THE ROLE OF ANTIBODY ISOTYPE IN IFN-GAMMA AND IL-2 PRODUCTION DURING ANTI-CD3-INDUCED T-CELL PROLIFERATION

Murine anti-CD3 mAb of the IgG2a isotype are effective in the reversal of graft rejection. However, the first injection of these mAb causes a transient T cell activation in vivo, resulting in the release of cytokines that are held responsible for the sometimes severe febrile and adverse circulatory reactions associated with this therapy. Previously, we and others have reported that there is a polymorphism in the interaction of human Fc-gamma-R with mouse IgG1 and mouse IgG2b. This polymorphism implies that IgG1 and IgG2b mAb are mitogenic for T cells from respectively 70% and less than 5% of healthy individuals. By contrast, Fc-gamma-R interact with murine IgG2a and IgG3 mAb in virtually all individuals. We have now investigated the role of the isotype of the anti-CD3 mAb with respect to in vitro T cell proliferation and production of IFN-gamma and IL-2. IFN-gamma and IL-2 production always accompanied IgG2a- and IgG3-induced mitogenesis, whereas with IgG1 mAb the polymorphism in mitogenic effects completely correlated with IFN-gamma and IL-2 production. With IgG2a, IgG3, and IgG1 mAb, proliferation and IFN-gamma production were, at least in part, dependent on IL-2 production. On the other hand, IgG2b-induced proliferation was not accompanied by measurable IFN-gamma or IL-2 production. This suggests a fundamental difference in the way T cells are activated by IgG2b mAb. Given the role of IFN-gamma and IL-2 in the generation of adverse events during in vivo administration of anti-CD3 mAb, the sue of IgG1 anti-CD3 or anti-TRC mAb offers a tool to further analyze the role of isotype in this respect. Moreover, the clinical use of IgG2b might result in immunosuppression without side effects.