期刊
BLOOD
卷 137, 期 15, 页码 2114-2124出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020009497
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资金
- Canadian Blood Services Intramural Research Grant Program
- Canadian Institutes of Health Research Foundation [389035]
- Canadian Blood Services Graduate Fellowship Program - federal government (Health Canada)
- provincial and territorial ministries of health
Anti-CD44 exhibits anti-inflammatory effects in murine ITP by inhibiting macrophage phagocytosis through blockade of Fc gamma R, potentially serving as an alternative to IVIg. The specific Fc gamma R blockade mechanism of anti-CD44 contributes to its therapeutic efficacy in ITP models, highlighting its potential as a treatment option.
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 Fc gamma Rs in 2 separate systems of IgG-opsonized platelets and erythrocytes. Phagocytosis inhibition by anti-CD44 was mediated by blockade of the Fc gamma R IgG binding site without changing surface Fc gamma R expression. Anti-CD44 of different subclasses revealed that Fc gamma R blockade was specific to receptors that could be engaged by the respective anti-CD44 subclass, and Fc-deactivated anti-CD44 variants lost all Fc gamma R-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 Fc gamma R that could be engaged by the CD44 antibody's subclass. Consistent with Fc gamma R blockade, Fc-deactivated variants of anti-CD44 were completely unable to ameliorate ITP. Together, anti-CD44 inhibits macrophage Fc gamma R function and ameliorates ITP consistent with an Fc gamma R blockade mechanism. Anti-CD44 is a potential IVIg alternative and may be of particular benefit in ITP because of the significant role that Fc gamma Rs play in human ITP pathophysiology.
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