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Potentiation of Lymphocyte Responses by Monoclonal Antibodies to the Ganglioside G_D3¹

Oncology and Immunology Unit, David Maddison Clinical Sciences Building, Royal Newcastle Hospital, Newcastle, New South Wales 2300, Australia [P. H., S. D. S., P. T., C. B.], and Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, California 92037 [D. A. C.]

Previous studies have shown that the ganglioside G_D3 is expressed in high concentrations on melanoma cells and that monoclonal antibodies (MAbs) against G_D3 may induce partial remissions in tumor growth in patients with melanoma. The present studies indicated that incubation of interleukin 2 (IL2) dependent murine natural killer cells with several MAbs against the ganglioside G_D3 potentiated the proliferative response to IL2. There was no effect on cell division in the absence of added IL2. Similarly the mitogenic response of human blood lymphocytes to phytohemagglutinin (PHA) or the T3 antigen was enhanced by coculture with these MAbs. This was noted when the MAbs to G_D3 were added either before or up to 48 h after addition of PHA or MAb to T3. Kinetic analysis revealed that the potentiation of the PHA induced mitogenic response followed the expected response to PHA suggesting that the MAbs amplified normal activation pathways. These effects were also seen with MAb to G_D3 and the T10 structure on T-cells but not with MAbs to the transferrin receptor or isotype MAb controls. Studies on T-cell subsets suggested that the enhanced PHA responses were confined mainly to the T8 subset and responses of the T4 subset were not enhanced. Flow cytometric analysis revealed low levels of G_D3 expression on blood lymphocytes which increased during culture with PHA. IL2 receptor (Tac epitope) expression did not show close correlation with the enhanced lymphocyte responses and the mechanism of the potentiation remains uncertain.

These studies raise questions concerning the role of gangliosides in T-cell activation and whether these in vitro effects of MAbs to G_D3 may account in part for their antitumor effects in patients with melanoma.

¹ This work was supported by the National Health and Medical Research Council and the New South Wales State Cancer Council.

² To whom requests for reprints should be addressed.

Received 5/ 8/86. Revised 8/ 5/86. Accepted 8/12/86.