A Novel Bioenergetic Strategy to Treat GVHD

项目总结(见说明)： 移植物抗宿主病(GVHD)仍然是同种异体骨的主要和棘手的并发症。 骨髓移植(BMT)。GVHD的两个主要效应机制是炎性细胞因子和 激活的淋巴细胞。在这个新项目中，我们探索了一种新的生物能量策略来消除 GHVD中的淋巴细胞效应因子。初步研究表明，在GVHD期间， 长期被宿主的组织相容性抗原激活，具有异常的生物能量谱。 与急性激活的淋巴细胞相比，GVHD效应淋巴细胞的糖酵解水平较低 表现出线粒体应激的迹象，包括活性氧(ROS)水平升高。效应器 细胞毒性的苯二氮卓类药物BZ-423可以选择性地诱导淋巴细胞凋亡。 一种线粒体ATPase。BZ-423在GVHD诱导后7天开始给药2例 单独的小鼠模型通过所有临床和组织学参数逆转GVHD，并显著 提高长期存活率。本项目将研究BZ-423的分子作用机制 并探讨其对血液病关键细胞亚群生物能量谱的影响 这些动物模型的骨髓移植后的免疫重建。该项目还将定义 人类异基因骨髓移植临床标本中白细胞亚群的生物能量学特征 收件人。我们的具体目标是： 1.分析BZ-423及其类似物在移植物抗宿主病中清除效应淋巴细胞的作用 2.确定BZ-423对免疫重建的影响 3.分析BZ-423对骨髓移植后关键骨髓系的影响 4.分析异基因骨髓移植后人外周血单核细胞群体的生物能量学特征

PROJECT SUMMARY (See instructions): Graft versus host disease (GVHD) remains a major and intractable complication of allogeneic bone marrow transplantation (BMT). Two major effector mechanisms of GVHD are inflammatory cytokines and activated lymphocytes. In this new project, we explore a novel bioenergetic strategy to eliminate lymphocyte effectors in GHVD. Preliminary studies show that during GVHD lymphocytes that are chronically activated by histocompatibility antigens of the host have abnormal bioenergetic profiles. GVHD effector lymphocytes have low levels of glycolysis compared to acutely activated lymphocytes and show signs of mitochondrial stress, including elevated levels of reactive oxygen species (ROS). Effector lymphocytes can be selectively induced to apoptose with a cytotoxic benzodiazepine, Bz-423, that inhibits a mitochondrial ATPase. Administration of Bz-423 beginning seven days after induction of GVHD in two separate mouse models reverses GVHD by all clinical and histologic parameters and significantly improves long term survival. This project will investigate the molecular mechanisms of action of Bz-423 and explore its effects on the bioenergetic profiles of critical cellular subpopulations during hematologic and immunologic reconstitution after BMT in these animal models. This project will also define the bioenergetic profiles of leukocyte subpopulations in clinical samples from human allogeneic BMT recipients. Our Specific Aims are: 1. To analyze Bz-423 and its analogs in eliminating effector lymphocytes during GVHD 2. To determine the effects of Bz-423 on immunologic reconstitution 3. To analyze the impact of Bz-423 on key myeloid populations following BMT 4. To analyze the bioenergetic profiles of human PBMC populations after allogeneic BMT