Antibody-dependent destruction of neoplastic cells by cellular effectors

Dearman, Rebecca Jane (1988) Antibody-dependent destruction of neoplastic cells by cellular effectors. University of Southampton, Doctoral Thesis.

Abstract

The in vitro cytotoxic potential of a range of antibodies reacting with surface antigens of neoplastic B- lymphocytes has been investigated in an antibody-dependent cell- mediated cytotoxicity assay (ADCC). The majority of the work has involved antibodies reacting with the surface im-munoglobulin molecules of the guinea pig leukaemic L3C cell and the human lymphoblastoid Daudi cell.

Except where otherwise stated lysis was mediated by human effector cells prepared from venous blood of normal donors. There was marked variation in cytotoxic capacity from one donor to another, but much less variation among different samples from individual donors. Otherwise in both target cell systems cytotoxic capacity was shown to be dependent upon both the nature of the antibody and of the effector cell population.

In the L2C target cell system, sheep antibody did not direct lysis with lym-phocytic or monocytic effectors. Mouse monoclonal antibodies of IgGl, IgG2a and IgG2b isotypes directed lysis only with monocytic effectors whilst antibodies with human, guinea pig and rabbit Fc regions directed lysis which was mediated mainly by lymphocytic effectors. Li the Daudi cell system, antibodies with sheep, human and rabbit Fc regions yielded the same lytic profiles with lymphocytic and monocytic effectors as they did in the L2C cell system, but the mouse monoclonal IgGl antibody was ineffective at directing lysis with either effector. Polymorphonuclear leukocytic effectors did not mediate lysis of LjC cells coated with any antibody but efficiently lysed Daudi cells coated with any of the antibodies at high concentrations. The modulatory capacity of antibody, that is its tendency to cause redistribution and internalization of surface antigen, was not of major importance in determining the ability to direct ADCC in either target cell system.

The ADCC mediated by human lymphocytes could be enhanced by treatment of effectors with human recombinant interferon--y (sixteen hours) or interleukin-2 (three hours). The conventionally defined lymphokine-activated killer (LAK) cell population, obtained by five-day culture of blood mononuclear (lymphocytic plus monocytic) cells in interleukin-2, yielded greater ADCC than did the same effectors unstimulated. The same dependence on antibody isotype was observed as occurred with stimulated and unstimulated lymphocytic effectors.

Lysis of a range of antibody-coated targets (L2C, Daudi and chick ery-throid cells) mediated by guinea pig lymphocytic effectors was also investigated because of our interest in immunotherapy in these animals. Daudi

and L2C cells proved to be resistant to ADCC directed by all antibodies

tested. Only the erythroid targets were susceptible. Oestrogen-treatment

of the donors, reported to augment effector cell cytotoxic potential, yielded

cells capable of inflicting a significant degree of lysis irrespective of the

presence of antibody.

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