Modulation of Fc receptor clearance and antiplatelet antibodies as a consequence of intravenous immune globulin infusion in patients with immune thrombocytopenic purpura
Bronchoalveolar Lavage Fluid
In 1981 Paul Imbach first reported the usefulness of intravenous immune globulin infusions in the treatment of children with immune thrombocytopenic purpura. Other studies have shown that intravenous immune globulin was associated with the fastest platelet increase of any therapy, confirming the initial observation in children and adults. We and other investigators have used intravenous immune globulin as a maintenance therapy and speculated that repeated single infusions might have a curative value, in addition to an acute effect. The best-defined mechanism of intravenous immune globulin in this model autoimmune disease is Fc receptor blockade. This was first demonstrated by a slowing of antibody-coated, chromium-labeled red blood cell survival. Subsequent confirmation has come from the use of intravenous anti-D and a monoclonal anti-FcRIII that has been used in patients refractory to treatment. In vitro studies have demonstrated alteration in Fc receptor expression on circulating cells, and this mechanism is presumed to be related intimately to the acute platelet increase seen after intravenous immune globulin. Studies with the latest platelet antibody methodology do not support interference with binding of antiplatelet antibodies as an important mechanism, but there are in vitro data to support this hypothesis. Another leading hypothesis is that intravenous immune globulin decreases the production of autoantibodies. Clinically, this has been suspected in immune thrombocytopenic purpura in which there are apparent improvements in patients with chronic disease, but no controlled studies have been performed to verify this. In acquired hemophilia and von Willebrand's disease, however, it seems quite clear that there is direct neutralization of autoanti-factor VIII antibodies by intravenous immune globulin by a presumed Fab-mediated anti-idiotype mechanism. This hypothesis has appeal and has been postulated on the basis of in vitro studies, as well as looking directly at the B cell. Another study supporting this mechanism showed that intravenous immune globulin preparations with altered Fc portions still mediate some platelet increase, even if not as much as intact IgG molecules. It remains unclear whether any effects that are the result of a lower level of autoantibody could be mediated through T cells or macrophages, rather than having direct action on the B cell. In any event, these findings strongly support the hypothesis that decreased levels of autoantibody lead to intermediate (weeks) and long-term (months to years) responses after intravenous immune globulin treatment.