Fas/FasL mediated apoptosis in GVHD and aplastic anemia

Fas/FasL 介导 GVHD 和再生障碍性贫血中的细胞凋亡

• 批准号: 6667400
• 负责人: CURT I CIVIN
• 金额: $ 22.86万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667400
• 关键词: CD95 molecule; NOD mouse; SCID mouse; aplastic anemia; apoptosis; autoimmune disorder; cell population study; clinical research; cytotoxic T lymphocyte; dendritic cells; gene therapy; genetic manipulation; genetic transduction; graft versus host disease; hematopoietic stem cells; hematopoietic tissue transplantation; human subject; human tissue; immunopathology; paroxysmal nocturnal hemoglobinuria

The ability to stably transduce lympho-hematopoietic stem-progenitor cells (HSCs) allows us to genetically engineer HSCs and their progeny to serve as improved cellular tools to treat disease and complications. In Specific Aim 1, we propose preclinical studies in mouse and human models to confirm the concept and elucidate the principal cellular and molecular mechanisms by which Fas ligand-transduced (FasL*) dendritic cells (DCs) or HSCs may selectively kill the T and NK cells that mediate GVHD. The results of Aim 1 will also provide modeling information on the application of transduced FasL+ cells to reduce immune attack against HSCs in severe aplastic anemia (SAA) (Specific Aim 3). Since it is expected that transduced FasL+ cells may be toxic in potential future translational in vivo applications, we will investigate technologies to limit potential FasL toxicity, eg by eliminating the transduced cells (or their FasL expression) after tolerance to HSCs has been generated. A novel transduced FasL+ cell therapy approach to reduce effector lymphocytes attacking host cells in GVHD (Aim 1) and SAA (Aim 3) may eventually be used in transplants for SAA, PNH and other diseases, and a potential clinical trial is outlined in Aim 1. In addition, our accompanying mechanistic studies on apoptotic pathways in alloimmune cells will increase information on the fundamentals of the Fas pathway in the effector cells mediating GVHD (and SAA), which in turn, should increase understanding of death pathways in the biology of (a) alloimmune responses, (b) hematologic malignancies that evade immune surveillance, and (c) transplanted organs (or pluripotent stem cells). In Specific Aim 2, Projects 1, 2 and 4 will cooperate to investigate the potential role of the Fas pathway in the pathophysiology of HSCs from SANPNH patients. Specific Aim 1: To engineer FasL+ host DCs or HSCs to selectively kill the cellular effectors of GVHD. Specific Aim 2: To investigate the role of the Fas pathway in the pathogenesis of SAA and PNH. Specific Aim 3: To investigate whether FasL+ HSCs selectively kill autologous anti-HSC CTLs in SAA.

稳定地培养淋巴造血干祖细胞（HSC）的能力使我们能够 基因工程改造HSC及其后代，以作为治疗疾病和并发症的改进的细胞工具。在具体目标1中，我们提出在小鼠和人类模型中进行临床前研究，以确认Fas配体转导（FasL*）树突状细胞（DC）或HSC可能选择性杀死介导GVHD的T细胞和NK细胞的概念并阐明其主要细胞和分子机制。目标1的结果还将提供关于应用转导的FasL+细胞以减少针对重型再生障碍性贫血（SAA）中的HSC的免疫攻击的建模信息（具体目标3）。由于预期转导的FasL+细胞在潜在的未来体内翻译应用中可能是有毒的，因此我们将研究限制潜在FasL毒性的技术，例如在产生对HSC的耐受性后消除转导的细胞（或其FasL表达）。一种新的转导FasL+细胞治疗方法，以减少 在GVHD（Aim 1）和SAA（Aim 3）中攻击宿主细胞的效应淋巴细胞最终可用于SAA、PNH和其它疾病的移植，并且在Aim 1中概述了潜在的临床试验。此外，我们对同种异体免疫细胞凋亡途径的机制研究将增加有关效应细胞介导GVHD（和SAA）中Fas途径基本原理的信息，这反过来又会增加对（a）同种异体免疫反应，（B）逃避免疫监视的血液恶性肿瘤和（c）移植器官（或多能干细胞）生物学中死亡途径的理解。在具体目标2中，项目1、2和4将合作研究Fas通路在SANPNH患者HSC病理生理学中的潜在作用。具体目标1：设计FasL+宿主DC或HSC以选择性地杀死GVHD的细胞效应物。目的二：探讨Fas通路在SAA和PNH发病中的作用。具体目的3：研究FasL+ HSC是否选择性地杀死SAA中的自体抗HSC CTL。