Enhanced modulation of antibodies coating guinea pig leukemic cells in vitro and in vivo. The role of Fc gamma R expressing cells. We have investigated the antigenic modulation induced by a number of antibody fragments and derivatives directed against the idiotype of the surface Ig of the L2C guinea pig B lymphoblastic leukemia, and studied the effects upon such modulation of the simultaneous presence of cells expressing Fc gamma receptors (FcR). In vitro studies confirmed previous work showing that antibody bivalency is required to induce modulation in vitro in simple systems. However, in the presence of isolated Kupffer cells, Fc-containing univalent antibodies were found to induce significant antigenic modulation, and the modulation induced by intact IgG was also found to be more rapid and extensive. Fragments that did not contain Fc regions behaved similarly in the presence or absence of Kupffer cells. Further investigations demonstrated that all three classes of human FcR can mediate modulation enhancement, and suggest that the mechanism involves indirect cross-linking of cell surface Ag via the antibody and effector cell FcR. In vivo studies showed that univalent antibody derivatives containing Fc regions did induce antigenic modulation, but that this was significantly reduced in comparison with bivalent antibodies, confirming their potential advantage for immunotherapy. 