Brutons tyrosine kinase inhibitor Zanubrutinib modulates Fc gamma receptors to inhibit platelet destruction for alleviation of refractory immune thrombocytopenia

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count (PLT). Bruton tyrosine kinase (Btk) is a therapeutic target in immune-mediated diseases. This study aimed to evaluate the effects of a Btk Inhibitor, zanubrutinib (Zan), on refractory ITP.

Methods: Peripheral blood was collected from healthy controls (HC) and refractory ITP patients (n = 15), and peripheral blood mononuclear cell (PBMC) extraction was performed. The proportion of myeloid-derived suppressor cells (MDSCs) in PBMCs and Arg-1, iNOS, Fc gamma receptor (FcγR), GPIIb/IIIa, and GPIb/IX autoantibody levels were measured. ITP monocytes were separated into control (Con), Zan (Zan), dexamethasone (DXM), and combination (Zan + DXM) groups. Detection ophagocytosis and platelet activation by flow cytometry; FcγR expression by qRT-PCR and western blot; and IFN-γ, IL-4, IL-2, and IL-10 levels were determined by ELISA.

Results: PBMCs from the ITP group demonstrated lower MDSCs proportions and Arg-1 levels, but higher iNOS, FcγRIII, FcγRIIb, FcγRI, GPIIb/IIIa, and GPIb/IX autoantibody levels than those in the HC group. Following Zan intervention, ITP monocytes exhibited decreased phagocytosis, FcγRIIa, FcγRI protein, IFN-γ, IL-2, p-mTOR/mTOR levels, and increased FcγRIIb, PLTs, IL-4, PAC-1, and CD62p levels.

Conclusion: Zan may modulate FcγR toward FcγRIIb to inhibit platelet destruction, thereby improving refractory ITP.