Thymic Rejuvenation for the Induction of Transplantation Tolerance

描述（由申请方提供）：小型猪为移植生物学研究提供了独特的临床前模型，包括最近获得的高度近交系，其中可以在不需要免疫抑制的情况下成功移植组织和器官。先前使用该模型的研究已经证明了功能性幼年胸腺对于通过钙调磷酸酶抑制剂的短疗程高剂量免疫抑制诱导耐受的重要性。此外，我们最近表明，移植一个老年人，退化的胸腺作为血管化胸腺叶（ESTA）移植到一个匹配的，青少年，胸腺切除主机导致结构和功能的复兴的胸腺，这意味着宿主因素的外在胸腺能够逆转胸腺退化。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，确定其在此过程中的相对作用，并使用此信息来检验以下假设：通过对幼龄动物有效的相同简单方法，使老龄胸腺返老还童将允许在成年动物中诱导耐受性。具体而言，我们将1）使用血管化胸腺叶移植模型建立胸腺退化和复壮的基线测定，并确定宿主环境对于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体在胸腺复壮中的重要性; 3）确定选定的受体激素和细胞因子在胸腺复壮中的重要性;和4）检查在这些实验中鉴定的最有希望的细胞和/或分子组分逆转胸腺结构老化并由此允许在成年动物中诱导耐受性的能力。除了更好地理解胸腺外在因素在确定胸腺退化和恢复活力中的作用的理论意义外，这些研究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已经证明：1）幼年胸腺是通过短期免疫抑制药物诱导对血管化肾同种异体移植物的耐受所必需的; 2）衰老的胸腺可以通过移植到年轻的受体中恢复到其幼年状态，这表明胸腺外的因素是导致这种再生的原因。该建议旨在确定这些因素是什么，以便它们可用于恢复成年动物的胸腺，从而使它们易于通过在青少年中有效的相同简单治疗方案诱导耐受性。.

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. .