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  • 1
    Electronic Resource
    Electronic Resource
    Cytostatic and cytotoxic activity of lymphokine-activated killer cell supernatants (1989)
    Springer
    Cancer immunology immunotherapy 30 (1989), S. 65-70 
    Details
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Incubation of peripheral blood mononuclear cells with interleukin-2 (IL-2) results in the release of a factor which is cytostatic and cytotoxic both to tumor cell lines (A375M, A375P, C480, MCF-7, Hey) and fresh tumor cells (in the human tumor cloning assay), including breast cancer, colon cancer, melanoma, myeloma and ovarian cancer. The factor cannot be detected in a 4-h chromium-release assay, but is best demonstrated after tumor cells have been to it for exposed 3 days. The factor is not cytotoxic to normal peripheral blood leukocytes or normal fibroblasts, and is not toxic to certain targets sensitive to lymphokine-activated killer (LAK) cells, such as K562 and Daudi cells. The factor is diffusible, non-dialyzable, relatively stable to heat and acid and does not contain appreciable amounts of targets resistant to interferon-α and β, tumor necrosis factor β and interleukin-1. The data suggest that there are several mechanisms of LAK cell activity against tumor cells including one which requires direct interaction of LAK and tumor cells and one which is mediated by LAK cell supernatant. The former is detected by 4-h chromium release while the latter is not.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01665032
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  • 2
    Electronic Resource
    Electronic Resource
    Monoclonal antibodies anti-CD3, anti-TCRαβ and anti-CD2 act synergistically with tumor cells to stimulate lymphokine-activated killer cells and tumor-infiltrating lymphocytes to secrete interferon γ (1992)
    Springer
    Cancer immunology immunotherapy 35 (1992), S. 335-341 
    Details
    ISSN: 1432-0851
    Keywords: IFNγ ; LAK ; TIL ; Anti-CD3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Peripheral blood lymphocytes cultured in interleukin-2 IL-2 acquire the ability to recognize and kill a wide range of tumor cells. Such promiscuous killer cells are termed lymphokine-activated killer (LAK) cells. We recently reported that the interaction of LAK cells with tumor cells stimulated the LAK cells to release interferon (IFN)γ. Here, we report that the release of IFNγ by LAK cells can be further enhanced by addition of the monoclonal antibodies (mAbs), anti-CD3, anti-(T cell receptor αβ) (TCRαβ) and a mitogenic combination of anti-CD2 (T112+T113). Other antibodies, including a non-mitogenic anti-CD2 mAb (Leu5b), that recognize T cell-associated antigens were not stimulatory. The same stimulatory mAbs also synergized with tumor cells to stimulate tumor-infiltrating lymphocytes (TIL) to secrete IFNγ. Additional experiments indicated that it was the T cell subset of LAK cells (LAK-T cells) that was stimulated by tumor cells and mAbs to release IFNγ. Inhibition studies with specific mAbs suggest that the stimulation of IFNγ release by LAK-T cells was dependent both on the aggregation of TCR-CD3 complexes on the LAK-T cell, and on the interaction of accessory molecules with their ligands. The accessory molecules we have identified as critical are LFA 1 and CD2/LFA-2 on LAK-T cells interacting with their respective ligands ICAM-1 and LFA3. Thus our data suggest that cytokine production in LAK-T cells can be regulated by multiple molecular interactions, involving the TCR-CD3 complex and adhesion molecules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01741147
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  • 3
    Electronic Resource
    Electronic Resource
    Phenotypic analyses of lymphokine-activated killer cells that release interferon γ and tumor necrosis factor α (1990)
    Springer
    Cancer immunology immunotherapy 31 (1990), S. 255-259 
    Details
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We recently reported that interleukin-2(IL-2)-activated peripheral blood lymphocytes and CD3+, lymphokine-activated killer (LAK) cell clones release tumor necrosis factor α(TNFα) and interferon γ (IFNγ) when stimulated with K562 erythroleukemia cells. We examined the phenotype of IL-2-activated peripheral blood leukocytes that secrete TNFα and IFNγ when stimulated with K562 cells and demonstrated that TNFα secretion is not due to the presence of contaminating mononuclear phagocytes. Further, we demonstrate that IL-2-activated natural killer (NK) cells release only IFNγ when stimulated with K562 cells while T lymphocytes exposed to monoclonal anti-CD3 and K562 cells secrete both TNFα and IFNγ. However, T cells stimulated only with K562 cells did not release IFNγ or TNFα while the admixture of these T cells with NK cells, when stimulated with K562 cells, released levels of TNFα comparable to those produced by the unseparated cells. At present it is unclear whether only one or both effector cell types respond to K562 by releasing TNFα or why the presence both cell types is needed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01789178
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  • 4
    Electronic Resource
    Electronic Resource
    ICAM-1 and LFA-3 enhance the ability of anti-CD3 mAb to stimulate interferon γ production in interleukin-2-activated T cells (1994)
    Springer
    Cancer immunology immunotherapy 39 (1994), S. 127-134 
    Details
    ISSN: 1432-0851
    Keywords: Key words: LAK – T lymphocytes – ICAM-1 – LFA-3 – IFNγ
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Interleukin-2 (IL-2)-activated killer cells, also referred to as lymphokine-activated killer (LAK) cells, are stimulated by tumor cells to express cytotoxic activity and to also secrete cytokines such as interferon γ (IFNγ) and tumor necrosis factor α (TNF α). We previously reported that secretion of cytokines by IL-2-activated T cells (LAK-T cells) is dependent on the initial cross-linking of the T cell receptor (TCR)-CD3-molecular complex, but the cross-linking of accessory molecules, such as LFA-1, CD2, CD44 and CD45, on LAK-T cells can enhance this cytokine production. We have developed an approach involving interspecific gene transfer to define further the contributions of LFA-1 and CD2 to the activation of LAK-T cells. The genes for huICAM-1 (a ligand for LFA-1) and huLFA-3 (a ligand for CD2) were transfected singly and in combination into a null mouse melanoma background, and clonal populations of cells that stably express ICAM-1 and/or LFA-3 were derived. Expression of the introduced ICAM-1 and/or LFA-3 by transfected cells enhanced their ability to bind LAK-T cells; the LFA-1/ICAM-1-mediated binding was not further enhanced by activation with phorbol 12-myristate 13-acetate. ICAM-1- and/or LFA-3-transfected cells, in the presence of immobilized anti-CD3, exhibited a greater ability to stimulate IFNγ secretion by LAK-T cells compared to the untransfected parental lines. This experimental system, which allows ICAM-1/LFA-1 and CD2/LFA-3 interactions to occur on the LAK-T cell at a site distal from the anti-CD3 signal, extends our understanding of LAK-T cell activation by establishing that both LFA-1/ICAM-1 and CD2/LFA-3 can mediate co-stimulation via adhesion and signaling events.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01525318
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  • 5
    Electronic Resource
    Electronic Resource
    ICAM-1 and LFA-3 enhance the ability of anti-CD3 mAb to stimulate interferon γ production in interleukin-2-activated T cells (1994)
    Springer
    Cancer immunology immunotherapy 39 (1994), S. 127-134 
    Details
    ISSN: 1432-0851
    Keywords: LAK ; T lymphocytes ; ICAM-1 ; LFA-3 ; IFNγ
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Interleukin-2 (IL-2)-activated killer cells, also referred to as lymphokine-activated killer (LAK) cells, are stimulated by tumor cells to express cytotoxic activity and to also secrete cytokines such as interferon γ (IFNγ) and tumor necrosis factor α (TNF α). We previously reported that secretion of cytokines by IL-2-activated T cells (LAK-T cells) is dependent on the initial cross-linking of the T cell receptor (TCR)-CD3-molecular complex, but the cross-linking of accessory molecules, such as LFA-1, CD2, CD44 and CD45, on LAK-T cells can enhance this cytokine production. We have developed an approach involving interspecific gene transfer to define further the contributions of LFA-1 and CD2 to the activation of LAK-T cells. The genes for huICAM-1 (a ligand for LFA-1) and huLFA-3 (a ligand for CD2) were transfected singly and in combination into a null mouse melanoma background, and clonal populations of cells that stably express ICAM-1 and/or LFA-3 were derived. Expression of the introduced ICAM-1 and/or LFA-3 by transfected cells enhanced their ability to bind LAK-T cells; the LFA-1/ICAM-1-mediated binding was not further enhanced by activation with phorbol 12-myristate 13-acetate. ICAM-1- and/or LFA-3-transfected cells, in the presence of immobilized anti-CD3, exhibited a greater ability to stimulate IFNγ secretion by LAK-T cells compared to the untransfected parental lines. This experimental system, which allows ICAM-1/LFA-1 and CD2/LFA-3 interactions to occur on the LAK-T cell at a site distal from the anti-CD3 signal, extends our understanding of LAK-T cell activation by establishing that both LFA-1/ICAM-1 and CD2/LFA-3 can mediate co-stimulation via adhesion and signaling events.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01525318
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  • 6
    Electronic Resource
    Electronic Resource
    Phenotypic and functional analysis of lymphokine-activated killer (LAK) cell clones (1989)
    Springer
    Cancer immunology immunotherapy 29 (1989), S. 270-278 
    Details
    ISSN: 1432-0851
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Lymphokine-activated killer (LAK) cells are generated by the culture of peripheral blood lymphocytes with interleukin-2 (IL-2). A variety of cells, including T-lymphocytes and natural killer (NK) cells, can be activated by IL-2 to exhibit the ability to kill multiple tumor and “modified-self” targets. Recent reports indicate that culture conditions can determine the phenotype of cells expressing LAK activity. Using limiting dilution techniques, we first generated cloned LAK cells with three culture conditions: autologous human serum (AHS)+IL-2; AHS+IL-2+0.1 μg/ml phytohemagglutinin and fetal bovine serum and IL-2. We determined that all but one of the 47 LAK cell clones generated with the three culture conditions were CD3+ and T-cell like; one NK-like clone was observed. Clones that were cytotoxic for one target could generally kill multiple targets, and the absence of phytohemagglutinin did not significantly affect the ability of the LAK cell clones to kill multiple targets. The presence of phytohemagglutinin was, however, necessary for the long-term maintenance of proliferation and cytotoxic activity of the LAK cell clones. The mechanism by which LAK cells kill tumor targets is not known. We here demonstrate that LAK cells and LAK cell clones can produce interferon-γ and tumor necrosis factor (TNF) when stimulated with an erythroleukemia cell, K562. Five of the six CD3+, LAK cell clones tested could be stimulated by K562 cells to produce both interferon-γ and TNF. However, the ability of the cloned LAK cells to kill K562 cells, as measured in a 4-h 51Cr-release assay, did not correlate with their ability to produce these cytokines. Furthermore, specific antibodies that neutralize the cytotoxic activity of interferon-γ and TNF did not inhibit killing of K562 cells by LAK cells as measured with a 4-h cytotoxic assay. The cytostatic and cytotoxic activities of interferon-γ and TNF for tumor cells are well documented, but these cytolytic activities are slower acting and exhibit their maximum effect after 48–96 h. We here propose that LAK cells kill tumor targets by a combination of cell-to-cell-mediated killing and by the release of slower acting cytostatic/cytotoxic cytokines that can inhibit the growth of tumors some distance from the effector cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199215
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  • 7
    Electronic Resource
    Electronic Resource
    A phase I trial of recombinant tumor necrosis factor (rTNF) administered by continuous intravenous infusion in patients with disseminated malignancy (1989)
    Springer
    Biotherapy 1 (1989), S. 207-214 
    Details
    ISSN: 1573-8280
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract rTNF was administered to 28 patients with advanced metastatic cancers by continuous intra venous infusion for 5 consecutive days every 2 weeks. The dose levels were 30, 40, 70, 110, 180 and 290 µg/M2/day. Groups of 3 patients were started at each successive dose level and then on subsequent courses treated with the next dose level through 4 escalations as tolerated. Tumor types were: colon cancer 14; adenocarcinoma of unknown primary, 2; renal cancer, 2; leiomyosarcoma, 2; lung cancer, 1; prostate cancer, 1; thymona, 1; bladder cancer; 1; parotid, 1; Kaposi's sarcoma 2; ovarian 1. Toxicities included fever and chills (usually within the first 8 hours of infusion), fatigue, headache, decreased performance status, hypotension and CNS. All patients experienced leukopenia and thrombocytopenia within 24 hours or less after start of infusion with return of baseline by 72 hours after rTNF was stopped. The fall in these counts averaged 50% and was not dose related. No major changes in liver or renal function, coagulation or blood lipids were seen. Major dose limiting toxicities were fatigue, confusion, thrombocytopenia, seizures, hypotension and decreased performance status. NK cell activity measured against K562 target cells was augmented from about 30% target cell lysis to about 70% target cell lysis over the first 7 days of treatment. Two patients, both with metastatic colon cancer showed transient, objective tumor regression which did not qualify as a partial response. One patient with ovarian cancer had a stable partial response but progressed after 13 courses of treatment. Continuous infusion of TNF can be safely administered to patients with a maximum tolerated dose of only between 30 and 40 µg/M2/day. In addition, the MTD with continuous infusion seems to be highly variable and unpredictable from patient to patient. These data suggest that continuous infusion will not be an optimal way to administer TNF.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02170889
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  • 8
    Electronic Resource
    Electronic Resource
    Increased peripheral blood leukocyte cytotoxic activity in cancer patients during the continuous intravenous administration of recombinant human tumor necrosis factor (1989)
    Springer
    Journal of clinical immunology 9 (1989), S. 34-38 
    Details
    ISSN: 1573-2592
    Keywords: Tumor necrosis factor ; natural killer cells ; cytotoxic leukocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Peripheral blood leukocyte cytotoxic activity was studied in cancer patients being treated with a continuous 5-day intravenous infusion of recombinant human tumor necrosis factor (TNF) at a dose of 40 µg/m2/day. All of the nine patients tested experienced a marked increase in circulating leukocyte cytotoxic activity over the 5-day course of treatment. The increase in cytotoxic activity was paralleled by an overall decrease in the number of peripheral blood leukocytes. The percentage of circulating Leu 19+ natural killer cells fell in all patients, while the numbers of both Leu 4+ T cells and Leu 19+/Leu 4+ cytotoxic T cells remained constant. Our findings suggest that the intravenous administration of recombinant TNF may be accompanied by an immunoenhancement due either to an improvement in cytotoxic cell function or to alterations in the trafficking of leukocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00917125
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  • 9
    Electronic Resource
    Electronic Resource
    The effect of age and diabetes mellitus on serum levels of lymphotoxin (1992)
    Springer
    Age 15 (1992), S. 95-99 
    Details
    ISSN: 1574-4647
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To determine whether chronic hyperglycemia or aging is associated with increased serum levels of lymphotoxin, sera were obtained from 29 insulin-treated diabetic patients and 50 healthy subjects ranging in age from 22 to 97 years old. An ELISA system specific for human lymphotoxin was developed with the lower limit of sensitivity at 76 pg/ml and interassay coefficient of variation of 〈7%. Serum levels of tumor necrosis factor (TNF) alpha, interleukin 1 (IL-1) alpha and beta were measured with previously described ELISA system. The WEHI 164 cytotoxicity assay was used to measure bioassayable TNF-like activity. Of the 29 diabetic patients, seven had detectable serum immunoreactive lymphotoxin levels and three had bioassayable serum levels of TNF-like activity. In contrast, only one healthy subject had detectable serum lymphotoxin levels (p〈0.01). Of the 22 diabetic patients who did not have detectable levels of lymphotoxin, 5 had detectable TNFα, 4 had detectable IL-1α, and none had detectable IL-1β levels. Thus, there was no correlation between serum lymphotoxin level and serum levels of TNF α, IL-1 α, or IL-1 β. Aging is not associated with altered serum levels of lymphotoxin while 24% of diabetic patients have increased serum levels of immunoreactive lymphotoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02435008
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  • 10
    Electronic Resource
    Electronic Resource
    Serum levels of tumor necrosis factor alpha, interleukin-1 alpha and beta in healthy elderly subjects (1991)
    Springer
    Age 14 (1991), S. 61-64 
    Details
    ISSN: 1574-4647
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To determine the age-related changes in monokine secretion, the serum concentrations of tumor necrosis factor alpha (TNF), interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) were measured in 31 young healthy subjects (21–35 years old) and 19 healthy elderly subjects (65–83 years old). There were no differences between the two groups with respect to serum concentrations of these cytokines. We also measured in a subgroup of young (n=8–11) and elderly (n=8–10) subjects the in vitro secretion of TNF and IL-1β in response to adding to the medium lipopolysaccharide (LPS, 2 ng/ml), interferon gamma (50 U/ml) or advanced glycosylation endproduct of bovine serum albumin (250 ug/ml). Only LPS-stimulated IL-1β production was significantly reduced in elderly subjects (456.7 ± 229.9 vs 1118.8 ± 494.8 pg/ml). It is concluded that with the possible exception of LPS-stimulated IL-1β production, monokine secretion measured in this study is well preserved in elderly subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02434091
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