Thymic Rejuvenation for the Induction of Transplantation Tolerance

描述(申请人提供)：小型猪为移植生物学研究提供了一种独特的临床前模型，包括最近获得的高度近亲繁殖的品系，在这种品系中，组织和器官可以在不需要免疫抑制的情况下成功移植。以前使用这个模型的研究已经证明，一个有功能的青少年胸腺对于通过用钙调神经磷酸酶抑制剂进行短疗程大剂量免疫抑制来诱导耐受具有重要意义。此外，我们最近发现，将老化、消退的胸腺作为带血管的胸腺叶(VTL)移植到匹配的、年轻的、切除胸腺的宿主体内，可以导致胸腺结构和功能的恢复，这意味着胸腺外部的宿主因素能够逆转胸腺退化。这项建议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角色，并利用这些信息来检验这样一种假设，即衰老的胸腺返老还童将允许成年动物通过对幼年动物有效的相同、简单的代谢学来诱导耐受性。具体地说，我们将1)使用带血管的胸腺叶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青少年胸腺状态的重要性；2)确定选定的受体细胞群在胸腺年轻化中的重要性；3)确定受体的特定激素和细胞因子在胸腺年轻化中的重要性；以及4)检测在这些实验中确定的最有希望的细胞和/或分子成分逆转胸腺结构性衰老的能力，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退化和再生中的作用的理论意义外，这些研究还可能对诱导成人移植耐受具有实际意义。 公共卫生相关性：在大型动物模型中的研究表明：1)通过短期免疫抑制药物诱导对带血管同种异体肾移植的耐受需要幼年胸腺；2)通过移植到年轻的受者体内，老年胸腺可以恢复到其幼年状态，这表明胸腺以外的因素对这种恢复起作用。这项建议旨在确定这些因素是什么，以便它们可以用来恢复成年动物的胸腺，从而使它们容易受到同样对青少年有效的简单治疗方案的耐受诱导。。

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. .