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Thromb Haemost 2018; 118(10): 1752-1764
DOI: 10.1055/s-0038-1669921
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Proteasome Inhibition with Bortezomib Induces Apoptosis of Long-Lived Plasma Cells in Steroid-Resistant or Relapsed Immune Thrombocytopaenia

Guosheng Li   *
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Shuang Wang   *
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Na Li
2   Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China
,
Yang Liu
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Qi Feng
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Xinyi Zuo
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Xin Li
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Yu Hou
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Linlin Shao
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
,
Chunhong Ma
3   Department of Immunology, Shandong University School of Medicine, Shandong University, Jinan, China
,
Chengjiang Gao
3   Department of Immunology, Shandong University School of Medicine, Shandong University, Jinan, China
,
Ming Hou
2   Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China
4   Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China
,
Jun Peng
1   Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
› Author Affiliations Funding This work was supported by grants from the Major Research plan of the National Natural Science Foundation of China (91442204), National Natural Science Foundation for Distinguished Young Scholars of China (81125002), National Natural Science Foundation of China (81370623, 81770133, 81770114, 81470284 and 81500094), Natural Science Foundation of Shandong Province (ZR2017PH022, ZR2017PH041, ZR2016HP01) and Tai Shan Scholar Foundation.
Further Information

Publication History

14 January 2018

06 August 2018

Publication Date:
20 September 2018 (online)

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Abstract

Primary immune thrombocytopaenia (ITP) is the most common haemorrhagic disease. Although most patients respond initially to mainstream therapies, such as corticosteroids, immunosuppressants or rituximab, a large proportion of patients fail to respond or relapse. These treatments only affect B lymphocytes or short-lived plasma cells, but not already existing long-lived plasma cells (LLPCs) which persistently secrete antibodies. We hypothesized that LLPCs may play a role in the corticosteroid-resistant or relapsed ITP patients, and bortezomib, a proteasome inhibitor, may act on plasma cells and offer a therapeutic effect. Although a significant difference in the proportion of CD19−CD38hiCD138+ total LLPCs was not observed by flow cytometry, a glycoprotein (GP) IIb/IIIa-specific enzyme-linked immunosorbent spot (ELISpot) assay of sorted CD19−CD138+ LLPCs confirmed the existence of anti-platelet antibody-secreting LLPCs in ITP patients in contrast to healthy controls. Moreover, the LLPCs could be eliminated in the presence of bortezomib by ELISpot assay, which was also confirmed by flow cytometry. Accordingly, a modified monoclonal antibody immobilization of platelet antigen assay of sorted CD19−CD138+ LLPCs revealed that the concentration of anti-platelet antibodies decreased remarkably when cultured with 0.25 ng/mL bortezomib for 5 days. The apoptosis assay demonstrated that bortezomib could induce apoptosis of LLPCs in a concentration-dependent manner. The proteasome activity assay showed that bortezomib significantly reduced the proteasome activity in sorted CD19−CD138+ LLPCs. Furthermore, in active ITP murine models, bortezomib eliminated LLPCs in vivo and alleviated thrombocytopaenia. We conclude that LLPCs participate in the pathogenesis of ITP and bortezomib may have potential as a novel therapeutic regimen.

Keywords

proteasome inhibition - bortezomib - long-lived plasma cell - immune thrombocytopaenia - apoptosis

Authors' Contributions

G.L. and S.W. designed and performed research, analysed data and wrote the paper. N.L., Y.L., Q.F., X.L. and X.Z. performed research and analysed data. Y.H., C.M., L.S. and C.G. evaluated the data and corrected the article. M.H. and J.P. designed and performed research and reviewed the work. All authors read and edited the manuscript.


* Guosheng Li and Shuang Wang contributed equally to this study.


Supplementary Material

 

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