Cadaveric Donor Lung and Bone Marrow Transplantation in Immunodeficiency Diseases

翻译后摘要：骨髓移植（BMT）可以是一种治愈性治疗原发性免疫缺陷患者 (PID)综合征，然而，那些患有终末期肺病的人不适合BMT或双侧 原位肺移植（BOLT）。因此，PID/终末期肺病患者的确定性治疗 代表未满足的临床需求。本U 01项目提出了一项单中心临床试验，以评价 以及从同一尸体进行BOLT后进行CD 3 +/CD 19+去除的BMT的有效性，部分 HLA匹配供体，PID/终末期肺病患者。我们假设串联BOLT/BMT在 患有PID/终末期肺病的患者将导致潜在PID的校正，肺功能正常化， 病原体特异性免疫的功能、恢复/保持和免疫耐受的建立 这将允许撤销免疫抑制治疗（IST）。为了验证我们的假设，我们提出了三个目标。在 目的1，我们将在8例PID/终末期肺患者中进行I/II期串联BOLT/BMT临床试验 疾病本试验将在两名具有互补专业知识的Co-PI的指导下进行：Paul博士 Szabolcs（联系PI; BMT）和Dr. John McDyer（合作PI;肺移植）。主要监督机构将包括： NIAID指定的监查员NIAID DSMB和匹兹堡大学教育和合规办公室 人类研究。本试验包括强化安全性监测、里程碑驱动的方案， 安全性报告和终点分析的严格数据收集和管理。预定收集 每例研究患者基础研究的血液、支气管肺泡灌洗（BAL）和支气管刷样本将 与常规临床监测一致。在目标2中，我们将检验串联BOLT/BMT恢复 和/或在研究患者中保持病原体特异性T细胞粘膜/全身宿主免疫。我们将执行 基于流式细胞术的测定，以询问病原体特异性全身/肺粘膜T细胞对关键 机会致病菌如CMV、EBV、曲霉菌、假单胞菌、葡萄球菌、RSV、流感病毒，并使用RNA 序列分析以评估气道转录组。在目标3中，我们将测试串联的假设， BOLT/BMT将导致足以建立长期肺同种异体移植物/BMT耐受性的嵌合体水平， 从而促进IST的撤回。我们将使用超敏感技术评估嵌合体， 全面的混合淋巴细胞反应研究，以测试同种异体反应性并评估 在整个研究过程中，预期免疫耐受性达到完全停用IST的目标。法律与正义党 我已经组建了一支具有广泛专业知识的杰出的多学科团队，并将使用多个PI格式 关于U 01项目Szabolcs博士，McDyer和他们的团队高度致力于推进目前的 PID/终末期肺病患者的治疗选择有限。U 01项目的成功将是 代表肺移植和BMT领域的范式转变，以及串联的概念验证。 BOLT/BMT有可能扩展到其他实体器官候选者，以实现耐受性。

Abstract: Bone marrow transplant (BMT) can be a curative therapy for patients with primary immunodeficiency (PID) syndromes, however those with end-stage lung disease are ineligible for either BMT or bilateral orthotopic lung transplantation (BOLT). Thus, definitive treatment for patients with PID/end-stage lung disease represents an unmet clinical need. This U01 project proposes a single center clinical trial to evaluate the safety and efficacy of performing BOLT followed by CD3+/CD19+-depleted BMT from the same cadaveric, partially HLA-matched donor, in patients with PID/end-stage lung disease. We hypothesize that tandem BOLT/BMT in patients with PID/end-stage lung disease will result in correction of the underlying PID, normalization of lung function, restoration/preservation of pathogen-specific immunity and the establishment of immune tolerance that will allow withdrawal of immunosuppression therapy (IST). To test our hypothesis, we propose 3 aims. In Aim 1, we will conduct a phase I/II tandem BOLT/BMT clinical trial in 8 patients with PID/end-stage lung disease. This trial will be conducted under the direction of two Co-PIs with complementary expertise: Dr. Paul Szabolcs (contact PI; BMT) and Dr. John McDyer (Co-PI; lung transplant). Key oversight bodies will include the NIAID DSMB, a NIAID-appointed monitor, and the University of Pittsburgh Education and Compliance Office for Human Research. This trial incorporates intensive safety monitoring, a milestone-driven protocol, and rigorous data collection and management for safety reporting and endpoint analyses. Scheduled collection of blood, bronchoalveolar lavage (BAL) and bronchial brush samples for basic studies in each study patient will coincide with routine clinical monitoring. In Aim 2, we will test the hypothesis that tandem BOLT/BMT restores and/or preserves pathogen-specific T cell mucosal/systemic host immunity in study patients. We will perform flow cytometry-based assays to interrogate pathogen-specific systemic/lung mucosal T cell responses to key opportunistic pathogens such as CMV, EBV, Aspergillus, Pseudomonas, Staph, RSV, flu and use RNA sequence analysis to assess the airway transcriptome. In Aim 3, we will test the hypothesis that tandem BOLT/BMT will result in a level of chimerism sufficient to establish long-term lung allograft/BMT tolerance, thereby facilitating withdrawal of IST. We will assess chimerism using an ultra-sensitive technique and perform comprehensive mixed lymphocyte reaction studies to test alloreactivity and evaluate differential mechanisms of anticipated immune tolerance throughout the study toward the goal of complete withdrawal of IST. The PIs have assembled an outstanding, multidisciplinary team with broad expertise, and will use the multiple PI format for this U01 project. Drs. Szabolcs, McDyer and their teams are highly dedicated to advancing the currently limited treatment options for patients with PID/end-stage lung disease. Success in this novel U01 project will be represent a paradigm shift in the fields of lung transplantation and BMT, and proof-of-concept for tandem BOLT/BMT could potentially be extended to other solid organ candidates in an effort to achieve tolerance.