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)

Previous studies have demonstrated that T cell-depleted (TCD) syngeneic marrow protects against graft-versus-host disease (GVHD) when given along with an allogeneic lymphocyte plus bone marrow (BM) inoculum to lethally irradiated mice. In spite of this anti-GVHD effect, TCD syngeneic marrow is ultimately eliminated by non-TCD allogeneic marrow, permitting complete allogeneic reconstitution. These observations suggested that allogeneic BM might also eliminate host-type leukemic cells in a model in which TCD syngeneic marrow is co-administered to provide protection from GVHD. In the present studies, we describe the establishment of a new model using the EL4 leukemia/lymphoma. Lethally irradiated B10 (H-2b) mice were given a lethal dose of EL4 cells (H-2b) along with syngeneic marrow or a mixture of TCD syngeneic plus non-TCD allogeneic (B10.D2, H-2d) marrow. Non-TCD allogeneic marrow, in contrast to TCD or unmanipulated syngeneic marrow, delayed or prevented mortality from the otherwise lethal EL4 inoculum, without producing clinically apparent GVHD. The anti-leukemic effect of allogeneic marrow alone was not attenuated by the co-administration of TCD syngeneic marrow, and such animals repopulated as completely allogeneic chimeras. Similar anti-leukemic effects of mixed marrow inocula in a haploidentical strain combination, and an anti-leukemic effect against established tumor were also demonstrated. This model may have the potential to increase the safety of clinical bone marrow transplantation across greater HLA disparities, while permitting utilization of the anti-leukemic and alloengraftment-promoting effects of T cells in allogeneic marrow inocula.
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PMID:Graft-versus-leukemia effect using mixed allogeneic bone marrow transplantation. 279 Mar 25

Mouse cell lines of different lineages have been established which constitutively secrete large quantities of recombinant mouse interleukins (mIL2, mIL3, mIL4 or mIL5). An existing bovine papilloma virus-based expression vector, pBV-1MTHA, was modified to allow transformed X63Ag8-653 myeloma cells, NIH 3T3 fibroblasts and C127 mammary tumor cells to stably carry multiple copies of the vector, to express the inserted cDNA encoding a single interleukin constitutively, and to secrete the interleukin in high quantities. Cell lines transformed with mIL2 cDNA stably carried 30-100 copies of the plasmid per cell and constitutively secreted biologically active mIL2 in quantities similar to those produced by murine EL4 thymoma cells or rat spleen cells stimulated with mitogens. Deletion of the 3' untranslated region containing AT-rich sequences from the mIL2 cDNA resulted in a 100-fold increase in the constitutive production and secretion of mIL2 by the transformants. Addition of a heavy metal further increased the production 2 to 6-fold. Cells transformed with 3'-deleted mIL3 cDNA constitutively secreted 300-1000 times higher activities of mIL3 than the myelomonocytic leukemia line WEHI3. mIL4 produced by the similar transformants induced [3H]thymidine uptake of a T cell line, a mast cell line and B leukemia cells, and enhanced the production of IgG1 by B cells. IL4 titers were 150 times higher than those produced by the concanavalin A-stimulated T cell line 2.19. mIL5 was secreted by similar transformants at 10-fold higher titers than those produced by concanavalin A-stimulated 2.19 T cells, as judged by the proliferation and maturation of B cell leukemia BCL1. The expression vectors should be useful in establishing eukaryotic cell lines producing proteins from full length cDNA clones at higher rates. The established cell lines secreting IL2, 3, 4 or 5 at high rate should be useful sources for these interleukins in the investigation of their function in the immune system.
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PMID:Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. 283 Oct 66

Murine splenocytes were used to study the in vitro immunosuppressive effects of UV-inactivated feline leukemia virus (FeLV-UV). FeLV-UV blocks both alloantigen (DBA/2)-induced and Con A-induced proliferation of C57BL/6 splenocytes in a dose-dependent manner. Furthermore, C57BL/6 anti-DBA/2 mixed lymphocyte cultures containing FeLV-UV fail to develop detectable DBA/2-specific cytolytic activity, although FeLV-UV has no effect on the cytolytic activity of preformed C57BL/6 anti-DBA/2 cytolytic T cells (CTL). Disruption of lymphocyte proliferation and CTL generation by FeLV-UV could not be overcome by the addition of exogenous lymphokines. These data suggest that FeLV-UV can interfere with the lymphokine reactivity of alloactivated lymphocytes. In fact, FeLV-UV blocks the lymphokine-induced proliferation of the murine IL 2-dependent cell line CTLL-20. The CTLL-20 cells were subsequently used to study the mechanism(s) by which retroviruses alter T lymphocyte function. Normally, CTLL-20 cells undergo significant proliferation when cultured in EL4 SN, an IL 2-containing culture supernatant from PMA-stimulated EL4 cells. This lymphokine-induced CTLL-20 proliferation is abrogated in a dose-dependent manner by UV-inactivated murine leukemia virus (MuLV-UV), FeLV-UV, and a purified 15,000 dalton viral protein, p15, derived from FeLV. Suppression of CTLL-20 proliferation requires only brief contact (6 hr) with FeLV-UV or with p15, but is most efficient after prolonged (24 hr) contact with these agents. Furthermore, suppression of CTLL-20 proliferation by FeLV-UV and p15 is reversible, because CTLL-20 cells which have been pretreated for 24 hr with FeLV-UV or p15 are equally as efficient at responding to EL4 SN as untreated CTLL-20. Additional studies indicate that CTLL-20 cells continue to remove IL 2 activity from EL4 SN in the presence of suppressive concentrations of FeLV-UV, and that suppressive concentrations of FeLV-UV do not remove IL 2 activity from EL4 SN. This suggests that FeLV does not block CTLL-20 proliferation by absorbing or inactivating IL 2, or by occluding IL 2 receptors, and that T lymphocytes develop an insensitivity to lymphokines after contact with FeLV-UV, which may be caused by a metabolic, rather than an immunologic, defect. Because lymphokines are requisite signals for T cell function, considerable immunosuppression would be associated with acquired lymphokine insensitivity.
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PMID:Retrovirus-mediated immunosuppression. I. FeLV-UV and specific FeLV proteins alter T lymphocyte behavior by inducing hyporesponsiveness to lymphokines. 298 89

The aim of this study was to test whether colony stimulating factors (CSF) and other cytokines facilitate the recovery of a variety of immunohematopoietic functions in lethally irradiated mice undergoing bone marrow transplantation (BMT). Two experimental systems were employed: (a) lethally irradiated mice transplanted with syngeneic or T cell-depleted semi-allogeneic bone marrow (BM) cells (0.1-10 x 10(6)), subsequently treated by multiple doses of cytokines; and (b) lethally irradiated mice transplanted with BM cells that had previously been cultivated with cytokines. The cytokines used were: pure natural mouse interleukin-3 (IL-3); recombinant mouse granulocyte-macrophage CSF (rGM-CSF); recombinant human interleukin-2 (rIL-2); and crude cytokine preparations obtained from the culture supernatants of murine leukemia WEHI-3b cells (containing mainly IL-3), and of phorbol myristate acetate (PMA)-stimulated EL4 leukemia cells and concanavalin A-stimulated rat splenocytes (each containing a multitude of cytokines). For BM cultures (1-9 days), the cytokines were used at a dosage of 1-100 U/ml; for in vivo treatment, 2 x 10(2)-5 x 10(4) units were administered intraperitoneally and subcutaneously at different schedules for varying periods (1-3 weeks). The following parameters were tested 1-10 weeks post-BMT: white blood cell count, colony formation in agar and in the spleen of lethally irradiated mice, proliferative responses to mitogens and alloantigens, allocytotoxicity and antibody production (serum agglutinins and plaque-forming cells) against sheep red blood cells. Under appropriate conditions, cytokine treatment either in vitro or in vivo significantly enhanced (2- to 50-fold compared with controls) most functions tested at 2-8 weeks post-BMT, and shortened the time interval required for full immunohematopoietic recovery by 2-5 weeks. In recipients of semi-allogeneic, T lymphocyte-depleted BM no evidence of graft-versus-host disease was found. It is suggested that judicious application in vitro and/or in vivo of certain pure cytokines (e.g. GM-CSF, IL-3) or cytokine 'cocktails' might be beneficial in enhancing hematopoiesis and in the treatment of immunodeficiency associated with BMT.
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PMID:In vitro and in vivo cytokine-induced facilitation of immunohematopoietic reconstitution in mice undergoing bone marrow transplantation. 304 95

The expression of several lymphokine gene is characterized by a common pattern of induction, suppression and superinduction. This pattern was studied at the level of cellular mRNA in the mouse T-lymphoma cell line EL4, the human T-leukemia line Jurkat and in normal human peripheral blood lymphocytes. Lymphokine mRNA was induced by stimulating the cells with the phorbol diester PMA (TPA), with or without T-lymphocyte mitogens. The induction of Interleukin-2, Interferon gamma and the Colony Stimulating Factor for granulocytes and macrophages was suppressed by Cyclosporin A at moderate concns. Furthermore, these mRNAs accumulated to extraordinarily high levels (superinduction) if the protein synthesis inhibitor cycloheximide was added during transcription. Superinduction was not due to an increased rate of transcription. CsA interrupted ongoing transcription of IL2 by a mechanism not dependent on the induction of a new protein. The co-ordinate regulation of these genes strongly suggests that common intracellular signals mediate their expression.
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PMID:Induction, suppression and superinduction of lymphokine mRNA in T lymphocytes. 311 4

The structural specificities of the natural polyamines putrescine (Put), spermidine (Spd) and spermine (Spm) for cell growth are rather stringent, suggesting that appropriate structural analogues of these polycations could serve as potential antineoplastic agents via polyamine antagonism. Norspermidine (Nspd), a homologue of spermidine, had significant antitumor activity against L1210 leukemia, 3LL carcinoma and EL4 lymphoma in mice. The observed antitumor activity of the compound was potentiated by administration of a - difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. DFMO treatment alone, or in combination with Nspd reduced tumoral Put and Spd levels by greater than 50% in all three tumor models. In animals receiving both Nspd and DFMO, Nspd accumulation in the tumor cells was increased by 50% or more compared to cells from animals receiving Nspd only. Co-administration of Spd, but not Put, abolished the antitumor activity of L1210 observed with DFMO and Nspd treatment, and also reduced the tumoral accumulation of Nspd. These results indicate that appropriate structural analogues of the natural polyamines may be useful as antineoplastic agents.
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PMID:Antitumor activity of norspermidine, a structural homologue of the natural polyamine spermidine. 314 Jul 10

A multivalent hybrid antibody complex composed of two IgG molecules specific for ricin toxin and two specific for the H-2 antigens of murine leukemia EL4 cells, cross-linked by SpA, was used as vector of the toxin to the target cells. The high affinity of the hybrid antibody for the specific antigens achieved an efficient attachment to the EL4 cell membrane and binding of ricin toxin; this high-molecular-weight complex, introduced by endocytosis into the leukemic cell cytoplasm, was able to specifically deliver the toxin to the target cells. The effect of multivalent hybrid antibody-vectorized toxin was followed up in vivo. This method enabled determination of the proportion of killed cells (over 90% after a single treatment of leukemic cells or about 99% after double treatment). The presence of a low proportion of tumoral cells maintaining their proliferative capacity is discussed.
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PMID:In vivo follow up of the cytotoxic effect of ricin toxin vectorized by multivalent hybrid antibody on target cells. 325 46

Antibodies of the IgG class, specifically interacted with H-2 antigens of murine leukemia EL4 cells, were used to bind the ricin toxin covalently linked to protein A of Staphylococcus aureus. The toxin thus complexed, introduced in the cytoplasm by endocytosis, was able to kill the leukemic cells inoculated in animals. The interaction of immunotoxin with the leukemic cells was performed in vitro using one, two or three treatments and the cytotoxic effect on the target cells was followed up in vivo. The time interval between immunotoxin treatments was indicated by the membrane turn-over study of EL4 cells coated with specific antibodies in their monomeric form, complexed by protein A or interacted with protein A--ricin toxin conjugate. A proportion of 99.8% cells killed was obtained after three treatments.
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PMID:In vivo follow-up of the cytotoxic effect of protein A--ricin toxin conjugate, on antibody-coated target cells. 337 32

We have studied the maturation of cytotoxic T-lymphocytes (CTL) following primary and anamnestic responses in vivo and in vitro. Parameters evaluated included: frequency of effector CTL, specificity of binding to and lysis of target cells, killing and recycling ability of individual CTL, and the avidity of effector-target conjugation. While the frequency of effector CTL in the peritoneal cavity of BALB/c mice immunized against leukemia EL4 of C57BL/6 origin increases from 0 to 35% in 11 days of priming, a paradoxically lower frequency has been observed usually after 2 degrees and repeatedly after 3 degrees immunizations both in the peritoneal cavity and in the spleen. The H-2 haplotype and H-2 sub-loci specificity of CTL is preserved upon repeated immunizations. Likewise, the rate of killing and recycling of individual CTL do not change throughout immunizations, suggesting that the cytolytic activity of individual effector CTL is discrete ("quantal") and not subject to maturation upon repeated immunizations. On the other hand, inhibition of conjugate formation and of lysis by antibodies against target major histocompatibility complex (MHC) or effector Lyt-2 determinants is consistently less effective with 3 degrees CTL, suggesting an increase in avidity of effector/target interaction upon repeated immunizations. A striking increase in apparent avidity has been observed during CTL priming in mixed lymphocyte reaction, as deduced from blocking by target cell MHC antibodies. These results suggest that alloimmune CTL undergo maturation with respect to their ability to interact with the target, and that the composition of the responding population is subject to moderate selective processes driven by repeated antigenic stimuli.
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PMID:Maturation of cytolytic T lymphocytes. 349 78

Protein A of Staphylococcus aureus (mol. wt 43,000) was covalently bound to ricin toxin (mol. wt 60,000) by N-succinimidyl 3-(2-pyridyldithio) propionate. The conjugate consisting of one molecule of protein A bound to one molecule of ricin toxin (mol. wt 100,000) was purified by successive affinity chromatographies on IgG-Sepharose 4B and ConA-Sepharose 4B. The purified protein A-ricin toxin conjugate was able to bind and kill IgG antibody coated leukemia EL4 cells leaving unaffected EL4 cells not coated with antibody. The cytotoxic efficacy of the conjugate was comparable to that of nonconjugated ricin toxin. The results recommend the use of protein A-ricin toxin conjugate as a "universal" specific toxin for the "in vitro" killing of various antibody-coated target cells.
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PMID:Protein A vectorized toxins--I. Preparation and properties of protein A-ricin toxin conjugates. 349 27


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