Key Points

  • CD44 antibodies block FcγR IgG binding function on macrophages.

  • CD44 antibody blockade of FcγRs leads to inhibition of macrophage phagocytosis of platelets and explains murine ITP amelioration.

Abstract

Monoclonal immunoglobulin G (IgG) antibodies to CD44 (anti-CD44) are anti-inflammatory in numerous murine autoimmune models, but the mechanisms are poorly understood. Anti-CD44 anti-inflammatory activity shows complete therapeutic concordance with IV immunoglobulin (IVIg) in treating autoimmune disease models, making anti-CD44 a potential IVIg alternative. In murine immune thrombocytopenia (ITP), there is no mechanistic explanation for anti-CD44 activity, although anti-CD44 ameliorates disease similarly to IVIg. Here, we demonstrate a novel anti-inflammatory mechanism of anti-CD44 that explains disease amelioration by anti-CD44 in murine ITP. Macrophages treated with anti-CD44 in vitro had dramatically suppressed phagocytosis through FcγRs in 2 separate systems of IgG-opsonized platelets and erythrocytes. Phagocytosis inhibition by anti-CD44 was mediated by blockade of the FcγR IgG binding site without changing surface FcγR expression. Anti-CD44 of different subclasses revealed that FcγR blockade was specific to receptors that could be engaged by the respective anti-CD44 subclass, and Fc-deactivated anti-CD44 variants lost all FcγR-inhibiting activity. In vivo, anti-CD44 functioned analogously in the murine passive ITP model and protected mice from ITP when thrombocytopenia was induced through an FcγR that could be engaged by the CD44 antibody’s subclass. Consistent with FcγR blockade, Fc-deactivated variants of anti-CD44 were completely unable to ameliorate ITP. Together, anti-CD44 inhibits macrophage FcγR function and ameliorates ITP consistent with an FcγR blockade mechanism. Anti-CD44 is a potential IVIg alternative and may be of particular benefit in ITP because of the significant role that FcγRs play in human ITP pathophysiology.

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