Strategies to Prevent and Repair Thymic Microenvironment

预防和修复胸腺微环境的策略

• 批准号: 6764088
• 负责人: Bruce R Blazar
• 金额: $ 37.13万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764088
• 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）： BMT 后免疫缺陷会导致 BMT 接受者显着的发病率和死亡率。大多数 T 细胞充足的匹配同胞或无关供体 HSC 移植物的接受者都会经历 BMT 后晚期感染，迫切需要加速胸腺生成恢复的策略。 BMT 后免疫缺陷的一个主要原因是胸腺生成能力的丧失。正常的胸腺生成取决于胸腺基质衍生的受体和配体的相互作用。 BMT 前调理对胸腺上皮细胞 (TEC) 的损伤会损害 BMT 后胸腺生成成熟 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，正如接受者在 BMT 后经历晚期感染的倾向所表明的那样。特定的细胞因子已被证明可以调节上皮细胞的发育和增殖，上皮细胞是有效胸腺生成所需的胸腺微环境的关键成分。角质形成细胞生长因子（KGF）就是这样的一种细胞因子。基于 TEC 是 BMT 相关胸腺损伤目标的模型，我们假设 KGF 预处理可以预防 BMT 后的 TEC 损伤。我们的初步数据表明情况确实如此。在本提案中，我们将探讨 KGF 对促进 BMT 接受者胸腺生成作用的机制。 p53 的抑制已被证明可以保护小鼠免受预处理方案损伤引起的致命性基因毒性应激。我们的初步数据表明，p53 抑制剂可加速同种异体 TCD BM 致命辐射受体的胸腺生成恢复。我们将确定 KGF 和 p53 抑制剂是否在非重叠途径上起作用，因此在保护 TEC 免受损伤方面可能具有累加或协同作用。众所周知，胸腺生成能力会随着年龄的增长而下降，从青春期后开始。胸腺微环境在衰老过程中受到严重破坏，阻止性类固醇的产生可以使胸腺生成正常化。我们建议确定在 BMT 前使用 LHRH 类似物（激动剂或拮抗剂）化学阻断性类固醇产生是否会加速遭受强化调理损伤的年轻或老年 BMT 接受者的胸腺生成恢复。我们的具体目标是： 1. 确定针对上皮细胞增殖、抑制细胞凋亡或阻断破坏胸腺生成的内源性激素的负调节作用的 TEC 保留剂对胸腺生成和外周 T 细胞免疫功能的影响； 2. 确定胸腺微环境发育或抗辐射所需的细胞内途径对于保护胸腺免受调理方案损伤的影响是否至关重要。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。