Strategies to Prevent and Repair Thymic Microenvironment

预防和修复胸腺微环境的策略

• 批准号: 7068029
• 负责人: Bruce R Blazar
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068029
• 关键词: T cell receptor; biological signal transduction; bone marrow transplantation; cell proliferation; cellular immunity; confocal scanning microscopy; cytokine; cytotoxic T lymphocyte; cytotoxicity; enzyme linked immunosorbent assay; fibroblast growth factor; genetically modified animals; gonadotropin releasing factor; helper T lymphocyte; intracellular; laboratory mouse; polymerase chain reaction; radiation resistance; radiation therapy; recombinant proteins; terminal nick end labeling; thymus

DESCRIPTION (provided by applicant): Post-BMT immune deficiency causes significant morbidity and mortality in BMT recipients. Most recipients of T-cell replete matched sibling or unrelated donor HSC grafts experience late post-BMT infections, Strategies are urgently needed to speed thymopoietic recovery. A major cause of post-BMT immune deficiency is the loss of thymopoietic capacity. Normal thymopoiesis depends on the interaction of the thymic stroma-derived receptors and ligands. Damage to thymic epithelial cells (TEC) by pre-BMT conditioning impairs the ability of the thymus to generate mature T lymphocytes after BMT. Our overall hypothesis is that thymic microenvironmental injury is the major limiting factor responsible for slow T cell immune reconstitution and function, as indicated by the predisposition of the recipient to experience late infections post-BMT. Specific cytokines have been shown to regulate the development and proliferation of epithelial cells, key components in the thymic microenvironment which are needed for effective thymopoiesis. Keratinocyte growth factor (KGF) is one such cytokine. Based on the model that TEC are targets for BMT-associated thymic damage, we hypothesized that KGF pre-treatment would prevent TEC damage after BMT. Our preliminary data indicate this to be the case. In this proposal, we will explore the mechanism(s) responsible for the effects of KGF on facilitating thymopoiesis in BMT recipients. Inhibition of p53 has been shown to protect mice from the lethal genotoxic stress induced by conditioning regimen injury. Our preliminary data indicate a p53 inhibitor speeds thymopoietic recovery in lethally irradiated recipients of allogeneic TCD BM. We will determine whether KGF and p53 inhibitors operate on non-overlapping pathways and thus may be additive or synergistic in protecting TEC against injury. Thymopoiesis is well-known to decline with age, beginning after puberty. The thymic microenvironment is severely disrupted in aging and that blocking sex steroid production normalizes thymopoiesis. We propose to determine whether pre-BMT chemical blockade of sex steroid production using LHRH analogues (agonist or antagonist) will speed thymopoietic recovery in young or aged BMT recipients subjected to intensive conditioning injury. Our specific aims are: 1. To determine the thymopoietic and peripheral T cell immune functional effects of TEC sparing agents that target epithelial cell proliferation, inhibit apoptotic cell death, or block the negative regulatory effects of endogenous hormones that disrupt thymopoiesis; 2. To determine whether intracellular pathways required for thymic microenvironmental development or radiation resistance are essential for protecting the thymus from the effects of conditioning regimen injury. These data will lead to clinical trials designed to protect the thymic microenvironment against chemoradiotherapy injury and augment thymopoiesis.

描述(由申请人提供)： 骨髓移植后免疫缺陷会导致骨髓移植受者显著的发病率和死亡率。大多数T细胞完全相合的同胞或无关供者的HSC移植的受者都经历了骨髓移植后的晚期感染，迫切需要一些策略来加速胸腺的恢复。骨髓移植后免疫缺陷的一个主要原因是胸腺生成能力的丧失。正常的胸腺生成依赖于胸腺基质衍生受体和配体的相互作用。骨髓移植预适应对胸腺上皮细胞(TEC)的损伤会削弱骨髓移植后胸腺产生成熟T淋巴细胞的能力。我们的总体假设是，胸腺微环境损伤是导致T细胞免疫重建和功能缓慢的主要限制因素，这一点从受者在骨髓移植后经历晚期感染的易感性中可见一斑。特定的细胞因子已被证明调节上皮细胞的发育和增殖，上皮细胞是胸腺微环境中有效胸腺生成所需的关键成分。角质形成细胞生长因子(KGF)就是这样的细胞因子。基于TEC是BMT相关胸腺损伤的靶点的模型，我们假设KGF预处理可以预防BMT后TEC的损伤。我们的初步数据表明情况的确如此。在这项建议中，我们将探讨KGF促进骨髓移植受者胸腺生成的机制(S)。抑制P53已被证明可以保护小鼠免受条件性损伤诱导的致命性遗传毒性应激。我们的初步数据表明，P53抑制剂加速了同种异体TCD BM致死照射受者的胸腺生成恢复。我们将确定KGF和P53抑制剂是否在不重叠的通路上发挥作用，从而在保护TEC免受损伤方面可能是相加的或协同的。众所周知，胸腺生成会随着年龄的增长而下降，从青春期开始。随着年龄的增长，胸腺微环境会受到严重破坏，而阻滞性类固醇的产生会使胸腺生成正常化。我们建议确定在BMT前使用LHRH类似物(激动剂或拮抗剂)化学阻滞性类固醇的产生是否会加速遭受强烈条件性损伤的年轻或老年BMT受者的胸腺生成恢复。我们的具体目标是：1.确定TEC保留剂对胸腺生成和外周T细胞免疫功能的影响，这些药物针对上皮细胞增殖、抑制细胞凋亡或阻断内源性激素干扰胸腺生成的负性调节作用；2.确定胸腺微环境发育所需的细胞内途径或辐射抵抗是否对保护胸腺免受预适应方案的影响至关重要。这些数据将导致旨在保护胸腺微环境免受放化疗损伤并增强胸腺生成的临床试验。