Guo W H, Tian L, Chan K L, Dallman M, Tam P K
Division of Pediatric Surgery, Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong SAR, P.R. China.
J Pediatr Surg. 2001 Feb;36(2):352-6. doi: 10.1053/jpsu.2001.20715.
BACKGROUND/PURPOSE: Results of small bowel transplantation remain unsatisfactory because of severe immune rejection. The current study aims to elucidate the role of activation of CD4+ and CD8+ T cells in early and late acute rejection of small bowel allograft and, hence, provide the immunologic basis for developing new therapeutic strategies.
We used an MHC fully mismatched (DA to Lewis) heterotopic rat small bowel transplant model and a unique FK506-based immunosuppressive regimen, which suppresses early acute rejection but does not prevent late acute rejection. Flow cytometric analysis was used to quantitate the number of activated CD4+ and CD8+ T cells in graft and host mesenteric lymph nodes.
The survival (mean +/- SD) of intestinal allograft was significantly prolonged, from 6.6 +/- 0.84 days for the untreated group to 40.7 +/- 14.1 days for the FK506-treated group. Activation of CD4+ cells was suppressed significantly in the FK506-treated group on postoperative day 7 compared with the untreated group (29.4% +/- 3.55% v 52.83% +/- 11.9%; P <.01). Activation of CD8+ cells was similarly suppressed (31.5 +/- 10.34% v 48.53 +/- 14.34%; P <.05). Interestingly, at late acute rejection, activated CD4+ and CD8+ T cells remained at almost the same low levels as those on postoperative day 7 in the FK506-treated group. The spleen to body weight ratio was significantly increased in the untreated group (0.53 +/- 0.07), and slightly increased in the FK treated group (0.27 +/- 0.07, on postoperative day 7; 0.24 +/- 0.07 at late acute rejection) compared with the syngeneic group (0.18 +/- 0.02).
The activation of CD4+ and CD8+ T cells was suppressed effectively by early potent immunosuppressive treatment resulting in prolonged survival of intestinal allograft. At late acute rejection, the CD4+ and CD8+ T cells remained at low-level activation status, in contrast to the surge of CD4+ and CD8+ activation during early acute rejection. This suggests that persistent T cell activation even at low level is sufficient to cause the late acute rejection eventually. A therapeutic strategy targeting these cells is needed for long-term engraftment.
背景/目的：由于严重的免疫排斥反应，小肠移植的结果仍不尽人意。本研究旨在阐明CD4+和CD8+T细胞活化在小肠同种异体移植早期和晚期急性排斥反应中的作用，从而为开发新的治疗策略提供免疫学依据。
我们使用了一种MHC完全不匹配（从DA系大鼠到Lewis系大鼠）的异位大鼠小肠移植模型以及一种独特的基于FK506的免疫抑制方案，该方案可抑制早期急性排斥反应，但不能预防晚期急性排斥反应。采用流式细胞术分析来定量移植肠和宿主肠系膜淋巴结中活化的CD4+和CD8+T细胞数量。
小肠同种异体移植的存活时间（均值±标准差）显著延长，未治疗组为6.6±0.84天，FK506治疗组为40.7±14.1天。与未治疗组相比，FK506治疗组在术后第7天CD4+细胞的活化受到显著抑制（29.4%±3.55%对52.83%±11.9%；P<0.01）。CD8+细胞的活化也同样受到抑制（31.5±10.34%对48.53±14.34%；P<0.05）。有趣的是，在晚期急性排斥反应时，FK506治疗组中活化的CD4+和CD8+T细胞水平几乎与术后第7天相同。与同基因组（0.18±0.02）相比，未治疗组的脾重比显著增加（0.53±0.07），FK治疗组略有增加（术后第7天为0.27±0.07；晚期急性排斥反应时为0.24±0.07）。
早期强效免疫抑制治疗可有效抑制CD4+和CD8+T细胞的活化，从而延长小肠同种异体移植的存活时间。在晚期急性排斥反应时，CD4+和CD8+T细胞保持低水平活化状态，这与早期急性排斥反应时CD4+和CD8+活化激增形成对比。这表明即使是低水平的持续性T细胞活化最终也足以导致晚期急性排斥反应。为实现长期移植，需要针对这些细胞的治疗策略。
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