1 Centre for Transplant and Renal Research, The Westmead Institute for Medical Research, University of Sydney, Sydney, Australia. 2 Centre for Kidney Research, The Children's Hospital at Westmead, University of Sydney, Sydney, Australia.
Transplantation. 2017 Jul;101(7):1587-1599. doi: 10.1097/TP.0000000000001482.
Although islet xenotransplantation is a promising therapy for type 1 diabetes, its clinical application has been hampered by cellular rejection and the requirement for high levels of immunosuppression. The aim of this study was to determine the role of Foxp3 regulatory T (Treg) cells in costimulation blockade-induced dominant tolerance to porcine neonatal islet cell cluster (NICC) xenografts in mice.
Porcine-NICC were transplanted under the renal capsule of BALB/c or C57BL/6 recipients and given a single dose of CTLA4-Fc at the time of transplant and 4doses of anti-CD154 mAb to day 6. Depletion of Foxp3Treg cell was performed in DEpletion of REGulatory T cells mice at day 80 posttransplantation. Foxp3Treg cell from spleens of treated BALB/c mice (tolerant Treg cell), and splenocytes were cotransferred into islet transplanted nonobese diabetic background with severe combined immunodeficiency mice to assess suppressive function.
In treated mice, increased numbers of Foxp3Treg cell were identified in the porcine-NICC xenografts, draining lymph node, and spleen. Porcine-NICC xenografts from treated mice expressed elevated levels of TGF-β, IL-10 and IFN-γ. Porcine-NICC xenograft tolerance was abrogated after depletion of Foxp3Treg cell. Tolerant Treg cell produced high levels of IL-10 and had diverse T cell receptor Vβ repertoires with an oligoclonal expansion in CDR3 of T cell receptor Vβ14. These tolerant Treg cells had the capacity to transfer dominant tolerance and specifically exhibited more potent regulatory function to porcine-NICC xenografts that naive Treg cell.
This study demonstrated that short-term costimulation blockade-induced dominant tolerance and that Foxp3Treg cell played an essential role in its maintenance. Foxp3Treg cells were activated and had more potent regulatory function in vivo than naive Treg cells.
尽管胰岛异种移植是治疗 1 型糖尿病的一种很有前途的疗法，但由于细胞排斥反应和对高水平免疫抑制的需求，其临床应用受到了阻碍。本研究旨在确定 Foxp3 调节性 T（Treg）细胞在阻断共刺激诱导的猪新生胰岛细胞簇（NICC）异种移植物在小鼠中的优势耐受中的作用。
将猪-NICC 移植到 BALB/c 或 C57BL/6 受体的肾包膜下，并在移植时给予 CTLA4-Fc 单次剂量，并在第 6 天给予 4 剂抗 CD154 mAb。在移植后 80 天，用 DEpletion of REGulatory T cells 小鼠耗竭 Foxp3Treg 细胞。从经处理的 BALB/c 小鼠的脾脏中分离出 Foxp3Treg 细胞（耐受 Treg 细胞），并将其与非肥胖型糖尿病背景下的严重联合免疫缺陷小鼠的胰岛移植共转染，以评估其抑制功能。
在经处理的小鼠中，在猪-NICC 异种移植物、引流淋巴结和脾脏中鉴定出更多数量的 Foxp3Treg 细胞。来自处理过的小鼠的猪-NICC 异种移植物表达了更高水平的 TGF-β、IL-10 和 IFN-γ。在耗竭 Foxp3Treg 细胞后，猪-NICC 异种移植物的耐受性被破坏。耐受 Treg 细胞产生高水平的 IL-10，并且具有不同的 T 细胞受体 Vβ 谱，在 T 细胞受体 Vβ14 的 CDR3 中具有寡克隆扩增。这些耐受 Treg 细胞具有传递优势耐受的能力，并且对猪-NICC 异种移植物具有比幼稚 Treg 细胞更强的特异性调节功能。
本研究表明，短期阻断共刺激诱导的优势耐受，Foxp3Treg 细胞在其维持中发挥了重要作用。Foxp3Treg 细胞在体内被激活，并且具有比幼稚 Treg 细胞更强的调节功能。
