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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We have investigated the characteristics of IL2R alpha gene induction in untransformed murine T cells. Induction of IL2R alpha mRNA by TCR/CD3 ligands in a murine T cell clone and in short-term splenic T cell cultures was inhibited by protein synthesis inhibitors and by CsA. This result was contrary to previous observations in JURKAT T leukemia cells and human peripheral blood T cells, suggesting a difference in the mechanisms of IL2R alpha gene induction in these different cell types. The CsA sensitivity of IL2R alpha mRNA induction represented a direct effect on the TCR/CD3 response, and was not due to CsA-sensitive release of the lymphokines IL2 or tumour necrosis factor alpha (TNF alpha) and consequent lymphokine-mediated induction of IL2R alpha mRNA. The NF-kappa B site of the IL2R alpha promoter was essential for gene induction through the TCR/CD3 complex, and the induction of reporter plasmids containing multimers of this site was significantly inhibited by CsA. Northern blotting analysis indicated that while the p65 subunit of NF-kappa B was constitutively expressed and not appreciably induced upon T cell activation, mRNA for the p105 precursor of p50 NF-kappa B was induced in response to TCR/CD3 stimulation and this induction was sensitive to CsA. Electrophoretic mobility shift assays and antiserum against the p50 subunit of NF-kappa B indicated that p50 was a component of the inducible nuclear complex that bound to the IL2R alpha kappa B site. Appearance of the kB-binding proteins was insensitive to CsA at early times after activation (approximately 15 min), but was partially sensitive to CsA at later times. Based on these results, we propose that the NF-kappa B site of the IL2R alpha promoter mediates at least part of the CsA sensitivity of IL2R alpha gene induction in untransformed T cells, possibly because de novo synthesis of p105 NF-kappa B is required for sustained IL2R alpha expression.
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PMID:Cyclosporin A sensitivity of the NF-kappa B site of the IL2R alpha promoter in untransformed murine T cells. 802 23

It has recently been shown that chimeric toxin composed of IL2 fused tp PE40, a mutant form of Pseudomonas Exotoxin A devoid of its native cell recognition and binding domain was cytotoxic to IL2 receptor bearing cells. We here amplified the gene IL-2 (60), which codes for the N-terminal 1-60 amino acids of human IL-2 by PCR. After that, we fused it to PE40 and the new chimeric protein IL-2(60)-PE40 was expressed in E. coli. SDS-PAGE revealed that IL-2(60)-PE40 chimeric protein accounts for more than 18% of total cell proteins. As the region IL-2 binds with its receptor was defined in the N-terminal residues 8-54 of IL-2, such fusion proteins will have the same activity with IL-2-PE40. Following primary purification, IL-2(60)-PE40 was shown to be very toxic to IL-2 receptor-positive cells but non measurable effect on the cells lacking IL-2 receptors. Such a structure has not been reported by now. The fusion protein is useful for suppressing the immune response in cases of rejection of allografts and organ transplants and as therapeutic agents for the treatment of IL-2 receptor related diseases such as autoimmune disease, ATL (adult T-cell leukemia), et al.
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PMID:Cloning and expression of the gene coding for IL-2(60)-PE40, a molecular targeted protein. 858 Apr 81

Activated natural killer (A-NK) cells, a subset of CD56(dim)CD3- lymphocytes, are obtained from PBMC of normal donors by adherence to plastic and culture in the presence of IL2. In this study we tested the feasibility of generating A-NK cells in patients with Ph+ chronic myeloid leukaemia (CML). Cultures obtained from patients with early chronic phase (ECP; n=7) contained a mean (+/-SD) of83 +/- 7% of CD3- cells, and those from patients with advanced chronic phase (ACP; n=7) contained 27+/-33% CD56+CD3- cells. In three patients with leukaemia in a blastic phase (BP) it was only possible to obtain one culture enriched in CD56+CD3- cells (81%). Cellular aggregates of myeloid cells and large granular lymphocytes were observed in early A-NK cell cultures. Paired freshly-adherent and cultured A-NK cells were tested for the presence of BCR/abl mRNA by RT-PCR. The BCR/abl+ cells were detected in all 12 preparations of the freshly adherent A-NK cells tested. In 6/12 the BCR/abl+ cells were no longer detectable by RT-PCR on day 14 of culture. Both proliferation and antileukaemic cytotoxicity were significantly higher (P=0.002 and P=0.029, respectively) in the BCR/abl- cultures than those in the six BCR/abl+ cultures. 5/6 BCR/abl- cultures were highly enriched in A-NK cells on day 14, and 1/6 contained predominantly CD56+CD3+ cells. Only 2/6 BCR/abl + cultures were enriched in A-NK cells on day 14, but they had poor cytotoxicity and a low proliferative index. Myeloid cells (CD33+) were more frequently detected in the BCR/abl+ than BCR/abl- A-NK cell cultures (P=0.028). These observations suggest that: (1) populations of benign A-NK cells can be generated from the peripheral blood of CML patients; (2) the ability to generate A-NK cells is impaired in patients with advanced CML; and (3) the ability to generate A-NK cells with antileukaemic activity correlates with the disappearance of BCR/abl+ cells from these cultures.
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PMID:Generation of activated natural killer (A-NK) cells in patients with chronic myelogenous leukaemia and their role in the in vitro disappearance of BCR/abl-positive targets. 863 31

Spontaneous rat CD4+CD8-T-cell leukaemia transplanted in syngeneic recipients served as an experimental model system for IL-2 therapy. As a source of IL-2, supernatants from in vitro cultured plasmacytoma cell line X63-m-IL2 secreting constitutively recombinant murine IL-2 were utilized. Administration of IL-2, s.c. to the vicinity of the tumour inoculum, suppressed tumour growth. The tumour-inhibitory IL-2 effects were time- and dose-dependent. When the treatment has started 10 days after the challenge with 10(4) leukaemia cells, IL-2 inhibitory effects on the lymphoma growth in situ were demonstrated by lower tumour weight combined with necrotic changes. No histological signs of lymphoma generalization were found in parenchymatous organs of IL-2-treated rats in contrast to the untreated controls. No histological or functional injuries to the kidneys due to IL-2 administration were found. The results of effector cell phenotyping demonstrated the kinetics of the CD4+/CD8+ ratio characterized by CD4+ T-cell depletion and resulting increase in the percentage of CD8+ PBL.
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PMID:Treatment of transplanted spontaneous rat T-cell leukaemia with local administration of recombinant murine interleukin-2. 915 46

T lymphocyte functions in acute leukaemia patients with severe chemotherapy-induced leucopenia were investigated using 3 different approaches: (i) analysis of serum concentrations of the T cell cytokine interleukin 4 (IL4) demonstrated that serum IL4 levels increased during complicating bacterial infections. However, this response was modulated by a concomitant increase in serum levels of the potential IL4 antagonist soluble IL4 receptor alpha chain (sIL4R alpha). (ii) Even during leucopenia a subset of T lymphocytes derived from leucopenic patients expressed the activation markers CD25 (IL2 receptor), CD71 (transferrin receptor) and HLA-DR. (iii) Subsets of circulating CD4+ and CD8+ T lymphocytes could undergo clonogenic proliferation in vitro, and a majority of these clones secreted IL4. CD4+ clones showed higher IL4 levels than CD8+ clones. Our results indicate that T lymphocytes can be activated and contribute to cytokine responses in acute leukaemia patients with severe chemotherapy-induced cytopenia.
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PMID:Interleukin 4 responses in acute leukaemia patients with severe chemotherapy-induced leucopenia. 941 37

The results of the present study demonstrate that cells with the morphologic and phenotypic characteristics of blast cells that are obtained from the peripheral blood of patients with newly-diagnosed or recurrent acute myeloid leukemia (AML) can be stimulated by gamma interferon + lipopolysaccharide (IFN/LPS) to mediate in vitro cytolysis of an NK-insensitive hepatoma cell line. The conditions of IFN/LPS induction and subsequent assessment of cytotoxicity that were employed were identical to those used conventionally to test macrophage-mediated tumor cell cytotoxicity. What was totally unexpected was that these same blast cells, in the absence of stimulation with IFN/LPS, were also found to mediate high levels of spontaneous cytotoxicity against autologous bone marrow cells and against the U937 human promonocytic leukemia cell line in vitro. This high level of spontaneous cytotoxicity against autologous bone marrow or U937 promonocytic leukemia cells was not enhanced by IFN/LPS or MCSF under conditions that stimulated cytotoxic function in normal blood monocytes and was markedly reduced by pretreatment of the blast cells with IL2 under conditions that induced potent NK/LAK-mediated cytotoxicity. Neutralizing antibodies against TNFalpha and/or IL1alpha/beta eliminated the cytolytic function of blast cells against autologous bone marrow or U937 promonocytic leukemia targets. These findings demonstrate the existence of a population of cells with the morphologic characteristics of blast cells in the peripheral blood of AML patients which has the capacity to mediate spontaneous cytolysis of autologous bone marrow cells or a promonocytic leukemia cell line. These cells may be an immature variant of normal precursors produced as a consequence of the disordered hematopoietic environment in the marrow of AML patients. Alternatively, this function may be mediated by a subset of the leukemic blasts themselves.
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PMID:Cytolytic activity of peripheral blood blast cells from patients with acute myeloid leukemia. 947 27

The alpha chain of the interleukin 2 receptor (IL2R alpha; Tac) was targeted in clinical trials with adult T cell leukemia using murine anti-Tac antibody. Of 19 patients, a single individual achieved a durable complete remission. The mechanism of this action by murine anti-Tac has not been defined. We examined the hypothesis that the maintenance of the long-term response after treatment might be related to induction of a network of anti-idiotypic antibodies, as proposed in other tumor settings. In contrast to anti-Tac non-responders, the patient was found to have produced a human anti-mouse antibody (HAMA) response, and specifically an anti-idiotypic (Ab2) response, that was readily detectable by standard assays 4 years after treatment. Using phage display antibody libraries, this response was shown to be monoclonal, consisting of a single IgG1,kappa antibody of moderate affinity. No evidence was found for anti-anti-idiotypic (Ab3) antibodies with reactivity for sTac, which might alternatively have maintained an autogenic human anti-Tac antibody response. An area of limited homology was noted between the Ab2 antibody and the IL2R in the domain of IL2 binding, but no binding of Ab2 to IL2 could be shown that might have reduced endogenous ligand (IL2) concentrations. Similarly, no anti-anti-idiotypic (T3) T cell response was detected. Thus, we are unable to confirm features of idiotypy that could suggest a role in maintaining an anti-tumor response by anti-Tac antibody therapy.
Leukemia 1998 Jun
PMID:Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody. 963 30

Live attenuated simian immunodeficiency viruses (SIV), such as nef deletion mutants, are the most effective vaccines tested in the SIV-macaque model so far. To modulate the antiviral immune response induced by live attenuated SIV vaccines, we had previously infected rhesus monkeys with a nef deletion mutant of SIV expressing interleukin 2 (SIV-IL2) (B. R. Gundlach, H. Linhart, U. Dittmer, S. Sopper, S. Reiprich, D. Fuchs, B. Fleckenstein, G. Hunsmann, S. Stahl-Hennig, and K. Uberla, J. Virol. 71:2225-2232, 1997). In the present study, SIV-IL2-infected macaques and macaques infected with the nef deletion mutant SIVDeltaNU were challenged with pathogenic SIV 9 to 11 months postvaccination. In contrast to the results with naive control monkeys, no challenge virus could be isolated from the SIV-IL2- and SIVDeltaNU-infected macaques. However, challenge virus sequences could be detected by nested PCR in some of the vaccinated macaques. To determine the role of immune responses directed against Env of SIV, four vaccinated macaques were rechallenged with an SIV-murine leukemia virus (MLV) hybrid in which the env gene of SIV had been functionally replaced by the env gene of amphotropic MLV. All vaccinated macaques were protected from productive infection with the SIV-MLV hybrid in the absence of measurable neutralizing antibodies, while two naive control monkeys were readily infected. Since the SIV-MLV hybrid uses the MLV Env receptor Pit2 and not CD4 and a coreceptor for virus entry, chemokine inhibition and receptor interference phenomena were not involved in protection. These results indicate that the protective responses induced by live attenuated SIV vaccines can be independent of host immune reactions directed against Env.
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PMID:Env-independent protection induced by live, attenuated simian immunodeficiency virus vaccines. 973 21

The production of interleukin-5 (IL5) and interleukin-4 (IL4) by activated T-cells is important in the pathogenesis of helminth infections and allergy. Human Jurkat cells express IL4 but one of the main factors restricting studies of human IL5 expression has been the lack of human T-cell lines which express significant levels of IL5 in an inducible fashion. We report that the human T-cell leukemia cell line (PER-117), previously shown to produce IL2, also produces IL5 and IL4, and is a useful model for the study of the regulation of IL5 and IL4 gene expression. We show that expression of IL5 and IL4 mRNAs in PER-117 cells is stimulation dependent. IL5 and IL4 reporter constructs are also transiently expressed in these cells in an inducible fashion. IL5 production in the PER-117 cell line can be activated by phorbol 12-myristate 13-acetate alone and further enhanced by calcium ionophore A23187, cyclic adenosine 3', 5'-monophosphate or anti-CD28 antibodies. The conditions used to stimulate the PER-117 cells determined whether IL5 production was inhibited by cyclosporin A or dexamethasone. These data indicate that the PER-117 cell line is a model to study signal transduction and transcriptional activation of the human IL5 gene in human T-cells.
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PMID:A human T-cell line with inducible production of interleukins 5 and 4. A model for studies of gene expression. 1055 53


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