MONOCYTE-BOUND MONOCLONAL-ANTIBODIES INHIBIT THE FC-GAMMA-RI-MEDIATEDPHAGOCYTOSIS OF SENSITIZED RED-CELLS - THE EFFICIENCY AND MECHANISM OF INHIBITION ARE DETERMINED BY THE NATURE OF THE ANTIGEN

Monocyte-binding monoclonal antibodies (mAbs) inhibited the Fc gamma r eceptor I (Fc gamma RI)-mediated phagocytosis of red cells sensitized with human monoclonal immunoglobulin G (IgG) anti-D (E-IgG) via three distinct mechanisms depending on their specificity. First, all monocyt e-binding mAbs tested inhibited the adherence (and hence the phagocyto sis) of E-IgG. They also inhibited the binding of fluorescein isothioc yanate (FITC) conjugated IgG anti-D. This inhibition of ligand binding was more efficiently promoted by murine (m) IgG2a than mIgG1 mAbs and presumably involved receptor blockade via the formation of antigen (A g)-mAb-Fc gamma RI complexes on the monocyte membrane. Monocytes passi vely sensitized with human monoclonal anti-D (M-IgG) were used in expe riments to distinguish between inhibition of ligand binding and inhibi tion of phagocytosis. In this way, it was shown that mAbs to transmemb rane molecules (CD11b/CD18, CD44, and HLA) inhibited the phagocytosis of red cells adherent to M-IgG. Under the same conditions, mAbs to gly cosylphosphatidylinositol (GPI) linked molecules (CD14, CD55 and CD59) did not inhibit phagocytosis. These data suggested a second mechanism of inhibition of Fc gamma RI-mediated phagocytosis that involved the cross-linking of a proportion of Fc gamma RI (i.e. those not ligated w ith IgG anti-D) to molecules which are relatively constrained in the c ell membrane. A third mechanism of inhibition was revealed by the use of F(ab')(2) fragments of mAb to CD11b which inhibited Fc gamma RI-med iated interactions with E-IgG in a manner that did not involve IgG (Fc ) crosslinking or blockade of Fc gamma RI. In this respect, Fc gamma R I-mediated phagocytosis was more susceptible to inhibition than recept or-mediated adherence.