Role of the thymic epithelium on the outcome of allogeneic transplantation

胸腺上皮对同种异体移植结果的作用

基本信息

批准号：
8308335
负责人：
KONSTANTINA ALEXANDROPOULOS
金额：
$ 42.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308335
关键词：
Allogeneic Bone Marrow Transplantation Allogenic Animal Model Animals Autoantigens Autoimmune Process Autoimmunity Biochemical Biological Preservation Blood Cell Maturation Cells Cellular Immunity Cellularity Clinical Development Disease Epithelial Epithelial Cells Epithelium Generations Genetically Modified Animals Hematopoietic Stem Cell Transplantation Homologous Transplantation Immune response Immune system Individual Injection of therapeutic agent Injury Lead Ligands Malignant Neoplasms Mediating Mitogens Molecular Mus Natural regeneration Outcome Peripheral Physiological Population Prevention Process Radiation Reagent Recovery Regimen Role Signal Transduction Signaling Protein Surface Symptoms T cell response T-Cell Antigen Receptor Specificity T-Lymphocyte Testing Therapeutic Agents Therapeutic Intervention Thymic epithelial cell Thymus Gland Toxic effect Toxicity due to chemotherapy Transplant Recipients Transplantation Transplantation Conditioning aged autoreactive T cell base cell mediated immune response cellular targeting conditioning fibroblast growth factor 10 graft vs host disease graft vs leukemia effect in vivo insight keratinocyte growth factor keratinocyte growth factor receptor leukemia mouse model novel novel strategies novel therapeutics pre-clinical prevent protective effect receptor reconstitution research study response restoration success therapeutic target thymocyte

项目摘要

DESCRIPTION (provided by applicant): The successful outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) depends on the complete reconstitution of the host's immune system by donor-derived T cells. While an intact thymus is critically important for T cell reconstitution, thymus-dependent T cell repertoire restoration may be limited by changes in the thymic epithelium, brought about by transplant-mediated toxicities from chemotherapy/radiation regimens or graft vs. host disease (GVHD). The aim of this proposal is to examine whether boosting the thymic epithelium by in vivo administration of epithelial-cell-trophic-factors, exerts beneficial effects on T cell regeneration and prevention of GVHD following allogeneic bone marrow transplantation (allo-BMT). The trophic factors we will use in these experiments include keratinocyte growth factor (KGF) and receptor activator of NF?B ligand (RANKL) in conjunction to a genetically modified animal model deficient in expression of the signaling protein Sin. KGF is a potent epithelial cell mitogen which has been shown to expand the cortical and medullary thymic epithelium, increase thymopoiesis, and prevent the development of GVHD in preclinical mouse models. RANKL on the other hand, is important for development and differentiation of a subpopulation of medullary thymic epithelial cells (mTECs) involved in suppressing autoimmunity through elimination of autoreactive T cell clones. We recently found that Sin is expressed in the thymic epithelium and Sin deficiency inhibits KGF- and RANKL-induced expansion of thymic epithelial cells. In this proposal we will test the following hypothesis: KGF- and RANKL-mediated expansion of the thymic epithelium leads to better T cell reconstitution and protection from GVHD following allo-BMT. Sin deficiency inhibits KGF/RANKL signaling and ameliorates the beneficial effects of these factors after transplantation. To test this hypothesis we will: 1) Use allo-BMT mouse models in the Sin-deficient background to examine whether Sin is required for KGF-mediated a) T cell repertoire regeneration; b) reconstitution of T cell-mediated immune responses and c) protection from GVHD. 2) Examine whether RANKL administration can also protect from allo-BMT-related toxicity, whether it acts independently of or in conjunction with KGF and if Sin is required for the effects of RANKL in allo-BMT. 3) Use Sin deficient mice to identify the thymic epithelial cell targets of KGF and RANKL as well as elucidate the molecular mechanisms through which Sin regulates KGF/RANKL-mediated thymic epithelial cell expansion. We anticipate that these experiments will provide novel insight into how the thymic epithelium regulates thymopoiesis under normal or transplantation conditions, may identify RANKL and Sin as regulators of thymic epithelia-mediated T cell reconstitution following allo-BMT, and may lead to the identification of novel strategies/targets to better manage the outcome of HSCT.

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）的成功取决于供体来源的 T 细胞对宿主免疫系统的完全重建。虽然完整的胸腺对于 T 细胞重建至关重要，但胸腺依赖性 T 细胞库的恢复可能会受到胸腺上皮变化的限制，而胸腺上皮变化是由化疗/放疗方案或移植物抗宿主病 (GVHD) 引起的移植介导的毒性引起的。。本提案的目的是检查通过体内施用上皮细胞营养因子增强胸腺上皮是否对同种异体骨髓移植（allo-BMT）后 T 细胞再生和预防 GVHD 产生有益影响。我们将在这些实验中使用的营养因子包括角质形成细胞生长因子 (KGF) 和 NFκB 配体受体激活剂 (RANKL) 以及信号蛋白 Sin 表达缺陷的转基因动物模型。 KGF 是一种有效的上皮细胞有丝分裂原，已被证明可以扩张皮质和髓质胸腺上皮，增加胸腺生成，并在临床前小鼠模型中预防 GVHD 的发生。另一方面，RANKL 对于髓质胸腺上皮细胞 (mTEC) 亚群的发育和分化非常重要，该亚群通过消除自身反应性 T 细胞克隆来抑制自身免疫。我们最近发现 Sin 在胸腺上皮中表达，Sin 缺乏会抑制 KGF 和 RANKL 诱导的胸腺上皮细胞的扩张。在本提案中，我们将测试以下假设：KGF 和 RANKL 介导的胸腺上皮扩张导致更好的 T 细胞重建和异基因 BMT 后免受 GVHD 的保护。 Sin 缺乏会抑制 KGF/RANKL 信号传导并改善这些因子在移植后的有益作用。为了检验这一假设，我们将： 1) 在 Sin 缺陷背景下使用异基因 BMT 小鼠模型来检查 Sin 是否是 KGF 介导的所必需的 a) T 细胞库再生； b) 重建 T 细胞介导的免疫反应和 c) 预防 GVHD。 2) 检查 RANKL 给药是否也可以防止同种异体 BMT 相关的毒性，它是否独立作用或与 KGF 联合作用，以及 RANKL 在异体 BMT 中的作用是否需要 Sin。 3) 使用Sin缺陷小鼠鉴定KGF和RANKL的胸腺上皮细胞靶点，并阐明Sin调节KGF/RANKL介导的胸腺上皮细胞扩张的分子机制。我们预计这些实验将为胸腺上皮如何在正常或移植条件下调节胸腺生成提供新的见解，可能会鉴定 RANKL 和 Sin 作为同种异体 BMT 后胸腺上皮介导的 T 细胞重建的调节因子，并可能导致鉴定新的胸腺上皮介导的 T 细胞重建。更好地管理 HSCT 结果的策略/目标。