCR technique. The characteristics of leukemia cells in chimeras with overt leukemia were not directly affected by IL-2 administration. It is suggested that partial inhibition of spontaneous T cell leukemia development in AKR/J mice by allogeneic BMT and IL-2 may be due to the enhancement of graft-versus-leukemia effects. Further study may provide insights into the mechanisms involved in preventing leukemia development after allogenic BMT and IL-2 in AKR/J mice.
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PMID:Antileukemic effect of interleukin-2 on spontaneous development of leukemia after H-2-compatible allogenic bone marrow transplantation in AKR/J mice. 792 84


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