During the past several years it has become clear that there are three distinct Fc receptors for IgG (Fc gamma R) which are associated with human myeloid cells and thus potentially involved in antibody dependent killing (ADK) by these cells. With the development of monoclonal antibodies (MAb) to each of these Fc gamma R, it has now become possible to explore in a definitive way the properties and functional capabilities of each receptor. We have been involved in the development of MAb to these Fc gamma R which have been used by us and by other investigators to develop a substantial base of information on the functional properties of each of these receptors. We now propose to use these MAb and the hybridoma cells that produce them to systematically explore the functional properties of the different Fc gamma R. In particular, we propose to use Ig bearing hybridoma cells as targets to further define the cytotoxic potential of different effector cells and trigger molecules as well as to develop insights into the triggering events, their requirements and mechanisms. To facilitate our studies on one of these receptors, Fc gamma R II, we would develop a panel of MAb to Fc gamma RII comparable to those we have already prepared against Fc gamma RI. MAb which react with Fc gamma RII at epitopes other than the ligand binding site would be used in an analysis of the initial events associated with ADK through this receptor. Studies would be carried out on the ability of MAb specific for different Fc gamma R to modulate the expression of these receptors. The conditions for, and effects of, triggering of each of the Fc gamma R on different effector cells would be examined. This analysis would include studies of early signaling, superoxide generation, enzyme and monokine release and phagocytosis. The ability of various biological mediators to modulate the expression and cytotoxic capabilities of each of the Fc gamma R and the effector cells with which they are associated would also be determined. Finally, we would prepare and use heteroantibodies for dissection of the functional activities of the different Fc gamma R. Specifically, we would investigate the capability of each Fc gamma R and their associated effector cells to mediate killing and/or phagocytosis of red blood cell, bacterial, parasite and nucleated cell targets. These studies should permit us to clearly define the functional properties of each of the Fc gamma R, their capability to mediate killing of a variety of target cells, and their associated cytotoxic mechanisms.
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