Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect

Recently, it has been postulated that the beneficial effect of intravenous immunoglobulins (IVIGs) in antibody-mediated autoimmune disorders is based on accelerated catabolism of autoantibodies. In the current study, in vivo experiments were performed with mice in which autoantibody production was m imicked by continuous infusion of monoclonal antibodies. In this model, a s ingle dose of IVIG reduced the plasma concentrations of the infused immunog lobulin (Ig)G1 monoclonal antibody (mAb) by approximately 40% after 3 days, whereas the concentration of an IgA mAb was not affected. To extrapolate t hese findings to humans, a computational model for IgG clearance was establ ished that accurately predicted the time course and magnitude of the decrea se in IgG plasma levels observed in mice. Adapted for humans, this model pr edicted a gradually occurring decrease in autoantibody levels after IVIG ad ministration (2 g/kg), with a maximum reduction of approximately 25% after 3 to 4 weeks and a continued decrease of several months. In conclusion, a s ingle high dose of IVIG induces a relatively small but long-lasting reducti on of autoantibody levels by accelerated IgG clearance. This mechanism has clinical relevance in the sense that it can fully explain, as the sole mech anism, the gradual decrease in autoantibody levels observed in several pati ent studies. However, in some clinical studies, larger or more rapid effect s have been observed that cannot be explained by accelerated clearance. Hen ce, IVIG can also reduce autoantibody levels through mechanisms such as dow n-regulation of antibody production or neutralization by anti-idiotypic ant ibodies. (C) 2001 by The American Society of Hematology.