Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, Tokyo, Japan.
Liver Transpl. 2012 Apr;18(4):444-54. doi: 10.1002/lt.22480.
Here we examined whether the expression of a novel immunoregulatory gene set could be used to predict outcomes in murine models of rapamycin-induced cardiac tolerance, spontaneous hepatic tolerance, and cardiac rejection. The expression of the immunoregulatory gene set was assessed with the GeXP multiplex reverse-transcription polymerase chain reaction (RT-PCR) analysis system, and it was correlated to the pathological and biochemical parameters of the allografts. In rejecting cardiac grafts, the increased expression of an inflammatory set of genes, which included CD45, CD4, CD25, suppressor of cytokine signaling 2, cytotoxic T lymphocyte-associated protein 4 (CTLA4), selectin lymphocyte, interferon-γ (IFN-γ), programmed cell death 1 (Pdcd1), and granzyme B (Gzmb), was seen 8 days after transplantation along with histological evidence of severe allograft rejection. In tolerant cardiac allografts, the expression of fibrinogen-like protein 2 (Fgl2), Pdcd1, killer cell lectin-like receptor G1 (Klrg1), CTLA4, and lymphocyte-activation gene 3 was associated with tolerance. In a model of liver allograft tolerance, the increased expression of lectin galactose-binding soluble 1, Fgl2, CD39, phosphodiesterase 3B, Klrg1, forkhead box P3 (Foxp3), and transforming growth factor β as well as the inflammatory set of genes was observed 8 to 14 days after transplantation (ie, when there was severe inflammatory injury). At a later time when the liver allografts had been fully accepted and were histologically normal, the expression of the inflammatory set of genes returned to the baseline, but the expression of the tolerogenic set of genes was still increased. Genes that were expressed in tolerant cardiac and liver allografts included Fgl2, Klrg1, and Foxp3, whereas genes associated with rejection included CD25, Gzmb, and IFN-γ. Our data indicate that monitoring the graft expression of a novel biomarker gene set with the GeXP multiplex RT-PCR analysis system may allow differentiation between rejection and tolerance.
在这里，我们研究了一组新型免疫调节基因的表达是否可用于预测雷帕霉素诱导的心脏耐受、自发性肝耐受和心脏排斥的小鼠模型中的结局。使用 GeXP 多重逆转录聚合酶链反应 (RT-PCR) 分析系统评估免疫调节基因的表达，并将其与同种异体移植物的病理和生化参数相关联。在排斥的心脏移植物中，在移植后 8 天观察到一组炎症基因的表达增加，包括 CD45、CD4、CD25、细胞因子信号转导抑制物 2、细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）、选择素淋巴细胞、干扰素-γ（IFN-γ）、程序性细胞死亡 1（Pdcd1）和颗粒酶 B（Gzmb），同时伴有严重同种异体移植物排斥的组织学证据。在耐受的心脏移植物中，纤维蛋白原样蛋白 2（Fgl2）、Pdcd1、杀伤细胞凝集素样受体 G1（Klrg1）、CTLA4 和淋巴细胞激活基因 3 的表达与耐受相关。在肝移植耐受模型中，在移植后 8 至 14 天观察到凝集素半乳糖结合可溶性 1、Fgl2、CD39、磷酸二酯酶 3B、Klrg1、叉头框 P3（Foxp3）和转化生长因子-β以及炎症基因的表达增加（即在严重炎症损伤时）。在稍后的时间，当肝移植物已被完全接受且组织学正常时，炎症基因的表达恢复到基线，但耐受基因的表达仍在增加。在耐受的心脏和肝移植物中表达的基因包括 Fgl2、Klrg1 和 Foxp3，而与排斥相关的基因包括 CD25、Gzmb 和 IFN-γ。我们的数据表明，使用 GeXP 多重 RT-PCR 分析系统监测新型生物标志物基因的移植表达可能有助于区分排斥和耐受。
