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
• 负责人: DAVID R ARCHER
• 金额: $ 35.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-08 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076922
• 关键词: cytokine; genetically modified animals; hematopoietic stem cells; hemoglobinopathy; histocompatibility; inflammation; laboratory mouse; sickle cell anemia; stem cell transplantation; transplant rejection; transplantation immunology

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）：镰状细胞疾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的唯一治疗疗法。然而，有毒的脊髓性调节方案和同种异体移植的障碍限制了其对患有严重并发症和HLA匹配供体的儿童的使用。新的骨髓抑制/免疫抑制策略正在出现，以降低发病率和死亡率，并通过故意诱导混合造血性嵌合体，使大量患者获得细胞移植。但是，这些协议提出了可以在临床前模型中最好解决的重大问题。使用镰状细胞疾病的鼠模型，该模型完全表达人类镰状血红蛋白，我们定义了一种非乳房的移植方案，该方案诱导混合的造血嵌合体和对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AIM 1中，我们将扩展这些研究，以确定提供镰状细胞病血液学和/或生理治疗的供体嵌合体的水平。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的耐受性，以及是否可以扩展基因修饰的细胞种群以提供永久性纠正的混合嵌合状态。现在，镰状细胞疾病被认为是多种细胞类型之间具有复杂的炎症相互作用，导致病理性结果。这些相互作用也可能导致镰状细胞疾病的干细胞移植中发现的排斥率增加。在AIM 2中，我们将研究拒绝过程中涉及的炎症和免疫机制。我们将研究共刺激阻滞阻滞反应，免疫效应子种群，粘附分子和细胞因子的参与和对同种异体排斥的贡献。这些目的提供了一种全面的系统方法，可以研究混合嵌合和镰状病理生理学之间的关系，以及在移植镰状细胞疾病中发现的抑制率提高。这两个目的都涉及移植耐受性和排斥的基本机制，并提供了设计未来非毛刺移植协议所需的关键临床前数据。

项目成果

Hematopoietic stem cell function in a murine model of sickle cell disease.

镰状细胞病小鼠模型中的造血干细胞功能。

• DOI: 10.1155/2012/387385
• 发表时间: 2012
• 期刊: Anemia
• 影响因子: 2.9
• 作者: Javazon,ElisabethH;Radhi,Mohamed;Gangadharan,Bagirath;Perry,Jennifer;Archer,DavidR
• 通讯作者: Archer,DavidR