Allogeneic chimerism in murine sickle cell disease
小鼠镰状细胞病的同种异体嵌合
基本信息
- 批准号:6990435
- 负责人:
- 金额:$ 1.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-07-08 至 2007-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Sickle cell disease is a debilitating inherited hemoglobin disorder that is the most common single-gene disease in the world. Hematopoietic stem cell transplantation is the only curative therapy for SCD; however toxic myeloablative conditioning regimens and barriers to allotransplantation have limited its use to children with major complications and HLA matched donors. New myelosuppressive/immunosuppressive transplant strategies are emerging to reduce morbidity and mortality and to make cell transplantation available to a larger number of patients by intentionally inducing mixed hematopoietic chimerism. However, these protocols raise significant issues that can be best addressed in a preclinical model. Using a murine model of sickle cell disease that expresses exclusively human sickle hemoglobin we have defined a non-myeloablative transplant protocol that induces mixed hematopoietic chimerism and tolerance to MHC disparate donors while correcting hematologic and pathologic manifestations of the disease. In Aim 1, we will extend these studies to determine the levels of donor chimerism that provide hematologic and/or physiologic cure of sickle cell disease. We will determine if very low levels of stem cell chimerism can induce and maintain allogeneic tolerance, and whether genetically modified cell populations can be expanded to provide a permanently corrective mixed chimeric state. Sickle cell disease is now recognized as having complex inflammatory interactions between multiple cell types that lead to pathological outcomes. These interactions may also be responsible for the increased rate of rejection found in stem cell transplantation for sickle cell disease. In Aim 2 we will investigate inflammatory and immunological mechanisms involved in this rejection process. We will investigate co-stimulation blockade resistant rejection, immune effector populations, adhesion molecules and cytokines for their involvement and contribution to allogeneic rejection. These aims provide a comprehensive systematic approach to studying the relationship between mixed chimerism and sickle pathophysiology and the enhanced rejection rate found in transplantation for sickle cell disease. Both Aims address basic mechanisms of transplantation tolerance and rejection as well as providing the critical preclinical data that are required for the design of future non-myeloablative transplants protocols.
描述(由申请人提供):镰状细胞病是一种使人衰弱的遗传性血红蛋白疾病,是世界上最常见的单基因疾病。造血干细胞移植是SCD的唯一治愈性疗法;然而,毒性清髓性预处理方案和同种异体移植的障碍限制了其在具有重大并发症的儿童和HLA匹配供体中的使用。新的骨髓抑制/免疫抑制移植策略正在出现,以降低发病率和死亡率,并通过有意诱导混合造血嵌合体使细胞移植可用于更多患者。然而,这些方案提出了可以在临床前模型中最好地解决的重要问题。使用仅表达人镰状血红蛋白的镰状细胞病的鼠模型,我们定义了非清髓性移植方案,其诱导混合造血嵌合体和对MHC不同供体的耐受性,同时纠正疾病的血液学和病理学表现。在目标1中,我们将扩展这些研究以确定提供镰状细胞病的血液学和/或生理学治愈的供体嵌合体水平。我们将确定非常低水平的干细胞嵌合体是否可以诱导和维持同种异体耐受,以及遗传修饰的细胞群是否可以扩增以提供永久纠正的混合嵌合状态。镰状细胞病现在被认为是多种细胞类型之间复杂的炎症相互作用,导致病理结果。这些相互作用也可能是镰状细胞病干细胞移植中发现的排斥率增加的原因。在目标2中,我们将研究参与这一排斥过程的炎症和免疫机制。我们将研究共刺激阻断抵抗性排斥反应,免疫效应细胞群,粘附分子和细胞因子对同种异体排斥反应的参与和贡献。这些目标提供了一个全面的系统的方法来研究混合嵌合体和镰状细胞病的病理生理学和增强的排斥率在镰状细胞病移植中发现之间的关系。这两个目标都涉及移植耐受和排斥的基本机制,并提供设计未来非清髓性移植方案所需的关键临床前数据。
项目成果
期刊论文数量(0)
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DAVID R ARCHER其他文献
DAVID R ARCHER的其他文献
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{{ truncateString('DAVID R ARCHER', 18)}}的其他基金
Small Molecule Therapeutics for Sickle Cell Anemia
镰状细胞性贫血的小分子疗法
- 批准号:
10601679 - 财政年份:2023
- 资助金额:
$ 1.87万 - 项目类别:
Impaired Collateral Vessel Formation in Sickle Cell Disease
镰状细胞病中侧支血管形成受损
- 批准号:
9751364 - 财政年份:2016
- 资助金额:
$ 1.87万 - 项目类别:
Impaired Collateral Vessel Formation in Sickle Cell Disease
镰状细胞病中侧支血管形成受损
- 批准号:
9335981 - 财政年份:2016
- 资助金额:
$ 1.87万 - 项目类别:
Endothelial Dysfunction in the Pathogenesis of Sickle Cell Nephropathy
镰状细胞肾病发病机制中的内皮功能障碍
- 批准号:
8221131 - 财政年份:2012
- 资助金额:
$ 1.87万 - 项目类别:
Endothelial Dysfunction in the Pathogenesis of Sickle Cell Nephropathy
镰状细胞肾病发病机制中的内皮功能障碍
- 批准号:
8403679 - 财政年份:2012
- 资助金额:
$ 1.87万 - 项目类别:
Endothelial Dysfunction in the Pathogenesis of Sickle Cell Nephropathy
镰状细胞肾病发病机制中的内皮功能障碍
- 批准号:
8996584 - 财政年份:2012
- 资助金额:
$ 1.87万 - 项目类别:
Allogeneic chimerism in murine sickle cell disease
小鼠镰状细胞病的同种异体嵌合
- 批准号:
7076922 - 财政年份:2003
- 资助金额:
$ 1.87万 - 项目类别:
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