Satoda Naoki, Shoji Tsuyoshi, Wu Yanling, Fujinaga Takuji, Chen Fengshi, Aoyama Akihiro, Zhang Ji Tian, Takahashi Ayuko, Okamoto Toshihiro, Matsumoto Izumi, Sakai Hiroaki, Li Ying, Zhao Xiangdong, Manabe Toshiaki, Kobayashi Eiji, Sakaguchi Shimon, Wada Hiromi, Ohe Hidenori, Uemoto Shinji, Tottori Junichi, Bando Toru, Date Hiroshi, Koshiba Takaaki
Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.
J Heart Lung Transplant. 2008 Dec;27(12):1293-301. doi: 10.1016/j.healun.2008.08.006.
Outcome for highly immunogenic lung transplantation remains unsatisfactory despite the development of potent immunosuppressants. The poor outcome may be the result of a lack of minimally invasive methods to detect early rejection. There is emerging clinical evidence that, paradoxically, expression of forkhead box P3 (FOXP3, a specific marker for the regulatory T cells) is upregulated within rejecting grafts.
Orthotopic lung transplantation was performed using miniature swine without immunosuppression. Rejection was monitored by chest radiography and open lung biopsy. Expressions levels of FOXP3, perforin, Fas-L and IP-10 mRNA were quantified in the peripheral blood. In addition, rescue immunosuppressive therapy (steroid plus tacrolimus) was administered on post-operative day (POD) 4 or 6.
Early rejection was detected by open lung biopsy, but misdiagnosed by chest radiography on POD 4. Expression of FOXP3 in the peripheral blood reached its highest value as early as POD 4, followed by a decline. Such an increase of FOXP3 was not observed in recipients given high-dose tacrolimus. Neither perforin, Fas-L or IP-10 in the peripheral blood exhibited significant fluctuations in the early phase of rejection. Rescue immunosuppressive therapy from POD 4, when peak FOXP3 was seen, prolonged graft survival (27.2 days, versus 9.1 days without immunosuppression, p < 0.001), in contrast to POD 6, when rejection was suspected by chest radiography (11.5 days, p = not statistically significant [NS]).
In a miniature swine lung transplantation model, the FOXP3 mRNA level in the peripheral blood was upregulated at an early phase of rejection. The clinical implication of this finding remains to be elucidated.
尽管强效免疫抑制剂不断发展，但高免疫原性肺移植的结果仍不尽人意。结果不佳可能是由于缺乏检测早期排斥反应的微创方法。有新出现的临床证据表明，矛盾的是，叉头框P3（FOXP3，调节性T细胞的特异性标志物）在排斥的移植物中表达上调。
在未进行免疫抑制的小型猪中进行原位肺移植。通过胸部X线摄影和开胸肺活检监测排斥反应。对外周血中FOXP3、穿孔素、Fas-L和IP-10 mRNA的表达水平进行定量。此外，在术后第4天或第6天给予挽救性免疫抑制治疗（类固醇加他克莫司）。
通过开胸肺活检检测到早期排斥反应，但在术后第4天被胸部X线摄影误诊。外周血中FOXP3的表达最早在术后第4天达到最高值，随后下降。在给予高剂量他克莫司的受者中未观察到FOXP3的这种增加。外周血中的穿孔素、Fas-L或IP-10在排斥反应的早期均未表现出明显波动。在FOXP3达到峰值的术后第4天开始进行挽救性免疫抑制治疗，可延长移植物存活时间（27.2天，而未进行免疫抑制时为9.1天，p<0.001），与之形成对比的是在胸部X线摄影怀疑有排斥反应的术后第6天开始治疗（11.5天，p=无统计学意义[NS]）。
在小型猪肺移植模型中，外周血中FOXP3 mRNA水平在排斥反应早期上调。这一发现的临床意义仍有待阐明。
