Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Transplantation. 2019 Nov;103(11):e334-e344. doi: 10.1097/TP.0000000000002911.
Renal allograft tolerance (TOL) has been successfully induced in nonhuman primates (NHPs) and humans through the induction of transient mixed chimerism. To elucidate the mechanisms of TOL, we compared local immunologic responses in renal allografts with those in T-cell-mediated rejection (TCMR) and chronic antibody-mediated rejection (CAMR) in NHPs.
Using the NanoString nCounter platform, we retrospectively studied 52 mRNAs in 256 kidney allograft samples taken from NHP kidney recipients of donor BMT. No immunosuppression was given after 1-month post-donor BMT. Recipients who achieved TOL (n = 13) survived for >1840 ± 1724 days with normal kidney function, while recipients with CAMR (n = 13) survived for 899 ± 550 days with compromised graft function, and recipients with TCMR (n = 15) achieved only short-term survival (132 ± 69 days).
The most prominent difference between the groups was FOXP3, which was significantly higher in TOL than in CAMR and TCMR, both early (<1 y, P < 0.01) and late (≥1 y, P < 0.05) after transplant. Other mRNAs related to regulatory T cells (Treg), such as IL10, TGFB, and GATA3, were also high in TOL. In contrast, transcripts of inflammatory cytokines were higher in TCMR, while activated endothelium-associated transcripts were higher in CAMR than in TOL. The receiver operating characteristic analyses revealed that intragraft FOXP3 and CAV1 can reliably distinguish TOL from CAMR.
High FOXP3 and other Treg-related mRNAs together with suppressed inflammatory responses and endothelial activation in renal allografts suggest that intragraft enrichment of Treg is a critical mechanism of renal allograft TOL induced by transient mixed chimerism.
通过诱导短暂的混合嵌合体，已成功在非人类灵长类动物（NHPs）和人类中诱导肾移植耐受（TOL）。为了阐明 TOL 的机制，我们比较了肾移植中的局部免疫反应与 NHPs 中的 T 细胞介导的排斥反应（TCMR）和慢性抗体介导的排斥反应（CAMR）。
使用 NanoString nCounter 平台，我们回顾性研究了 52 个 NHPs 肾移植受者的 256 个肾移植样本中的 52 个 mRNA。在接受供体 BMT 后 1 个月后未给予免疫抑制。实现 TOL（n=13）的受者存活时间超过 1840±1724 天，肾功能正常，而发生 CAMR（n=13）的受者存活时间为 899±550 天，移植肾功能受损，发生 TCMR（n=15）的受者仅存活短期（132±69 天）。
各组之间最显著的差异是 FOXP3，TOL 中的 FOXP3 明显高于 CAMR 和 TCMR，移植后早期（<1 年，P<0.01）和晚期（≥1 年，P<0.05）均如此。其他与调节性 T 细胞（Treg）相关的 mRNAs，如 IL10、TGFB 和 GATA3，在 TOL 中也较高。相比之下，TCMR 中的炎症细胞因子转录本较高，而 CAMR 中的活化内皮相关转录本高于 TOL。受试者工作特征分析显示，移植肾内 FOXP3 和 CAV1 可可靠地区分 TOL 与 CAMR。
移植肾内 FOXP3 和其他 Treg 相关 mRNAs 以及抑制的炎症反应和内皮细胞活化表明，短暂混合嵌合体诱导肾移植 TOL 的关键机制是移植肾内 Treg 的富集。
