Monoclonal IgG Specific for the CD44 Antigen Mimics the Action of IVIg in the Amelioration of ITP.

Previous work in our laboratory has shown that both IVIg and “anti-D like” erythrocyte-reactive antibodies ameliorate immune thrombocytopenia (ITP) in a murine model. However, they appear to function through different mechanisms: IVIg is dependent upon the inhibitory Fc receptor, FcγRIIB in the amelioration of ITP, but the anti-erythrocyte antibodies function independently of FcγRIIB expression. We have also demonstrated that anti-erythrocyte antibodies down-modulate the expression of the activating Fc receptor, FcγRIIIA in splenic macrophages during the amelioration of ITP. A monoclonal antibody to CD44, cell surface protein involved in cell homing, cancer progression and inflammation, can also ameliorate murine ITP. Elucidation of the mechanisms of action of anti-CD44 antibodies in the amelioration of ITP would be critical to the successful application of this potential therapy. In this report, two monoclonal antibodies against CD44, KM114 and IM7 were studied in C57BL/6 and FcγRIIB^−/− mice to assess their therapeutic activity in treating ITP. Both KM114 and IM7 bound well to splenic cells from all mice tested. Neither KM114 nor IM7 demonstrated any in vitro anti-idiotypic activity which could neutralize the binding of the thrombocytopenia-inducing anti-platelet antibody. At the dose that protected against thrombocytopenia, KM114 did not mediate RES blockade. In contrast, IM7, which did not at all protect against thrombocytopenia, blocked RES. Since FcγRIIB has been documented to play a key role in the function of IVIg in the amelioration of ITP, we questioned the significance of it in the function of KM114. Surprisingly, KM114 was not able to ameliorate ITP in mice genetically deficient in FcγRIIB. These results suggest that, like IVIg, monoclonal antibody against CD44 mediates amelioration of murine thrombocytopenia in a manner dependent upon the inhibitory FcγRIIB rather than via RES blockade.