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A Mechanism for Neutrophil-mediated Lysis of Human Neuroblastoma Cells¹

Department of Immunology, The Scripps Research Institute, 10666 North Torrey Pines Road, IMM13, La Jolla, California 92037

² To whom requests for reprints should be addressed, at Department of Immunology, IMM13, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037.

Neutrophils mediate the lysis of human neuroblastoma cells coated with human/mouse chimeric anti-G_D2 ganglioside antibody ch14.18. This study examined the mechanism(s) by which this occurs. Neutrophil degranulation was found to be a required step for lysis, since release of granular enzymes from neutrophils correlated with the lysis of antibody-coated neuroblastoma cells. In addition, agents which block degranulation specifically inhibited this process. Antibody-dependent lysis of neuroblastoma cells was enhanced by exposing neutrophils to granulocyte-macrophage colony stimulatory factor. An increased release of lytic granular molecules was found to be responsible for this lymphokine-mediated phenomenon. Among the molecules released from neutrophil granules that were shown to be involved in neuroblastoma cell lysis were defensins, M_r 3000–4000 neutrophil granular proteins which are known to bind and permeabilize tumor cells. In addition, cathepsin-G, a neutrophil granular protease, was demonstrated for the first time to mediate the lysis of human neuroblastoma cells. The enzymatic activity of cathepsin-G was found to be required for the lysis of these tumor cells, since phenylmethylsulfonyl fluoride blocks the lytic ability of this protein.

¹ Supported by NIH Grant IR35CA42508. This is Scripps Research Institute manuscript number 7173-IMM.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 3/92. Accepted 11/ 5/92.

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