BACKGROUND

Chronic rejection, closely related to the activation of B cells and donor-specific antibody (DSA) production, has unsatisfactory therapeutic outcomes. B lymphocyte stimulator (BLyS) is a major regulatory factor that controls the activation and differentiation of B cells. However, it remains unclear whether BLyS blockade can regulate B and plasma cells in the transplantation setting and affect chronic rejection. Here, we investigated the efficacy of the BLyS inhibitors belimumab and telitacicept in controlling B-cell response and preventing chronic rejection.

METHODS

The effects of belimumab and telitacicept on B-cell activation, differentiation and antibody production in vitro were determined. A chronic rejection model in mouse was established by allogeneic cardiac transplantation with CTLA4-Ig treatment. Allograft survival, histology, DSA levels, and B-cell responses were analyzed to evaluate the chronic rejection-preventive effects of belimumab and telitacicept.

RESULTS

In vitro experiments confirmed that belimumab and telitacicept inhibited B-cell activation and differentiation and reduced antibody production. In vivo experiments indicated that they significantly prolonged allograft survival, attenuated chronic rejection through significant suppression of myocardial ischemic necrosis and interstitial fibrosis, and reduced DSA-IgG levels, C4d deposition, and inflammatory cell infiltration. Furthermore, the frequencies of B cells, plasma cells and IgG producing cells in the recipients’ spleen, lymph nodes, bone marrow, and blood were decreased after BLyS inhibitors treatment.

CONCLUSIONS

This study demonstrated that belimumab and telitacicept inhibit B-cell responses and antibody production and alleviate chronic transplant rejection. Therefore, BLyS inhibitors are expected to be used for the prevention of chronic rejection in clinical practice.

中文翻译：

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阻断 BLyS 可抑制 B 细胞反应和抗体产生，从而预防慢性移植排斥

背景

慢性排斥反应与 B 细胞的激活和供体特异性抗体 (DSA) 的产生密切相关，其治疗效果并不令人满意。B淋巴细胞刺激因子（BLyS）是控制B细胞活化和分化的主要调节因子。然而，目前尚不清楚 BLyS 阻断是否可以调节移植环境中的 B 细胞和浆细胞并影响慢性排斥反应。在这里，我们研究了 BLyS 抑制剂贝利尤单抗和替利西普在控制 B 细胞反应和预防慢性排斥方面的功效。

方法

确定了贝利尤单抗和替利西普对体外 B 细胞活化、分化和抗体产生的影响。采用同种异体心脏移植联合CTLA4-Ig治疗建立小鼠慢性排斥反应模型。分析同种异体移植物存活、组织学、DSA 水平和 B 细胞反应，以评估贝利尤单抗和替利西西普的慢性排斥预防作用。

结果

体外实验证实贝利尤单抗和替利西普抑制 B 细胞活化和分化，并减少抗体产生。体内实验表明，它们显着延长了同种异体移植物的存活率，通过显着抑制心肌缺血性坏死和间质纤维化来减轻慢性排斥反应，并减少 DSA-IgG 水平、C4d 沉积和炎症细胞浸润。此外，BLyS抑制剂治疗后，受体脾脏、淋巴结、骨髓和血液中B细胞、浆细胞和IgG产生细胞的频率降低。

结论

这项研究表明，贝利尤单抗和替利西西普可抑制 B 细胞反应和抗体产生，并减轻慢性移植排斥。因此，BLyS抑制剂有望在临床上用于预防慢性排斥反应。