Thymic Rejuvenation for the Induction of Transplantation Tolerance

胸腺复兴诱导移植耐受

• 批准号: 8011723
• 负责人: DAVID H SACHS
• 金额: $ 41.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011723
• 关键词: Activities of Daily Living; Adolescent; Adult; Age; Aging; Allogenic; Animal Model; Animals; Biological Assay; Biology; Bone Marrow; Brothers; Calcineurin inhibitor; Cells; Clinical; Cyclosporins; Data; Dose; Elements; Environment; Goals; Histologic; Home environment; Hormonal; Hormones; Human; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; Inbred Strain; Inbreeding; Indium; Individual; Insulin-Like Growth Factor I; Integration Host Factors; Interleukin-7; Kidney; Laboratory Study; Lead; Lobe; Marrow; Measures; Methodology; Miniature Swine; Modeling; Molecular; Natural regeneration; Organ; Organ Transplantation; Pharmaceutical Preparations; Physiology; Population; Pre-Clinical Model; Predisposition; Process; Protocols documentation; Recombinants; Rejuvenation; Relative (related person); Research; Rodent; Role; Sister; Skin Transplantation; Skin graft; Structure; Techniques; Testing; Thymic Tissue; Thymus Gland; Time; Tissue Transplantation; Transplantation; Transplantation Tolerance; Treatment Protocols; aged; capsule; cytokine; design; juvenile animal; kidney allograft; mature animal; pre-clinical; public health relevance; reconstitution; research study; thymus transplantation

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. .

描述（由申请人提供）：微型猪提供了一种独特的临床前模型，用于研究移植生物学的研究，包括最近的高度近交菌株的可用性，其中可以成功地进行组织和器官的成功移植而无需免疫抑制。先前使用该模型的研究证明了功能性的，少年胸腺对通过钙调蛋白抑制剂的短剂量免疫抑制的诱导诱导耐受性的重要性。此外，我们最近表明，老化的胸腺作为血管化的胸腺叶（VTL）移植到匹配的，幼年，胸腺切除术的宿主中导致胸腺结构和功能性重新化，这暗示着宿主因胸腺的外观因素而有能力逆转甲状腺。该提案的主要目的是确定导致恢复活力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：老化的胸腺的再生能力将允许耐受性通过相同的，简单的动物学诱导成人动物，从而有效地有效，这是有效的幼年动物。具体而言，我们将使用血管化的胸腺叶移植模型建立基线测定法进行胸腺相关性和复兴，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种群在胸腺复兴中的重要性； 3）确定受体在胸腺复兴中选定的激素和细胞因子的重要性； 4）检查在这些实验中鉴定出的最有希望的细胞和/或分子成分逆转结构性胸腺衰老的能力，从而允许在成年动物中诱导耐受性。除了更好地理解外在因素对胸腺确定胸腺侵入和恢复活力的作用的理论意义外，这些研究可能对成人诱导移植耐受性具有实际意义。 公共卫生相关性：大型动物模型中的研究证明：1）通过短暂的免疫抑制药物诱导对血管化同种异体移植的耐受性需要少年胸腺； 2）可以通过移植到年轻的接受者将老化的百里香恢复到其少年状态，这表明胸腺之外的因素是造成这种恢复活力的原因。该提案针对确定这些因素是什么，以便它们可以用来使成年动物的胸腺恢复活力，从而使它们容易受到与少年有效的简单治疗方案的耐受性诱导。 。