ABSTRACT
To definitively determine whether the neonatal Fc receptor (FcRn) is required for the acute amelioration of immune thrombocytopenia (ITP) by IVIg, we used FcRn-deficient mice in a murine ITP model. Mice injected with antiplatelet antibody in the presence or absence of IVIg displayed no difference in platelet-associated IgG between FcRn deficient versus C57BL/6 mice. FcRn-deficient mice treated with high-dose (2 g/kg) IVIg or a low-dose (2 mg/kg) of an IVIg-mimetic CD44 antibody were, however, protected from thrombocytopenia to an equivalent extent as wild-type mice. To verify and substantiate the results found with FcRn-deficient mice, we used ß(2)-microglobulin-deficient mice (which do not express functional FcRn) and found that IVIg or CD44 antibody also protected them from thrombocytopenia. These data suggest that for both high-dose IVIg as well as low-dose CD44 antibody treatment in an acute ITP model, FcRn expression is neither necessary nor required.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Autoantibodies/therapeutic use , Histocompatibility Antigens Class I/physiology , Hyaluronan Receptors/chemistry , Immunoglobulins, Intravenous/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/prevention & control , Receptors, Fc/physiology , Animals , Disease Models, Animal , Histocompatibility Antigens Class I/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Platelet Count , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/immunology , Receptors, Fc/genetics , beta 2-Microglobulin/genetics , beta 2-Microglobulin/physiologyABSTRACT
To explore the potential for monoclonal antibodies as a treatment for immune thrombocytopenia (ITP) and to further explore their mechanisms of action, we tested 8 monoclonal CD44 antibodies in murine ITP and found 4 antibodies that could successfully ameliorate ITP; 2 of these antibodies function at a full 3-log fold lower dosage compared with IVIg. Further characterization of the 2 most successful antibodies (5035-41.1D and KM114) demonstrated that, similar to IVIg: (1) the presence of the inhibitory IgG receptor FcγRIIB was required for their ameliorative function, (2) complement-deficient mice responded to anti-CD44 treatment, and (3) human transgenic FcγRIIA-expressing mice also responded to the CD44 therapeutic modality. Dissimilar to IVIg, the Fc portion of the CD44 antibody was not required. These data demonstrate that CD44 antibodies can function therapeutically in murine ITP and that they could potentially provide a very-low-dose recombinant therapy for the amelioration of human ITP.
