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）可能有效治疗严重自身免疫性疾病（AD）的可能性产生了浓厚的兴趣。现有的临床试验正在测试高剂量准备方案，然后进行自体 HCT 治疗 AD。在临床前啮齿动物研究中，我们和其他人发现，虽然同种异体 HCT 在阻止 AD 发病机制方面非常有效，但同源或同基因（相当于自体）HCT 的疗效并不一致。阻碍使用同种异体 HCT 治疗人类 AD 的一个主要障碍是与 HCT 手术相关的发病率和死亡率。然而，最近开发的非清髓治疗方案用于治疗老年患者或同种异体 HCT 的医疗并发症，已证明可以成功减少 与治疗方案相关的毒性。我们机构开发的由全淋巴照射 (TLI) 和兔抗胸腺细胞球蛋白 (ATG) 组成的非清髓治疗方案用于晚期恶性肿瘤患者的初步研究。 TLI/ATG 方案背后的基本原理是减少移植物抗宿主病 (GVHD)，这对于其他非清髓方案来说仍然存在问题。 TLI/ATG 方案耐受性良好，所有患者均实现了供体 HLA 匹配造血细胞的植入。此外，17 名患者中只有 1 名出现急性 GVHD，17 名患者中有 3 名出现广泛的慢性 GVHD。所有 GVHD 病例均对类固醇有反应。该项目拟将 TLI/ATG 同种异体移植方案扩展到危及生命的系统性红斑狼疮 (SLE) 患者。总体目标 该项目的目的是评估 TLI/ATG 方案在选定的 SLE 人群中的安全性和有效性。迄今为止，一名 SLE 患者已使用该方案接受了同种异体 HCT，并显示出有希望的结果。该项目将进一步旨在了解这种基于 TLI/ATG 的 HCT 如何改变受体免疫反应。将通过表型分析、体外混合细胞测定和使用蛋白质组学方法的新型抗体分析来评估移植前和移植后淋巴细胞和抗原呈递细胞群的免疫重建。该项目与计划项目拨款中的所有项目相互作用。