Differential effects of calcineurin inhibitors on plasma cells: Potential therapy for antibody- mediated rejection

Author:

Tsai Ching-Yi1,Lin Yu-Li2,Lai Ting-Yu2,Chen Jia-Huang1,Chiang Chih-Kang1,Lee Chih Yuan2

Affiliation:

1. National Taiwan University

2. National Taiwan University Hospital

Abstract

Abstract

Calcineurin inhibitors, including cyclosporine and tacrolimus, are widely used to prevent postoperative rejection after solid organ transplantation and have successfully prolonged the survival of allografts since their introduction. The use of calcineurin inhibitors has dramatically reduced the rate of acute cellular rejection; however, the long-term survival of allografts is still compromised by the damage caused by alloantibodies and antibody-mediated rejection (AMR). Currently, AMR is the most important issue in controlling organ transplantation rejection. The pathophysiological mechanism of AMR is associated with organ damage after prolonged exposure to alloantibodies, which are synthesized and secreted by plasma cells. Therefore, targeting plasma cells to develop a treatment for AMR is an important issue. Since the introduction of tacrolimus (FK506) into the field of organ transplantation, FK506 has successfully suppressed the incidence of acute cellular rejection but is not satisfactory in terms of antibody-mediated rejection. In our study, we found that cyclosporine (CsA) induced endoplasmic reticulum (ER) stress in plasma cells, which was lower in the presence of FK506. The expression of CD138 in plasma cells can prolong the half-life of plasma cells; we found that ER stress in plasma cells induced by CsA could downregulate the protein expression of CD138, inhibit the p-STAT3 signaling and reduce cell survival, thus leading to cell death. Our findings offer an updated insight into the pharmacological effects of CsA on plasma cells, providing valuable options for tailoring treatment strategies in transplant patients undergoing treatment for AMR.

Publisher

Springer Science and Business Media LLC

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