Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.
Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.
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DOI：
10.1172/jci159672
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发表时间：
2022-12-15
影响因子：
15.9
通讯作者：
Abdi, Reza
中科院分区：
文献类型：
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作者：
Zhao, Jing;Jung, Sungwook;Li, Xiaofei;Li, Lushen;Kasinath, Vivek;Zhang, Hengcheng;Movahedi, Said N.;Mardini, Ahmad;Sabiu, Gianmarco;Hwang, Yoonha;Saxena, Vikas;Song, Yang;Ma, Bing;Acton, Sophie E.;Kim, Pilhan;Madsen, Joren C.;Sage, Peter T.;Tullius, Stefan G.;Tsokos, George C.;Bromberg, Jonathan S.;Abdi, Reza
淋巴结（LN）是移植过程中同种免疫激活和调节的主要部位。在这里，我们研究了成纤维网状细胞（FRC）如何促进抗CD 40 L诱导的小鼠心脏移植模型的耐受性。我们发现，LNs的缺乏和FRC耗竭都消除了抗CD 40 L在延长小鼠心脏移植物存活中的作用。在用抗CD 40 L治疗的心脏移植小鼠中，FRC的消耗损害了T细胞穿过高内皮微静脉（HEV）的归巢，并促进了LN中同种异体反应性T细胞的形成。LN的单细胞RNA测序显示，抗CD 40 L促进Madcam 1 + FRC亚群。FRC还促进体外调节性T细胞（Tcells）的形成。通过用MECA-79包被含有抗-CD 40 L的纳米颗粒（NP），将其选择性地递送至LN，MECA-79结合仅由HEV表达的外周淋巴结地址素（PNAd）糖蛋白。用这些MECA-79-抗-CD 40 L-NP治疗显著延迟心脏同种异体移植物排斥反应的发生并增加TclD的存在。最后，MECA-79-抗-CD 40 L-NPs和雷帕霉素联合治疗导致比可溶性抗-CD 40 L和雷帕霉素显著更长的同种异体移植物存活。这些数据表明，FRC是促进共刺激阻断的关键。LN靶向纳米递送抗CD 40 L可有效促进心脏移植物的接受。
The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79–anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79–anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.