Shen Jia, Liu Chang, Yan Pengpeng, Wang Meifang, Guo Luying, Liu Shuaihui, Chen Jianghua, Rosenholm Jessica M, Huang Hongfeng, Wang Rending, Zhang Hongbo
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China.
Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
Research (Wash D C). 2022 Jul 16;2022:9794235. doi: 10.34133/2022/9794235. eCollection 2022.
Antibody-mediated rejection (ABMR) is a major cause of dysfunction and loss of transplanted kidney. The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells. However, the prognosis of patients following current treatment is poor. T follicular helper cells (Tfh) play an important role in allograft-specific antibodies secreting plasma cell (PC) development. Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders, such as transplant rejection and autoimmune diseases. Tacrolimus (Tac), the primary immunosuppressant, prevents rejection by reducing T cell activation. However, its administration should be closely monitored to avoid serious side effects. In this study, we investigated whether Tac delivery to helper T (CD4) cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure. Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development, PC, and donor-specific antibody (DSA) generation without causing severe side effects compared with delivery through the drug administration pathway. This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation. The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.
抗体介导的排斥反应（ABMR）是移植肾功能障碍和丧失的主要原因。目前针对ABMR的治疗方法包括对T/B细胞或浆细胞进行非特异性抑制和清除。然而，当前治疗后患者的预后较差。滤泡辅助性T细胞（Tfh）在分泌同种异体特异性抗体的浆细胞（PC）发育中起重要作用。因此，Tfh细胞被认为是治疗抗体分泌过多性疾病（如移植排斥反应和自身免疫性疾病）的重要治疗靶点。他克莫司（Tac）是主要的免疫抑制剂，通过减少T细胞活化来预防排斥反应。然而，其给药应密切监测以避免严重副作用。在本研究中，我们调查了使用功能化介孔纳米颗粒将Tac递送至辅助性T（CD4）细胞是否能在同种异体抗原暴露后阻断Tfh细胞分化。结果表明，与通过药物给药途径递送相比，Tac递送通过抑制Tfh细胞发育、PC和供体特异性抗体（DSA）产生，改善了啮齿动物肾移植中的体液排斥损伤，且未引起严重副作用。本研究为预防实体器官移植中的体液排斥反应提供了一种有前景的治疗策略。这种特异性和可控的药物递送避免了目前临床方法中观察到的多种紊乱风险和副作用。
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