将白细胞介素-21中和纳米疗法靶向递送至淋巴结和肾脏同种异体移植物可减弱B细胞同种免疫。
Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.
作者信息
Zhang Hengcheng, Sabiu Gianmarco, Jung Sungwook, Podestà Manuel A, Zhao Jing, Gempler Maya, Yamamura Minako, Miao Jinxu, Tsokos George C, Karadagi Ahmad, Kawai Tatsuo, Abdi Reza, Sage Peter T
机构信息
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
出版信息
Kidney Int. 2025 Jul;108(1):48-56. doi: 10.1016/j.kint.2025.03.017. Epub 2025 Apr 21.
INTRODUCTION
Antibody-mediated rejection (ABMR) after allogeneic kidney transplantation is a substantial clinical problem for which there are no specific treatments. High endothelial venules (HEV) are specialized veins which are normally present only in lymph nodes (LN) facilitating immune cell entry. Here, we show that kidneys undergoing rejection develop HEV-like structures derived from host cells.
METHODS
We developed a nano-delivery system targeting HEVs to simultaneously deliver therapeutics to draining LN and kidney allografts.
RESULTS
Using this system, we preferentially delivered IL-21 neutralizing antibody (NP-HEV[αIL21]) to draining LN and kidney allografts resulting in improved graft function and recipient survival. The NP-HEV[αIL21] system also decreased alloreactive B cell responses, donor-specific antibody production, and ABMR-like lesions in kidney grafts.
CONCLUSIONS
Our study provides a therapeutic strategy to selectively target distinct effector sites to attenuate B-cell alloimmunity while limiting effects of broad systemic immunosuppression in kidney transplantation.
引言
同种异体肾移植后的抗体介导排斥反应（ABMR）是一个严重的临床问题，目前尚无特异性治疗方法。高内皮微静脉（HEV）是一种特殊的静脉，通常仅存在于淋巴结（LN）中，有助于免疫细胞进入。在此，我们表明发生排斥反应的肾脏会形成源自宿主细胞的类似HEV的结构。
方法
我们开发了一种靶向HEV的纳米递送系统，以同时将治疗药物递送至引流淋巴结和肾脏同种异体移植物。
结果
使用该系统，我们优先将IL-21中和抗体（NP-HEV[αIL21]）递送至引流淋巴结和肾脏同种异体移植物，从而改善了移植物功能并提高了受体存活率。NP-HEV[αIL21]系统还减少了同种异体反应性B细胞反应、供体特异性抗体产生以及肾移植中的ABMR样病变。
结论
我们的研究提供了一种治疗策略，可选择性地靶向不同的效应部位，以减弱B细胞同种异体免疫，同时限制肾移植中广泛全身免疫抑制的影响。
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