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

Guosheng Li; Shuang Wang; Na Li; Yang Liu; Qi Feng; Xinyi Zuo; Xin Li; Yu Hou; Linlin Shao; Chunhong Ma; Chengjiang Gao; Ming Hou; Jun Peng

doi:10.1055/s-0038-1669921

Thrombosis and Haemostasis, Table of Contents

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

Authors

Guosheng Li^*

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Shuang Wang^*

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Na Li

²Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China
Yang Liu

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Qi Feng

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Xinyi Zuo

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Xin Li

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Yu Hou

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Linlin Shao

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China
Chunhong Ma

³Department of Immunology, Shandong University School of Medicine, Shandong University, Jinan, China
Chengjiang Gao

³Department of Immunology, Shandong University School of Medicine, Shandong University, Jinan, China
Ming Hou

²Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China

⁴Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China
Jun Peng

¹Department of Haematology, Qilu Hospital, Shandong University, Jinan, China

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⁻CD38^hiCD138⁺ 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

Full Text

References

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