Potentiation of interleukin-2 production and its binding by monoclonal antibodies to the gangliosides GD3 and GD2.
Previous studies have shown that monoclonal antibodies (mAbs) against certain gangliosides, which induced remissions in patients with melanoma, also potentiated the response of lymphocytes to a variety of stimuli, including lectins, interleukin-2 (IL-2) and antigens. The present studies have investigated the mechanism of these effects on lymphocytes. Although the mAbs potentiated phytohemagglutinin(PHA)-induced IL-2 production at high concentrations of mAbs and of PHA, this did not appear to explain their potentiation of the proliferative responses of lymphocytes. Hence, although IL-2 production was minimal or absent from the CD8+ subset the latter showed the highest degree of augmentation. Furthermore, addition of IL-2 to PHA-stimulated cultures did not produce similar augmentation of mitogenic responses to that produced by the mAb to GD3 or GD2. The augmented and normal mitogenic responses were, however, dependent on IL-2, as shown by their inhibition with mAbs against IL-2. The antiganglioside mAbs did not have significant effects on IL-2 receptor expression measured by mAbs to Tac. However, the mAbs appeared to increase the affinity of binding of radiolabelled IL-2 to IL-2 receptor and increased internalization of the latter. These results suggest that the effects of the mAbs on IL-2 production may be distinguished from their effects on the proliferative responses of T cells and that the latter were associated with changes in affinity and internalization of 125I-IL-2. Whether the latter is a direct cause of the increased proliferative response remains unknown. The ability of mAbs to GD2 and GD3 to increase IL-2 production and to "enhance" IL-2-dependent proliferative responses suggests the may have valuable clinical roles as immunopotentiating agents.
Schibeci
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S
Immunology and Oncology Unit, Mater Misericordiae Hospital, Newcastle, N.S.W., Australia.
Hersey
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P
Cheresh
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D
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000502:physiology*; D001666:Binding Sites, Antibody; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004705:Endocytosis; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D005732:Gangliosides; D007376:Interleukin-2; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2; C026226:ganglioside, GD3; C019403:ganglioside, GD2