Small amounts of a monoclonal IgG anti-Fc receptor antibody (2.4G2 prepared by Dr. J. Unkeless of the Rockefeller Institute) or other anti-leukocyte antibodies and tenfold greater amounts of IgG aggregates, potently block Fc receptor function and to a lesser extent also block other MPS function in normal mice in vivo. Since monoclonal antibodies might be useful therapeutic agents for treating such autoimmune blood distruction in vivo, and IgG aggregates share many functional traits with clinically significant immune complexes, the following studies propose: 1.) to characterize the effects of 2.4G2, Fab2 fragments of 2.4G2, anti-leukocyte antibodies and IgG aggregates (or immune complexes) on MPS function. To this end, the clearance of IgG coated red cells and of several other radiolabeled ligands which are cleared by other mechanisms by mononuclear phagocytes, endothelial cells or liver parenchymal cells will be assessed. The mechanism by which monoclonal antibodies or IgG complexes suppress Fc receptor mediated, and other types of MPS clearance will be assessed by studying their effects on mononuclear cell phagocytic function and serum opsonic activity in vitro. 2.) to assess the efficacy and safety of 2.4G2 (and other blockers of MPS function), the effects of these agents on the rate of red cell turnover, on the level of red cell antibody, and on the level of circulating immune complexes will be assessed in normal and auto-immune mice, induced to develop autoimmune hemolysis by the infusion of rat red cells; and in NZB mice which develop autoimmune hemolysis spontaneously. 3.) to assess the importance of Fc receptor function and other aspects of MPS function in immune complex disease, the effect of 2.4G2 and other blockers on the clinical severity of autoimmune disease, on the levels of circulating immune complexes and on the degree of complex deposition in the kidney will be assessed in autoimmune animals. 4.) To better understand the spontaneous MPS defects observed in asymptomatic and symptomatic mice of strains susceptible to autoimmune disease, these defects will be characterized as in 1.). If these defects resemble those produced by anti-leukocyte antibodies and circulating immune complexes, attempts will be made to demonstrate humoral transmission of defects in vitro and in vivo. Since these studies are concerned with the physiologic effects of both monoclonal antibodies and immune complexes in vivo, they may have value both for those evaluating the therapeutic value of monoclonal antibodies, and for studying the pathophysiology of autoimmune disease.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Allergy and Immunology Study Section (ALY)
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Duke University
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Nataraj, C; Huffman, G R; Kurlander, R J (1998) H2M3wt-restricted, Listeria monocytogenes-immune CD8 T cells respond to multiple formylated peptides and to a variety of gram-positive and gram-negative bacteria. Int Immunol 10:7-15
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