靶向递送IL-21中和纳米疗法到淋巴结和肾同种异体移植物减弱B细胞同种免疫。

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international Pub Date : 2025-04-21 DOI:10.1016/j.kint.2025.03.017

Hengcheng Zhang,Gianmarco Sabiu,Sungwook Jung,Manuel A Podestà,Jing Zhao,Maya Gempler,Minako Yamamura,Jinxu Miao,George C Tsokos,Ahmad Karadagi,Tatsuo Kawai,Reza Abdi,Peter T Sage

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引用次数: 0

摘要

同种异体肾移植后抗体介导的排斥反应（ABMR）是一个重大的临床问题，目前尚无专门的治疗方法。高内皮小静脉（HEV）是一种特化的静脉，通常只存在于淋巴结（LN），促进免疫细胞进入。在这里，我们展示了遭受排斥的肾脏产生来自宿主细胞的hev样结构。方法：我们开发了一种靶向hev的纳米递送系统，可同时向引流LN和同种异体肾脏移植物递送治疗药物。结果使用该系统，我们优先将IL-21中和抗体（NP-HEV[aIL21]）递送到引流LN和肾异体移植物中，从而改善移植物功能和受体存活率。NP-HEV[aIL21]系统还降低了移植肾中的同种异体反应性B细胞反应、供者特异性抗体的产生和abmr样病变。结论我们的研究提供了一种治疗策略，可以选择性地靶向不同的效应位点来减弱b细胞异体免疫，同时限制肾移植中广泛的全身免疫抑制的影响。

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Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.

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[ aIL21] ) to draining LN and kidney allografts resulting in improved graft function and recipient survival. The NP-HEV[aIL21] system also decreased alloreactive B cell responses, donor-specific antibody production, and ABMR-like lesions in kidney grafts. CONCLUSION 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.

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来源期刊

Kidney international 医学-泌尿学与肾脏学

CiteScore

23.30

自引率

3.10%

发文量

490

审稿时长

3-6 weeks

期刊介绍： Kidney International (KI), the official journal of the International Society of Nephrology, is led by Dr. Pierre Ronco (Paris, France) and stands as one of nephrology's most cited and esteemed publications worldwide. KI provides exceptional benefits for both readers and authors, featuring highly cited original articles, focused reviews, cutting-edge imaging techniques, and lively discussions on controversial topics. The journal is dedicated to kidney research, serving researchers, clinical investigators, and practicing nephrologists.