No abstract

No abstract

Key Points• TPO-RAs shift monocyte FcgR balance toward the inhibitory FcgRIIb and correct the enhanced phagocytic capacity of macrophages in ITP.Elevated expression of the activating Fcg receptor (FcgR) I and FcgRIIa together with decreased expression of the inhibitory FcgRIIb are involved in the pathogenesis of primary immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) have been used clinically for the management of ITP; however, little is known about the effect of TPO-RAs on FcgR modulation in ITP. In this prospective study, we measured the alteration in monocyte FcgR expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of FcgRIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, FcgRI and IIa levels decreased remarkably, whereas FcgRIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of FcgR toward inhibitory FcgRIIb on monocytes was accompanied with a considerable decrease in monocyte/macrophage phagocytic capacity. The response to eltrombopag therapy in patients with ITP was associated with FcgR phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-b1 (TGF-b1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte FcgR balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61 1 severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory FcgRII expression and downregulated activating FcgRI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of FcgR balance toward the inhibitory FcgRIIb on monocytes, and suggested that thrombopoietic agents have a profound effect on immune modulation in ITP. This study is registered at ClinicalTrials.gov as #NCT01864512. (Blood. 2016;128(6):852-861)