未折叠蛋白反应
免疫抑制
免疫学
免疫系统
CD8型
效应器
体内
内质网
移植
癌症研究
移植排斥反应
医学
生物
细胞生物学
内科学
生物技术
作者
Yingying Shi,Yichao Lu,Chunqi Zhu,Zhenyu Luo,Xiang Li,Yu Liu,Mengshi Jiang,Liang Xu,Lihua Luo,Yongzhong Du,Jian You
出处
期刊:Biomaterials
[Elsevier]
日期:2021-05-01
卷期号:272: 120757-120757
被引量:10
标识
DOI:10.1016/j.biomaterials.2021.120757
摘要
Transplantation is the most effective, and sometimes the only resort for end-stage organ failure. However, allogeneic graft suffers greatly from lymphocyte-mediated immunorejection, which bears close relationship with a hyperactivation of endoplasmic reticulum (ER) stress response in host lymphocytes, especially in CD8+ T cells (T-8). Therefore, regulating lymphocytic ER unfolded protein response (UPR) might be a potential therapeutic breakthrough in alleviating graft rejection. Here, ER-targetable liposome is prepared via the surface modification of ER-targeting peptide (Pardaxin), which efficiently loads and directly delivers small molecule inhibitor of UPR sensor IRE1α into the ER of lymphocytes, inducing a systemic immunosuppression that facilitates tumorigenesis and metastasis in the tumor inoculation challenge in vivo. And in vitro, a stage-differential dependency of IRE1α in the phase transition of T-8 is identified. Specifically, inhibiting IRE1α at the early responding stages of T-8, especially at the activation phase, results in a shrunk proliferation, impaired effector function, and limited memory commitment, which might contribute centrally to the induced overall immunosuppression. Based on this, a classical acute rejection model, murine full-thickness trunk skin allograft that primary arises from the hyperactivity of T-lymphocyte, is used. Results suggest that lymphocytic IRE1α inactivation attenuates transplant rejection and prolongs graft survival, with a limited effector function and memory commitment of host T-8. Moreover, an even higher immunosuppressive effect is obtained when IRE1α inhibition is used in combination with immunosuppressant tacrolimus (FK506), which might owe to a synergistic regulation of inflammatory transcription factors. These findings provide a deeper insight into the biological polarization and stress response of lymphocytes, which might guide the future development of allogeneic transplantation.
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