Administration of high doses (e.g., 1g/kg/day) of intravenous immunoglobulin G (IVIG) to patients with autoimmune diseases such as chronic inflammatory demyelinating polyneuropathy (CID) has been found to induce clinical benefits, including complete remission of disease. The mechanisms responsible for therapeutic effects of IVIG are almost totally not known. Its clinical efficacy may be due, at lest in part, to regulatory effects of IVIG on cells bearing receptors for the Fc region of IgG (FcrR). Preliminary results demonstrated that: i) IVIG modulate in vivo and in vitro activities of human natural killer (NK) cells; ii) a small fraction of monomeric (m) IgG present in human sera and endowed with the property of cytophilia is responsible for inhibition of NK cell activity; iii) all commercial preparations of IVIG tested contain cytophilic MigG; iv) cytophilic mIgG interact with NK cells via FcrRIIIA, causing phenotypic and functional alterations of these effector cells (e.g., treatment of highly purified NK cells with mIgG obtained from IVIG modulate their in vitro proliferation, cytotoxic activity, and cytokine secretion). The major goal of this research project is to test the hypothesis that cytophilic IgG molecules in IVIG selectively bind to FcrRIIIA on NK cells, leading to changes in their function, which in turn may contribute to the clinical benefits induced by high doses of IVIG. Using cells and sera rom CIDP patients from the Department of Neurology of the University of Pittsburgh, currently undergoing therapy with IVIG, different immunologic parameters will be investigated: in vivo interactions of infused IgG with FcrRIIIA on NK and other mononuclear cells; effects of IVIG therapy on cytotoxicity, proliferation, and cytokine secretion of NK cells isolated from patients before and at different time intervals after infusion; the levels in the patients' sera of total IgG and of cytophilic IgG; the presence in these sera of circulating cytokines and their ability to modulate function of normal NK cells in vitro as determined by functional assays and by the intracellular level of mRNA for FCRIIIA expression and cytokine production. These experiments should provide a better understanding of the cellular mechanisms that might be responsible for beneficial effects of IVIG therapy and a more clear cut evidence regarding the in vivo regulatory effects of mIgG.
