Heterologous immunity provides a potent barrier to transplantation tolerance
Heterologous immunity provides a potent barrier to transplantation tolerance
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DOI：
10.1172/jci200317477
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发表时间：
2003-06-01
影响因子：
15.9
通讯作者：
Larsen, CP
中科院分区：
文献类型：
--
作者：
Adams, AB;Williams, MA;Larsen, CP
已经提出了许多策略来诱导啮齿动物对移植组织的耐受性;然而，当在非人灵长类动物移植模型中进行测试时，很少（如果有的话）显示出同等的功效。我们假设，无特定病原体的小鼠与非人灵长类动物或人类患者之间的关键区别是它们的获得性免疫史。在这里，我们表明，异源性免疫反应，特别是重要的诱导同种异体反应性记忆是一个有效的屏障耐受诱导。需要记忆T细胞的临界阈值来促进排斥反应，而CD 8（+）“中央”记忆T细胞是主要负责的。最后，用脱氧精胍菌素（一种NF-κ B易位抑制剂）与共刺激阻断一起治疗，协同损害记忆T细胞活化并促进记忆的抗原特异性耐受。这些数据为在非人灵长类动物和人类患者中诱导耐受时遇到的困难提供了潜在的解释，并为记忆T细胞活化和功能所必需的信号通路提供了深入了解。
Many strategies have been proposed to induce tolerance to transplanted tissue in rodents; however, few if any have shown equal efficacy when tested in nonhuman primate transplant models. We hypothesized that a critical distinction between specific pathogen-free mice and nonhuman primates or human patients is their acquired immune history. Here, we show that a heterologous immune response-specifically, vitally induced alloreactive memory-is a potent barrier to tolerance induction. A critical threshold of memory T cells is needed to promote rejection, and CD8(+) "central" memory T cells are primarily responsible. Finally, treatment with deoxyspergualin, an inhibitor of NF-kappaB translocation, together with costimulation blockade, synergistically impairs memory T cell activation and promotes antigen-specific tolerance of memory. These data offer a potential explanation for the difficulty encountered when inducing tolerance in nonhuman primates and human patients and provide insight into the signaling pathways essential for memory T cell activation and function.