Thymic rejuvenation and the induction of tolerance by adult thymic grafts
Thymic rejuvenation and the induction of tolerance by adult thymic grafts
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DOI：
10.1073/pnas.0605159103
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发表时间：
2006-12-12
影响因子：
11.1
通讯作者：
Yamada, Kazuhiko
中科院分区：
文献类型：
--
作者：
Nobori, Shuji;Shimizu, Akira;Yamada, Kazuhiko
胸腺是 T 细胞免疫的起源部位，通过正向选择发育中的 T 细胞来塑造 T 细胞反应性，并通过负向选择自身反应性 T 细胞来预防自身免疫。先前的研究表明，胸腺不仅在中枢缺失耐受中发挥着重要作用，而且在幼年小型猪受体中血管化肾同种异体移植物诱导外周耐受中也发挥着重要作用。相同的方案不会在胸腺切除的受者中或在超过胸腺复旧年龄的受者中诱导耐受性。我们随后报道，来自幼年供体的血管化胸腺叶移植物能够在胸腺切除的幼年宿主中诱导耐受性。然而，重要的问题仍然是，如果将衰老的、退化的胸腺移植到胸腺切除的宿主中，是否也可以诱导耐受性，如果这是真的，则意味着胸腺退化不是胸腺组织的内在特性，而是由胸腺外在的宿主因素决定。我们在此报告，将衰老的、退化的胸腺作为血管移植物移植到幼年受体中，导致胸腺结构和功能的复兴，这表明胸腺外在的因素能够恢复老年受体的幼年胸腺功能。我们进一步表明，恢复活力的老化胸腺能够诱导跨 I 类 MHC 屏障的移植耐受。这些发现表明，在胸腺退化年龄后，可能可以操纵成人的胸腺功能来诱导移植耐受。
The thymus, the site of origin of T cell immunity, shapes the repertoire of T cell reactivity through positive selection of developing T cells and prevents autoimmunity through negative selection of autoreactive T cells. Previous studies have demonstrated an important role for the thymus not only in central deletional tolerance, but also in the induction of peripheral tolerance by vascularized renal allografts in juvenile miniature swine recipients. The same protocol did not induce tolerance in thymectomized recipients nor in recipients beyond the age of thymic involution. We subsequently reported that vascularized thymic lobe grafts from juvenile donors were capable of inducing tolerance in thymectomized juvenile hosts. However, the important question remained whether aged, involuted thymus could also induce tolerance if transplanted into thymectomized hosts, which, if true, would imply that thymic involution is not an intrinsic property of thymic tissue but is rather determined by host factors extrinsic to the thymus. We report here that aged, involuted thymus transplanted as a vascularized graft into juvenile recipients leads to rejuvenation of both thymic structure and function, suggesting that factors extrinsic to the thymus are capable of restoring juvenile thymic function to aged recipients. We show furthermore that rejuvenated aged thymus has the ability to induce transplant tolerance across class I MHC barriers. These findings indicate that it may be possible to manipulate thymic function in adults to induce transplantation tolerance after the age of thymic involution.