Monocytes, macrophages and polymorphonuclear neutrophils (PMN) are critical to initiation of the immune response and to the effector phase of immune defense, and are involved in a variety of pathologic disorders. Fc receptors for IgG (FcgammaR) are important mediators of many activities of these cells. During the past four years, we have examined in some detail the properties of FcgammaR and their role in the functional activity of the cells on which they are expressed. In this renewal application, we propose studies to develop a better understanding of the additional molecular interrelationships that influence the activity of each of the classes of FcgammaR on monocytes, macrophages and polymorphonuclear neutrophils. In particular, 1) we propose to extend our studies of the signaling and functional properties of the FcgammaR on human myeloid cells to determine the effects of joint ligation of the different FcgammaR or their isoforms. These studies would involve the use of combinations of bispecific antibodies targeting to different FcgammaR types as well as quadroma self directed targets expressing two different anti-FcgammaR antibodies. 2) We would determine the role of cognate interactions in monocytes/macrophages activation and FcgammaR functional properties. Although it is clear that monocytes/macrophages require both cytokine and cognate interactions for appropriate function against some targets, the importance of these interactions in myeloid cell function has not been comprehensively explored. We would examine the role of CD40, TNFR, LFA- 3 and LFA-1 in signaling monocytes and macrophages activation and in several critical functions, including: phagocytosis, ADCC, superoxide generation, cytokine release and antigen presentation. 3) Finally, we would determine the role of myeloid cells and their receptors (FcgammaR and accessory molecules) in toxoplasma infection and killing, as a physiologically relevant model of FcgammaR function. These studies should result in a far clearer understanding of the functional abilities of the different FcgammaR on human myeloid cells and the influence of other physiologically relevant molecular interrelationships on the activity of each of the classes of FcgammaR. Since myeloid cell populations and FcgammaR are central to a number of critical functions, information obtained in the proposed studies will be useful in designing strategies for modulating the activity of these molecules and the critical cell populations with which they are associated.
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