ALLOGENEIC BLOOD STEM CELL TRANSPLANTATION FOR SLE

系统性红斑狼疮同种异体造血干细胞移植

• 批准号: 6930168
• 负责人: JUDITH SHIZRURU
• 金额: $ 25.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930168
• 关键词: autoantibody; clinical trials; combination therapy; globulins; graft versus host disease; hematopoietic stem cells; hematopoietic tissue transplantation; histocompatibility antigens; homologous transplantation; human genetic material tag; human subject; human therapy evaluation; human tissue; immune tolerance /unresponsiveness; immunogenetics; immunopathology therapy; immunoregulation; immunosuppressive; immunosuppressive antileukocyte serum; immunotherapy; isoantigen; longitudinal human study; patient oriented research; pluripotent stem cells; radiation immunosuppression; systemic lupus erythematosus; tissue mosaicism

In recent years, there has been significant interest in the possibility that hematopoietic cell transplantation (HCT) may effectively treat severe autoimmune diseases (ADs). Existing clinical trials are testing high dose preparative regimens followed by autologous HCT for ADs. In pre-clinical rodent studies, we and others have found that whereas allogeneic HCT is highly effective at halting AD pathogenesis, congenic or syngeneic (equivalent to autologous) HCT is inconsistent in its curative effects. A major barrier that has prevented the use of allogeneic HCT to treat human AD has been the morbidity and mortality associated with the HCT procedure. However, the recent development of non-myeloablative regimens to condition patients of older age or medical co-morbidities for allogeneic HCT have demonstrated successful reduction in regimen-related toxicities. A non-myeloablative regimen consisting of total lymphoid irradiation (TLI) and rabbit anti-thymyocyte globulin (ATG) developed at our institution was used in a pilot study of patients with advanced stage malignancies. The rationale behind the TLI/ATG regimen was to reduce graft-versus host disease (GVHD)which remains problematic with other non-myeloablative regimens. The TLI/ATG regimen was well-tolerated and all patients achieved engraftment of donor HLA-matched hematopoietic cells. Furthermore, only one of 17 patients developed acute GVHD and 3 of 17 patients developed extensive chronic GVHD. All cases of GVHD were steroid responsive. This project proposes to extend the TLI/ATG allograft regimen to the patients with life-threatening systemic lupus erythematosus (SLE). The overall aims of the project are to assess the safety and efficacy of the TLI/ATG regimen in a selected SLE population. To date one SLE patient has undergone allogeneic HCT using this regimen and demonstrates promising results. This project will further aim to understand the way that this TLI/ATG-based HCT alter recipient immune responses. Immune reconstitution will be evaluated in pre- and post-transplant lymphocyte and antigen-presenting cell populations by phenotype analysis, in vitro mixed cellular assays, and novel antibody profiling using a proteomics approach. This project interacts with all projects in the Program Project Grant.

近年来，人们对造血细胞移植（HCT）有效治疗严重的自身免疫性疾病（ADS）的可能性引起了重大兴趣。现有的临床试验是测试高剂量制备方案，然后是自体HCT进行广告。在临床前的啮齿动物研究中，我们和其他人发现，尽管同种异体HCT在停止AD发病机理方面非常有效，但先天性或同性恋（相当于自体）HCT在其治愈作用中却不一致。阻止使用同种异体HCT治疗人AD的主要障碍是与HCT程序相关的发病率和死亡率。然而，最近的非毛囊治疗方案的发展为年龄较大的患者或同种异体HCT的医疗合并症的患者已成功降低 在与方案有关的毒性中。一项针对晚期阶段恶性肿瘤的患者的试点研究，使用了由总淋巴样辐射（TLI）和兔抗胸腺细胞球蛋白（ATG）组成的非毛囊治疗方案。 TLI/ATG方案背后的基本原理是减少移植物抗宿主疾病（GVHD），这与其他非毛囊方案仍然存在问题。 TLI/ATG方案的耐受性良好，所有患者都植入了供体HLA匹配的造血细胞。此外，17例患者中只有一名患有急性GVHD，17例患者中有3例出现了广泛的慢性GVHD。所有GVHD病例均具有类固醇的反应。该项目建议将TLI/ATG同种异体移植方案扩展到威胁生命的全身性红斑狼疮（SLE）的患者。总体目标 该项目的旨在评估选定SLE人群中TLI/ATG方案的安全性和功效。迄今为止，一名SLE患者使用该方案进行了同种异体HCT，并证明了令人鼓舞的结果。该项目将进一步了解基于TLI/ATG的HCT改变受体免疫反应的方式。通过表型分析，体外混合细胞测定法以及使用蛋白质组学方法，将在移植前和移植前淋巴细胞和抗原呈递细胞群中评估免疫重建。该项目与计划项目赠款中的所有项目互动。