Lymphotoxins, macrophage cytotoxins, and tumor necrosis factors: An interrelated family of antitumor effector molecules

Granger, Gale A.; Orr, Sally L.; Yamamoto, Robert S.

doi:10.1007/bf00929455

Cited by 15 publications

(1 citation statement)

References 7 publications

(8 reference statements)

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“…The cytotoxic activities of interferon-,{ and TNF are well documented, as are their ability to act synergistically to kill more efficiently and to kill a larger range of tumor targets [9,30,41]. On the basis of our observations and reports in the literature of the cytotostatic and cytotoxic effects of interferon-y and TNF, we here propose that tumor cell lysis mediated by IL-2 and LAK cells may occur both by a direct LAK-cell -tumor cell interaction and also by the release of soluble, slower-acting, cytotoxic/cytostatic cytokines.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and functional analysis of lymphokine-activated killer (LAK) cell clones

Chong

Aleksijevic

Scuderi

et al. 1989

Cancer Immunol Immunother

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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 micrograms/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-gamma 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-gamma 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-gamma 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-gamma 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.

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Section: Discussionmentioning

confidence: 99%

Phenotypic and functional analysis of lymphokine-activated killer (LAK) cell clones

Chong

Aleksijevic

Scuderi

et al. 1989

Cancer Immunol Immunother

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Lymphokines and cytokines as cancer treatment.Immunotherapy realized

Borden¹,

Sondel

1990

Cancer

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Human proteins with identified effects on host responses to malignant cells have been established as effective therapeutic techniques in cancer. Lymphokines, products of activated cells of the immune system, have pleiotropic biochemical and cellular effects. These include stimulation of immune effector cell proliferation, augmentation of cytotoxicity of immune effector cells for tumor cell targets, enhancement in antigen-recognition potential by monocytes, and modulation of tumor-associated antigen expression on neoplastic cells. Interferons (IFN) and interleukin-2 (IL-2), purified to homogeneity, can induce regression of metastatic malignancy. Recombinant DNA technology has facilitated large-scale production of these and other lymphokines and cytokines. It has also made possible analyses of physical structures of the molecules themselves and has enabled creation of mutated molecules with specific, desired substitutions in their amino acid sequence. Monoclonal antibodies, directed at tumor-associated antigens, can augment antibody-dependent cell-mediated cytotoxicity and can selectively deliver cytotoxic techniques to malignant cells. Molecules that modify the host resistance to malignant disease also have potential to augment effectiveness of other cancer treatment techniques. Lymphokines, cytokines, and monoclonal antibodies, all products of biotechnology, have resulted in fulfillment of the promise of the immune system for inhibition of growth of human malignancy.

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CD40‐mediated lymphotoxin α expression in human B cells is tyrosine kinase dependent

Worm

Geha

1995

Eur J Immunol

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The cytokine lymphotoxin (LT)alpha is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LT alpha expression in human B cells after CD40 ligation. We demonstrate that anti-CD40 monoclonal antibody (mAb) induces strong LT alpha mRNA and surface-expression in human tonsil B cells. Induction of LT alpha mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose-dependent manner. The protein kinase C (PKC)-specific inhibitors sphingosine and bis-indolylmaleimide caused negligible inhibition of anti-CD40-induced LT alpha mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross-linking of the transmembrane phosphatase CD45 to CD40 by using goat-anti-mouse F(ab')2 fragments strongly inhibits CD40-mediated LT alpha expression in human B cells, confirming the role of PTK activation in CD40-mediated induction of LT alpha expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LT alpha mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti-CD40-induced LT alpha expression. These results suggest that induction of LT alpha expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.

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Lymphotoxins, macrophage cytotoxins, and tumor necrosis factors: An interrelated family of antitumor effector molecules

Cited by 15 publications

References 7 publications

Phenotypic and functional analysis of lymphokine-activated killer (LAK) cell clones

Phenotypic and functional analysis of lymphokine-activated killer (LAK) cell clones

Lymphokines and cytokines as cancer treatment.Immunotherapy realized

CD40‐mediated lymphotoxin α expression in human B cells is tyrosine kinase dependent

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