Evidence for Fc Gamma Receptor Inhibition in the Therapeutic Activity of CD44 Antibodies in a Murine Model of Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by low platelet counts. In a murine ITP model, thrombocytopenia has previously been treated using CD44 antibodies, although the mechanism of effect is not well understood. This thesis demonstrates that a monoclonal CD44 antibody can inhibit platelet phagocytosis in vitro and ameliorate murine ITP. A requirement for a functional Fc region was observed, as F(ab)’2 and deglycosylated anti-CD44 were not therapeutic. Furthermore, anti-CD44 (IgG1) could only inhibit platelet phagocytosis and ameliorate ITP in vivo when an IgG1 anti-platelet antibody was utilized, and not IgG2a. This subtype specific effect indicates that the anti-CD44 was therapeutic when able to interact with the same subclasses of Fc gamma receptors (FcyRs) as the anti-platelet antibody. Thus, binding to FcyRs, using their Fc region, and inhibiting the activating FcyR pathway of platelet destruction may potentially explain how CD44 antibodies inhibit platelet phagocytosis and ameliorate murine ITP.M.Sc.2021-06-22 00:00:0