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)

Interleukin 2 (IL 2) in high concentration induces lymphocytes to become nonspecifically cytolytic to a wide variety of tumor targets. We evaluated the therapeutic potential of such lymphokine-activated killer (LAK) cells in vivo and high-dose II 2 in vivo against disseminated murine leukemia. To quantitate the potential anti-leukemia effect of LAK cells in vivo, B6 mice were injected i.p. with graded doses of FBL-3 leukemia cells followed by LAK cells. In this Winn-type assay, 1 X 10(7) LAK cells were able to prevent the outgrowth of 1 X 10(2) FBL-3 cells in only 50% of mice and did not prevent the outgrowth of 1 X 10(6) tumor cells. Thus LAK cells, highly cytolytic to FBL-3 in vitro, mediated only a limited anti-tumor effect when applied directly to leukemia cells in vivo. LAK cells used as an adjunct to chemotherapy induced a small but non-curative effect against FBL-3, however. In this circumstance, LAK cells were markedly less effective than were immune spleen cells from mice previously sensitized to FBL-3. To test the anti-leukemia effect of high-dose IL 2 in vivo, B6 mice were inoculated with 5 X 10(6) FBL-3 cells followed by repeated doses of IL 2 at dose levels shown to induce LAK in vivo. "LAK-inducing" IL 2 doses on days 5 to 9 after FBL-3 inoculation, when tumor was disseminated, cured 50% of the mice. Treatment on days 5 to 9 was far more effective than on days 0 to 4, implying that the evolution of a host-tumor interaction was essential for the therapeutic effect of IL 2. Mice cured of FBL-3 by high-dose IL 2 were found to be immune to FBL-3, suggesting that tumor eradication resulted from a collaboration between LAK activity and tumor-specific immunity.
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PMID:Eradication of disseminated murine leukemia by treatment with high-dose interleukin 2. 349 Nov 45

Interleukin 2 (IL 2) has several potential uses in cancer therapy including: the augmentation of specific T cell mediated anti-tumor immunity and the activation of non-specific cytolytic effector cells, termed lymphokine-activated killer (LAK) cells. The current review will present data from our laboratory demonstrating in animal models the feasibility of both potential approaches. Studies to be reviewed show that: IL 2 can induce the proliferation and expansion in number of tumor-reactive T cells in vitro; T cells grown in culture in IL 2 can be effective reagents in vivo for specific tumor therapy; the administration of exogenous IL 2 can induce the growth and augment the function of cultured T cells in vivo; however, as a corollary, T cells cultured long-term in vivo with IL 2 are functionally limited in vivo without the administration of exogenous IL 2 in vivo; by contrast, T cells grown in vitro with specific antigen, as opposed to IL 2, as the major stimulus for proliferation are able to proliferate rapidly in vivo, distribute widely in host lymphoid organs, and mediate therapy of disseminated murine leukemia; importantly, such antigen-driven long-term cultured T cells can survive long-term in vivo and provide specific immunologic memory, and, the administration of low-dose IL 2 in vivo can induce the growth of antigen-driven long-term cultured T cells in vivo and thereby increase the number of functional memory T cells; the culture of lymphoid cells in high concentrations of IL 2 can induce LAK cells in vitro capable of lysing leukemia in vitro; LAK cells generated in vitro can mediate a small but detectable anti-tumor effect in vivo against disseminated leukemia as an adjunct to chemotherapy; and, high-dose IL 2 administered in vivo can activate LAK cells in vivo and cure disseminated murine leukemia. Therefore, it is highly likely that IL 2 can become an effective reagent for the therapy of human cancer.
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PMID:Potential uses of interleukin 2 in cancer therapy. 349 34

In 1958, a medium-sized cell was recognized in human lymph nodes and found to occur in clusters in about one out of every 10 cases of reactive hyperplasia. At first, it was interpreted as a lymphoblast. Later, electron-microscopic investigations revealed that the cell contained abundant rough endoplasmic reticulum and was apparently restricted to T-regions of lymph nodes. Recently, it was possible to analyze a malignant lymphoma uniformly composed of such cells with a panel of monoclonal antibodies. The cells proved to be Leu-1+, OKT4+, Leu-3a+, HLA-DR+, and weakly reactive with VIL-A1 (antibody to common ALL antigen) and clone F8-11-13, but negative for OKT3, OKT11, OKT8, cytoplasmic immunoglobulin, common B-cell antigen, and C3b receptors. Short-term, in vitro cultures of lymphoma cells showed weak responses to phytohemagglutinin and Interleukin 2 (IL2), but no IL2 production. Lymphoma cells had a low spontaneous proliferation rate (about 2% Ki-67+ cells). In view of these findings, the term "plasma-cytoid T-cell" is proposed. A functional relationship between these cells and the myeloid system was suggested because the patient developed a myelomonocytic leukemia 3 months after the diagnosis of malignant lymphoma was made.
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PMID:Malignant lymphoma of plasmacytoid T-cells. Morphologic and immunologic studies characterizing a special type of T-cell. 660 89

Mononuclear blood cells from patients with different types of leukemia, and from controls as well as cells from established lymphoblastic cell lines were analyzed with respect to terminal transferase (TdT) activity and T-cell growth factor (TCGF; Interleukin 2, IL-2), to determine the significance of TCGF production and response as functional markers for human leukemias. The data obtained so far suggest that the aberrant proliferation and lack of maturation observed in these leukemias may be associated with or be the result of a break-down in cellular-mediated control of proliferation.
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PMID:T-cell growth factor (interleukin 2) and terminal transferase activity in human leukemias and lymphoblastic cell lines. 694 97

To isolate a stable tumor cell line source of Interleukin 2 (IL-2 formerly referred to as T cell growth factor), over 40 murine leukemia and lymphoma cells as well as 9 clonal helper and killer IL-2-driven T cell lines were screened for both constitutive and mitogen-stimulated IL-2 production. A radiation-induced splenic lymphoma from the B10.BR mouse, the LBRM-33 cell line, could be stimulated to produce over 1000 units/ml of IL-2 after 24 hr exposure to T cell mitogens. Peak IL-2 activity was found in supernatants harvested from 24-hr cultures of either 1% PHA or 20 micrograms/ml Con A-stimulated LBRM-33 cells (10(6) cells/ml). IL-2 production observed in both serum-free and serum-containing cultures represented between 1000 and 5000 times the quantity of IL-2 produced in conventional cultures of mitogen-activated rat or mouse spleen cells. Peak IL-2 production by LBRM-33 cultures (stimulated at either optimal Con A or PHA concentrations or co-stimulated with suboptimal amounts of mitogen and phorbol myristate acetate) was consistently accompanied by LBRM-33 cell death. Phenotypic characterization of the producer cell revealed LBRM-33 cells to be Thy 1+, Ly 1+, Ly 2+, Ly 3+, Qa 2-3+, Qa 3.2+, Qat 4+, and Ly 5+. These studies provide further evidence that IL-2 is a T cell product and establish a source of IL-2 that will be a valuable reagent for the isolation and further molecular characterization of this immunoregulatory molecule.
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PMID:Biochemical and biologic characterization of lymphocyte regulatory molecules. III. The isolation and phenotypic characterization of Interleukin-2 producing T cell lymphomas. 696 90

Donor marrow transplantation can cure chronic myelogenous leukemia (CML). Unfortunately, the procedure is associated with severe complications and is limited to the minority of potential recipients with suitably matched donors. Autologous marrow transplantation using negative selection approaches such as incubation with gamma interferon (IFN-gamma) can produce cytogenetic and clinical remissions, but they are often associated with recurrent evidence of leukemia. A primitive progenitor population can be separated from normal human marrow on the basis of morphologic characteristics and cell surface antigen expression. Cell populations with similar morphologic and phenotypic characteristics obtained by positive selection from the marrow of patients with CML appear to be benign. Benign primitive and committed progenitors selected in this fashion can be expanded ex vivo when cultured in a "Transwell" system which physically separates hematopoietic cells from stromal feeder layers. Positive selection and ex vivo cultivation of benign progenitors from CML marrow may provide a source of hematopoietic stem cells suitable for autologous marrow transplantation. Autologous natural killer (NK) cells obtained from the peripheral blood of patients with CML are of benign origin and have antileukemia activity. Interleukin 2 (IL-2) activated autologous NK cells may be used in post-transplant cellular therapy to prevent recurrence of CML.
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PMID:Chronic myelogenous leukemia: in search of the benign hematopoietic stem cell. 790 18

Interleukin 2 (IL2) receptors (IL2R's) are found on malignant cells in many human leukemias and lymphomas and are expressed by activated T cells in many autoimmune disorders. Anti-Tac(Fv), a single-chain protein composed of the variable heavy and light domains of the anti-IL2R monoclonal antibody anti-Tac, can be genetically fused to derivatives of Pseudomonas exotoxin (PE) or diphtheria toxin (DT) to form potent immunotoxins. We have shown that anti-Tac(Fv) binds to low affinity IL2R's on fresh chronic lymphocytic leukemia (CLL) and adult T-cell leukemia (ATL) cells and can target either toxin to kill those cells. Anti-Tac(Fv)-PE40, containing the truncated form of PE without its binding domain, was cytotoxic to malignant cells from 8 of 8 ATL patients tested, with IC50's ranging from 0.11 to 5.5 ng/ml. Anti-Tac(Fv)-PE40KDEL, a derivative of anti-Tac(Fv)-PE40 which contains the KDEL carboxyl terminus, was more cytotoxic toward cells from all ATL patients and also killed CLL cells from 8 of 16 patients. DT388-anti-Tac(Fv), containing amino acids 1-388 of DT fused to the amino terminus of anti-Tac(Fv), was less cytotoxic than anti-Tac(Fv)-PE40 on ATL cells from 4 of 5 patients, but was cytotoxic toward CLL cells from 12 of 16 patients. DT388-IL2, where IL2 is substituted for anti-Tac(Fv), is similar to DAB389IL2, an IL2-toxin currently in clinical trials. DT388-IL2 and DAB389IL2 differ by only a few amino acids and have equal cytotoxic activity. DT388-IL2 was cytotoxic toward ATL cells from all patients tested, but usually required much higher concentrations than anti-Tac(Fv)-PE40 and was poorly active against CLL cells. Thus, recombinant toxins containing anti-Tac(Fv) are cytotoxic toward freshly isolated CLL and ATL cells and will be studied further as potential therapy for IL2R-related disorders.
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PMID:Recombinant single-chain immunotoxins against T and B cell leukemias. 802 11

Interleukin 2 (IL-2) is an important lymphokine required in the process of T cell activation, proliferation, clonal expansion and differentiation. The IL-2 gene displays both T cell specific and inducible expression: it is only expressed in CD4+ T cells after antigenic or mitogenic stimulation. Several cis-acting regulatory sites are required for induction of the IL-2 gene after stimulation. In this study, we have analysed the function of these cis-acting regulatory sites in the context of the native IL-2 enhancer and promoter sequence. The results of this study suggest that the NFAT (-276 to -261), the distal octamer (-256 to -248) and the proximal octamer (-75 to -66) sites not only act as enhancers of IL-2 gene transcription in the presence of cellular stimulation, but also have a silencing effect on IL-2 gene expression in resting cells. Two other sites display disparate effects on IL-2 gene expression in different T leukemia cell lines: the distal purine box (-291 to -277) and the proximal purine box sites (-145 to -128). Finally, the AP-1 (-186 to -176) and the kappa B sites (-206 to -195) respond to different cellular activation in EL4 cells. The AP-1 site mediated the response to PMA stimulation while the kappa B site responded to IL-1 stimulation. These data suggest that the regulation of IL-2 gene expression is a complex process and multiple cis-acting regulatory sites interact to exert different effects in T cells representative of alternative stages of differentiation.
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PMID:Positive and negative regulation of IL-2 gene expression: role of multiple regulatory sites. 805 77

Cytokines are decisive for the regulation of the immune system as well as the renewal and maturation of the haematopoietic cells. The most important groups of substances, several of which are already produced by gentechnology, are the interferons, the interleukins and the haematopoietic growth factors. The main indications for the application of alpha-(less often beta-)Interferon in children are the juvenile larynx papillomatosis, chronic hepatitis B, viral encephalitis, and also chronic myeloic leukemia, extended haemangiomas, recurrent Langerhans cell histiocytosis and nasopharynx carcinomas. gamma-Interferon is administered successfully for chronic granulomatous disease and has recorded positive effects in therapy resistant rheumatoid arthritis, in kidney cell carcinoma and in osteopetrosis. G-CSF, GM-CSF and Interleukin 3 are the most effective haematopoietic growth factors currently in use. Through G-CSF congenital agranulocytosis (Kostmann syndrome) has become a treatable disease. Other proven applications are in the reduction of aplastic phases after chemotherapy and in critical situations of primary bone marrow failure as well as myelodysplastic syndromes, for prevention of transplant rejections after bone marrow transplantation and for mobilisation of stem cells into peripheral blood before apheresis. Erythropoietin is established in the treatment of chronic renal anaemia and is currently used in the treatment of anaemia in preterm infants. Finally, Interleukin 2 is also used for adoptive immunotherapy in children with minimal residual tumors. The future will show us, whether the spectrum of indications will expand and whether a definite benefit for sick children will result from a wider application of these substances. As long as the cost/benefit ratio for certain indications is not clear, the use of these drugs should be tested in prospective studies.
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PMID:[Clinical applications of cytokines in pediatrics]. 815 1

Graft-versus-leukemia (GVL) effect is an immunologically important phenomenon which decreases the relapse rate of leukemia after allogeneic bone marrow transplantation. GVL effect is sometimes associated with the occurrence of graft-versus-host disease (GVHD). Analyses of GVL effect and GVHD showed that these two phenomena were separable in some conditions. Although we cannot yet completely control the development of the GVL effect without inducing GVHD in humans, basic analyses using animal models show potential benefits of the GVL effect for clinical applications. Autologous GVHD is another important phenomenon which can help to eradicate minimal residual disease. Interleukin 2 and/or cyclosporin A are extensively used in animal models and in humans to induce autologous GVHD, showing beneficial effects. In the future, cytokine usage and allogeneic stem cell transplantation or leukocyte infusion appear to be promising in the control of minimal residual disease. Further studies on the mechanisms of GVL effects and GVHD may well open a new era for cell transplantation.
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PMID:Graft-versus-leukemia effect and its clinical implications. 903 Oct 79


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