Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP.
Elevated expression of the activating Fcγ receptor (FcγR) I and FcγRIIa together with decreased expression of the inhibitory FcγRIIb 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 FcγR modulation in ITP. In this prospective study, we measured the alteration in monocyte FcγR expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of FcγRIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, FcγRI and IIa levels decreased remarkably, whereas FcγRIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of FcγR toward inhibitory FcγRIIb 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 FcγR phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-β1 (TGF-β1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte FcγR balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61(+) severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory FcγRII expression and downregulated activating FcγRI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of FcγR balance toward the inhibitory FcγRIIb 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.
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Xin-Guang
XG
Liu
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China; Department of Hematology, Taian Central Hospital, Taian, China;
Shuang
S
Liu
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Qi
Q
Feng
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Xue-Na
XN
Liu
Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China;
Guo-Sheng
GS
Li
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Zi
Z
Sheng
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Peng
P
Chen
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Yang
Y
Liu
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Yu
Y
Wei
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Xiao-Yuan
XY
Dong
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;
Ping
P
Qin
Department of Immunology, Shandong University School of Medicine, Jinan, China;
Chengjiang
C
Gao
Department of Immunology, Shandong University School of Medicine, Jinan, China;
Chunhong
C
Ma
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; and.
Lei
L
Zhang
Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China.
Ming
M
Hou
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China.
Jun
J
Peng
D000328:Adult; D000369:Aged, 80 and over; D001565:Benzoates / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D011446:Prospective Studies; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy* / Q000276:immunology; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D017452:Receptors, IgG / Q000032:analysis* / Q000276:immunology; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D053773:Transforming Growth Factor beta1 / Q000097:blood; D055815:Young Adult
D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D017452:Receptors, IgG; D053628:Receptors, Thrombopoietin; D053773:Transforming Growth Factor beta1; C520809:eltrombopag