Glucocorticoids, which are widely used to suppress immune function, are key agents for treatment of autoimmune disorders in which Fc receptors for IgG (Fc gamma R) appear to play a major role. However, the mechanisms by which glucocorticoids alter Fc gamma R functions remain unclear. Since the development of monoclonal antibodies (mAbs) that discriminate each of three major Fc gamma R types (Fc gamma RI, II and III), the specific effects of glucocorticoids, alone and in concert with immune cytokines, can now be definitively investigated. Moreover, cDNAs and additional mAbs have recently been developed that discriminate not only the major Fc gamma R types, but also subtypes that probably represent gene duplications, alternate processing and allotypic differences. Furthermore, approaches utilizing these mAbs have been developed that permit measurement of the number and functional activity of most of these Fc gamma R types and subtypes. Using this base of reagents and approaches, many developed by the investigator, he proposes to elucidate the effects of glucocorticoids, gamma interferon (IFN-gamma), and selected other immune cytokines on the expression and function of each Fc gamma R type and subtype. These studies will include quantitative flow cytometry to measure the number of each Fc gamma R expressed on monocytes, macrophages and PMN's that are cultured with glucocorticoids and/or recombinant immune cytokines. cDNA probes will be used to determine hormonal effects on expression of mRNA specific to each Fc gamma R. Functional assays will include glucocorticoid effects on antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and antigen processing and presentation mediated via each Fc gamma R type and subtype. Since other molecules certainly influence phagocyte functions, the applicant will characterize two IFN-gamma and glucocorticoid-inducible surface molecules of monocytes that we will have identified using new mAbs. Finally, to relate the in vitro findings on the role of glucocorticoids in regulation of Fc receptor expression and function to in vivo myeloid cell activation, the applicant would examine phagocytes from patients with streptococcal pharyngitis. Using this as a natural in vivo model system for leukocyte activation, he would determine whether there are similar glucocorticoid effects on phagocytes activated in vivo and those activated in cell culture by immune cytokines. The applicant states that these studies would provide a basis for understanding the interrelationships among myeloid cell Fc gamma R and the hormonal influences that regulate the functional activities of phagocytes.
| Backman, K A; Guyre, P M (1994) Gamma-interferon inhibits Fc receptor II-mediated phagocytosis of tumor cells by human macrophages. Cancer Res 54:2456-61 |
