Helper T Cell (CD4+) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity
Jia Shen,
Chang Liu,
Pengpeng Yan,
Meifang Wang,
Luying Guo,
Shuaihui Liu,
Jianghua Chen,
Jessica M. Rosenholm,
Hongfeng Huang,
Rending Wang,
Hongbo Zhang
Affiliations
Jia Shen
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China
Chang Liu
Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
Pengpeng Yan
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China
Meifang Wang
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China
Luying Guo
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China
Shuaihui Liu
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China
Jianghua Chen
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China
Jessica M. Rosenholm
Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland
Hongfeng Huang
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China
Rending Wang
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, China; Organ Donation and Coordination Office, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Hongbo Zhang
Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland; Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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.
