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在血管化复合组织同种异体移植中,调节性 T 细胞的原位募集促进了供体特异性耐受。

In situ recruitment of regulatory T cells promotes donor-specific tolerance in vascularized composite allotransplantation.

机构信息

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.

Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA.

出版信息

Sci Adv. 2020 Mar 13;6(11):eaax8429. doi: 10.1126/sciadv.aax8429. eCollection 2020 Mar.

Abstract

Vascularized composite allotransplantation (VCA) encompasses face and limb transplantation, but as with organ transplantation, it requires lifelong regimens of immunosuppressive drugs to prevent rejection. To achieve donor-specific immune tolerance and reduce the need for systemic immunosuppression, we developed a synthetic drug delivery system that mimics a strategy our bodies naturally use to recruit regulatory T cells (T) to suppress inflammation. Specifically, a microparticle-based system engineered to release the T-recruiting chemokine CCL22 was used in a rodent hindlimb VCA model. These "Recruitment-MP" prolonged hindlimb allograft survival indefinitely (>200 days) and promoted donor-specific tolerance. Recruitment-MP treatment enriched T populations in allograft skin and draining lymph nodes and enhanced T function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human T in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive T.

摘要

血管化复合组织同种异体移植(VCA)包括面部和肢体移植,但与器官移植一样,它需要终身使用免疫抑制药物来预防排斥反应。为了实现供体特异性免疫耐受并减少对全身免疫抑制的需求,我们开发了一种合成药物输送系统,该系统模拟了我们的身体自然利用招募调节性 T 细胞(T 细胞)来抑制炎症的策略。具体而言,使用基于微粒的系统来释放招募 T 细胞的趋化因子 CCL22,该系统用于啮齿动物后肢 VCA 模型。这些“招募-MP”可无限期延长后肢同种异体移植物的存活时间(>200 天),并促进供体特异性耐受。Recruitment-MP 治疗使移植物皮肤和引流淋巴结中的 T 细胞群富集,并增强了 T 细胞的功能,而不会影响常规 T 细胞的增殖能力。具有临床转化意义的是,合成的人 CCL22 诱导体外人 T 细胞的优先迁移。总的来说,这些结果表明,Recruitment-MP 通过局部富集抑制性 T 细胞来促进供体特异性免疫耐受。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8247/7069700/1502679472d8/aax8429-F1.jpg

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