Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA.
Sci Adv. 2020 Mar 13;6(11):eaax8429. doi: 10.1126/sciadv.aax8429. eCollection 2020 Mar.
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.
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。
