Apoptosis within spontaneously accepted mouse liver allografts: evidence for deletion of cytotoxic T cells and implications for tolerance induction.
Apoptosis within spontaneously accepted mouse liver allografts: evidence for deletion of cytotoxic T cells and implications for tolerance induction.
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DOI：
10.4049/jimmunol.158.10.4654
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发表时间：
1997-05
影响因子：
4.4
通讯作者：
S. Qian;Una Lu;F. Fu;Youping Li;Wei Li;T. Starzl;J. Fung;A. Thomson
中科院分区：
文献类型：
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作者：
S. Qian;Una Lu;F. Fu;Youping Li;Wei Li;T. Starzl;J. Fung;A. Thomson
MHC 不匹配的肝移植物可以在许多小鼠品系之间自发接受。根本机制尚不清楚。在本研究中使用的 B10 (H2(b)) 至 C3H (H2(k)) 菌株组合中，肝脏内的供体 T 细胞在移植后 2 至 4 天内迅速被受体 T 细胞取代。第 4 天和第 7 天收获的新鲜分离的肝移植浸润细胞表现出针对供体同种异体抗原的强烈 CTL 反应。然而，到第 14 天，CTL 活性大幅降低，尽管脾脏和肝脏中的 CTL 前体水平仍然很高。移植后第 4、7 和 14 天，通过原位末端脱氧核苷酸转移酶催化的 dUTP-地高辛缺口末端标记对肝脏同种异体移植物进行检查，发现明显的凋亡细胞分散在整个非实质细胞群中。当移植后第0天至第4天（中位生存时间，5天）施用IL-2诱导急性同种异体肝移植排斥时，细胞凋亡活性（第4天）显着降低，而CTL活性增强。移植后 4、7 和 14 天，从未修饰受体的同种异体移植物中分离出的非实质细胞在培养 18 小时后表现出比来自同种肝脏移植物的细胞显着更高的 DNA 断裂。此外，该水平比 IL-2 治疗小鼠的细胞（第 4 天）高 4 至 5 倍。这些观察结果表明，T 细胞缺失而非调节可能是自发性肝同种异体移植接受的原因。导致浸润性 T 细胞凋亡的分子识别事件以及为什么这种情况发生在肝移植物而不是心脏或皮肤移植物中，仍有待阐明。
MHC-mismatched liver grafts are accepted spontaneously between many mouse strains. The underlying mechanism(s) is unclear. In the B10 (H2(b)) to C3H (H2(k)) strain combination used in this study, donor T cells within the liver were rapidly replaced within 2 to 4 days of transplantation with those of the recipient. Freshly isolated liver graft-infiltrating cells harvested on days 4 and 7 exhibited strong CTL responses against donor alloantigens. CTL activity was reduced substantially, however, by day 14, although levels of CTL precursors in the spleen and liver remained high. Examination of the liver allografts by in situ terminal deoxynucleotidyltransferase-catalyzed dUTP-digoxigenin nick end labeling on days 4, 7, and 14 after transplantation revealed prominent apoptotic cells dispersed throughout the nonparenchymal cell population. When acute liver allograft rejection was induced by administration of IL-2 from days 0 to 4 post-transplant (median survival time, 5 days), apoptotic activity (day 4) was reduced substantially, whereas CTL activity was enhanced. Nonparenchymal cells isolated from allografts of unmodified recipients 4, 7, and 14 days after transplantation exhibited significantly higher DNA fragmentation after 18-h culture than cells from liver isografts. Moreover, the level was 4 to 5 times higher than that of cells from IL-2-treated mice (on day 4). These observations suggest that T cell deletion, not regulation, may be responsible for spontaneous liver allograft acceptance. The molecular recognition events that cause apoptosis of infiltrating T cells and why this occurs within liver grafts, but not heart or skin grafts, remain to be elucidated.