| During the past 20 years, intravenous immunoglobulin (IVIG) therapy has become a standard treatment for patients with immune thrombocytopenic purpura (ITP). However, the mechanism(s) by which IVIG achieves beneficial effects in ITP are uncertain. The purpose of this research was to investigate mechanisms of IVIG action in quantitative models of ITP.; IVIG effects were studied in vitro and in vivo. Investigations in a cell-culture system demonstrated that IVIG decreases the production rate of anti-platelet antibodies, in a concentration-dependent manner. To facilitate the investigation of IVIG action in vivo, a quantitative, passive immune model of ITP was developed by administering a monoclonal anti-platelet antibody (7E3) to rats. This animal model of ITP is quite unique, as it is quantitative with respect to anti-platelet antibody concentrations and anti-platelet antibody effects. 7E3 administration led to rapid, severe thrombocytopenia, and to increases in bleeding tendency. Administration of IVIG protected the rats from 7E3-mediated thrombocytopenia, and also led to an unexpected increase in the clearance of the anti-platelet antibody, an effect that had not been previously demonstrated for IVIG. Studies in mice lacking expression of the FcRn receptor showed that this effect of IVIG was mediated by competition with 7E3 for occupancy of the FcRn receptor.; Because it is likely that multiple pathways are involved in IVIG effects in ITP, pharmacokinetic/pharmacodynamic modeling was used to estimate the importance of this new mechanism of action. IVIG effects on 7E3 pharmacokinetics were characterized with a mechanism-based model of IgG pharmacokinetics, and an indirect response model was developed to relate 7E3 concentrations to the time-course of thrombocytopenia. These mathematical models predicted that ∼50% of the total effect of IVIG on 7E3-induced thrombocytopenia could be accounted for by MG effects on anti-platelet antibody clearance, suggesting that this may be an important mechanism of IVIG action.; This dissertation introduces the approach of using quantitative experimental models of ITP, together with pharmacokinetic/pharmacodynamic modeling, to delineate the complex actions of IVIG. This approach has led to a better understanding of IVIG effects in ITP, and may lead to the development of new therapies of ITP and other autoimmune conditions. |
