Testing time-, ignorance-, and danger-based models of tolerance
Testing time-, ignorance-, and danger-based models of tolerance
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DOI：
10.4049/jimmunol.166.6.3663
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发表时间：
2001-03-15
影响因子：
4.4
通讯作者：
Matzinger, P
中科院分区：
文献类型：
--
作者：
Anderson, CC;Carroll, JM;Matzinger, P
在这项研究中，我们提供的数据表明，外周对Ag的耐受性并不取决于Ag出现的时间，也不是由新生小鼠组织的特殊性质或新发育的免疫系统决定的。我们将雄性移植物放置在免疫功能不全的雌性小鼠身上，让移植物愈合长达5个月，然后用胎儿肝脏干细胞重新植入受体，我们发现新产生的T细胞既不耐受也不忽视移植物，而是立即排斥它们，尽管它们没有排斥雌性移植物，也没有表现出任何自身免疫的迹象。我们还发现H-Y Ag不断交叉呈递在宿主APC上，这种呈递是免疫原性的，而不是耐受性，并且它取决于移植物的持续存在。在寻找可能激活宿主 APC 的刺激物时，我们使用高度灵敏的实时定量 PCR 测定分析了 mRNA 表达，通过使用两种不同的“管家”分子进行比较，我们分析了愈合移植物中几种应激和/或炎症分子的信息水平。我们发现，长期愈合的移植物并不等同于“正常”皮肤，因为愈合的移植物表达的 GAPDH 水平较低。总而言之，这些数据表明，外周组织的接受与排斥并不归因于新生儿组织中幼稚 T 细胞的无知、基于时间的耐受性或特殊的循环特性。这更有可能归因于 Ag 呈现背景的一个方面仍有待确定。
In this study, we present data showing that tolerance to Ags in the periphery is not determined by the time at which the Ag appears, or by special properties of tissues in newborn mice or newly developing immune systems. We placed male grafts onto immunoincompetent female mice, allowed the grafts to heal for up to 5 mo, and then repopulated the recipients with fetal liver stem cells, We found that the newly arising T cells were neither tolerant nor ignorant of the grafts, but promptly rejected them, though they did not reject female grafts, nor show any signs of autoimmunity, We also found that the H-Y Ag was continuously cross-presented on host APCs, that this presentation was immunogenic, not tolerogenic, and that it depended on the continuous presence of the graft. In searching for the stimulus that might activate the host APCs, we analyzed mRNA expression with a highly sensitive real-time quantitative PCR assay, By using two different "housekeeping" molecules for comparison, we analyzed the message levels for several stress and/or inflammatory molecules in the healed grafts. We found that the long-healed grafts were not equivalent to "normal" skin because the healed grafts expressed lower levels of GAPDH. Altogether, these data suggest that acceptance vs rejection of peripheral tissues is not attributable to ignorance, timing-based tolerance, or special circulation properties of naive T cells in neonatal tissues. It is more likely attributable to an aspect of the context of Ag presentation that remains to be identified.