Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: Studies in experimental immune thrombocytopenia

Abstract

The clinical benefit of intravenous immunoglobulin (IVIG) preparations in the treatment of immune thrombocytopenic purpura (ITP) is supposed to be mediated by blockade of Fcγ receptor-bearing phagocytes. In 2 experimental models for ITP, it is shown that the therapeutic efficacy of IVIG preparations is related to the IgG dimer content present in these preparations. A rat monoclonal antibody (mAb; MWReg30) directed to the murine platelet-specific integrin αIIbβ3 (gpIIb/IIIa) was administered intraperitoneally either as bolus injection or continuous infusion. With bolus injection, the circulating platelet count dropped to almost zero within 3 hours. Pretreatment with cobra venom factor did not affect platelet depletion, whereas pretreatment with anti-FcγRII/III mAb 2.4G2 or IVIG greatly reduced platelet clearance. With continuous infusion, platelet numbers reached a steady state after 4 days, at approximately 25% of control. This reduction in platelets was, however, not observed in mice deficient for the FcRγ-chain, lacking FcγRI, FcγRIII, and FcγRIII-/- mice. Infusion of a single dose of IVIG with a high IgG dimer content on the 4th day-ie, mimicking therapeutic administration-resulted in a platelet increase for several days. IVIG predominantly consisting of monomeric IgG had no effect on platelet numbers. In conclusion, continuous infusion of MWReg30 induces thrombocytopenia in mice by enhancing Fcγ receptor-mediated clearance of platelets. In this model, it is shown that IgG dimers present in IVIG preparations are responsible for the increase in platelet counts. © 2001 by The American Society of Hematology.