Thymic Rejuvenation for the Induction of Transplantation Tolerance

描述（由申请人提供）：微型猪为移植生物学研究提供了一种独特的临床前模型，包括最近可用的高度近交系，可以在不需要免疫抑制的情况下实现组织和器官的成功移植。先前使用该模型的研究已经证明了功能性幼年胸腺对钙调磷酸酶抑制剂短期高剂量免疫抑制诱导耐受性的重要性。此外，我们最近的研究表明，将一个年老的、纠缠的胸腺作为血管化的胸腺叶（VTL）移植到一个匹配的、幼年的、胸腺去核化的宿主体内，可以导致胸腺的结构和功能再生，这意味着胸腺外部的宿主因素能够逆转胸腺的纠缠。本提案的主要目的是确定负责返老还童的细胞和体液宿主元素，确定它们在这一过程中的相对作用，并利用这些信息来验证一个假设，即衰老胸腺的返老还童将允许通过对幼年动物有效的相同的简单方法在成年动物中诱导耐受性。具体来说，我们将1)利用带血管的胸腺瓣移植模型建立胸腺退化和年轻化的基线分析，并确定宿主环境对诱导和维持幼年胸腺状态的重要性；2)确定选定的受体细胞群在胸腺再生中的重要性；3)确定受体选定的激素和细胞因子在胸腺再生中的重要性；4)检查在这些实验中发现的最有希望的细胞和/或分子成分的能力，以逆转结构胸腺老化，从而允许在成年动物中诱导耐受性。除了更好地理解胸腺外部因素在决定胸腺复旧和再生中的作用的理论意义外，这些研究可能对成人移植耐受的诱导具有实际意义。

DESCRIPTION (provided by applicant): Miniature swine provide a unique preclinical model for studies of transplantation biology, including the recent availability of a highly inbred strain, in which successful transplantation of tissues and organs can be achieved without the need for immunosuppression. Previous studies using this model have demonstrated the importance of a functional, juvenile thymus for the induction of tolerance by a short course of high-dose immunosuppression with calcineurin inhibitors. In addition, we have recently shown that transplantation of an aged, involuted thymus as a vascularized thymic lobe (VTL) graft into a matched, juvenile, thymectomized host leads to both structural and functional rejuvenation of the thymus, implying that host factors extrinsic to the thymus are capable of reversing thymic involution. The major objective of this proposal is to identify cellular and humoral host elements responsible for rejuvenation, determine their relative roles in this process, and use this information to test the hypothesis that rejuvenation of an aged thymus will allow tolerance to be induced in adult animals by the same, simple metodology that has been effective for juvenile animals. Specifically, we will 1) establish baseline assays for thymic involution and rejuvenation using the vascularized thymic lobe transplantation model and determine the importance of the host environment for inducing and maintaining the juvenile thymic state; 2) determine the importance of selected recipient cell populations in thymic rejuvenation; 3) determine the importance of selected hormones and cytokines of the recipient in thymic rejuvenation; and 4) examine the ability of the most promising cellular and/or molecular components identified in these experiments to reverse structural thymic aging and thereby permit tolerance to be induced in adult animals. In addition to the theoretical implications of a better understanding of the role of factors extrinsic to the thymus in determining thymic involution and rejuvenation, these studies could have practical implications for the induction of transplantation tolerance in adults. PUBLIC HEALTH RELEVANCE: Studies in a large animal model have demonstrated: 1) that a juvenile thymus is required for the induction of tolerance to vascularized renal allografts by a short course of immunosuppressive drugs; and 2) that the aged thymus can be restored to its juvenile state by transplantation into a young recipient, indicating that factors outside of the thymus are responsible for this rejuvenation. This proposal is directed toward determining what these factors are so that they may be used to rejuvenate the thymus of adult animals and thereby render them susceptible to tolerance induction by the same simple treatment regimen that is effective in juveniles. .