Cyclic Helix B Peptide Prolongs Skin Allograft Survival via Inhibition of B Cell Immune Responses in a Murine Model.

Long Zheng,Ruiming Rong,Weitao Zhang,Wenjun Gao,Linkun Hu,Cheng Yang,Chao Hu,Xuepeng Zhang,Xuanchuan Wang,Dong Zhu

doi:10.3389/fimmu.2021.682749

Abstract

Antibody-mediated rejection (AMR) represents a major cause of allograft dysfunction and results in allograft failure in solid organ transplantation. Cyclic helix B peptide (CHBP) is a novel erythropoietin-derived peptide that ameliorated renal allograft rejection in a renal transplantation model. However, its effect on AMR remains unknown. This study aimed to investigate the effect of CHBP on AMR using a secondary allogeneic skin transplantation model, which was created by transplanting skin from BALB/c mice to C57BL/6 mice with or without CHBP treatment. A secondary syngeneic skin transplantation model, involving transplantation from C57BL/6 mice to C57BL/6 mice, was also created to act as a control. Skin graft rejection, CD19+ B cell infiltration in the skin allograft, the percentages of splenic plasma cells, germinal center (GC) B cells, and Tfh cells, the serum levels of donor specific antibodies (DSAs), and NF-κB signaling in splenocytes were analyzed. Skin allograft survival was significantly prolonged in the CHBP group compared to the allogeneic group. CHBP treatment also significantly reduced the CD19+ B cell infiltration in the skin allograft, decreased the percentages of splenic plasma cells, GC B cells, and Tfh cells, and ameliorated the increase in the serum DSA level. At a molecular level, CHBP downregulated P100, RelB, and P52 in splenocytes. CHBP prolonged skin allograft survival by inhibiting AMR, which may be mediated by inhibition of NF-κB signaling to suppress B cell immune responses, thereby decreasing the DSA level.

Highlights

Antibody-mediated rejection (AMR) represents a major cause of allograft dysfunction and results in allograft failure in solid organ transplantation [1, 2]
These results suggested that Cyclic helix B peptide (CHBP) prolonged skin allograft survival, which was especially obvious in the high-dose group
The results revealed that the percentages of germinal center (GC) B cells and T follicular helper (Tfh) cells were significantly increased in the allogeneic group compared to the syngeneic group

Summary

Introduction

Antibody-mediated rejection (AMR) represents a major cause of allograft dysfunction and results in allograft failure in solid organ transplantation [1, 2]. It is driven by circulating donor-specific antibodies (DSAs), which are mainly secreted by plasma cells differentiated from B cells [2, 3]. Thereafter, some of the activated B cells enter the center of follicles to form germinal centers (GCs) [5]. In GCs, Tfh cells instruct GC B cells to proliferate and undergo affinity maturation, class switching, and eventually, differentiation into long-lived plasma cells [6]. As AMR, which is mediated by B cell immune responses, is an important contributor to allograft dysfunction and failure after organ transplantation and lacks effective therapies, there is an urgent need for novel therapies for AMR

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