Effect of immunoglobulin G (IgG) interchain disulfide bond cleavage on efficacy of intravenous immunoglobulin for immune thrombocytopenic purpura (ITP)

P>Intravenous immunoglobulin (IVIG) has been used widely to treat immune thrombocytopenic purpura (ITP), but the mechanisms of its action remain unclear. We investigated the affinity for Fc gamma receptors (Fc gamma Rs) and the thrombocytopenia-ameliorating effect of S-sulfonated gammaglobulin (SGG) and S-alkylated gammaglobulin (AGG), in comparison with unmodified gammaglobulin (GG), in a mouse ITP model. Cleavage of immunoglobulin (Ig)G interchain disulfide bonds by either S-sulfonation or S-alkylation did not decrease the affinity for Fc gamma RIIA (CD32A) and Fc gamma RIIB (CD32B), but did decrease the affinity for Fc gamma RIA (CD64A) and Fc gamma RIIIA (CD16A), presumably because of changes in H-chain configuration. The interchain disulfide bond cleavage decreased the affinity much more for mouse Fc gamma RIV than for mouse Fc gamma RIIB. The ability of AGG to ameliorate ITP was greatly diminished, while SGG, whose disulfide bonds are reconstituted in vivo, was as effective as GG. These results suggest that the interchain disulfide bonds are important for therapeutic effect. It is also suggested that the interaction of IVIG with the inhibitory receptor Fc gamma RIIB is insufficient for effective amelioration of ITP and that, at least in this model, direct binding of IVIG to Fc gamma RIIIA is also required.