Cadaveric Donor Lung and Bone Marrow Transplantation in Immunodeficiency Diseases

摘要：骨髓移植是治疗原发性免疫缺陷患者的一种根治方法。 (PID)综合征，但那些患有终末期肺部疾病的人没有资格接受骨髓移植或双侧移植 原位肺移植(Bolt)。因此，对弥漫性肺炎/终末期肺部疾病患者的最终治疗 代表一种未得到满足的临床需求。U01项目建议进行单中心临床试验，以评估其安全性 对同一具身体进行螺栓移植后CD3/CD19缺失的骨髓移植的疗效 配型相合的供者，在患有弥漫性肺病/终末期肺部疾病的患者中。我们假设串联螺栓/BMT在 患有慢性阻塞性肺疾病/终末期肺部疾病的患者将会纠正潜在的慢性阻塞性肺疾病，使肺部恢复正常。 病原菌特异性免疫的功能、恢复/保存及免疫耐受的建立 这将允许取消免疫抑制治疗(IST)。为了验证我们的假设，我们提出了三个目标。在……里面 目的1、我们将对8例弥漫性肺炎/终末期肺病患者进行I/II期串联Bolt/BMT临床试验 疾病。这项试验将在两名具有互补专业知识的合作个人的指导下进行：保罗博士 Szbolcs(联系Pi；BMT)和John McDyer博士(Co-Pi；肺移植)。主要监督机构将包括 NIAID DSMB，NIAID指定的监督员，以及匹兹堡大学教育和合规办公室 人类研究中心。该试验结合了密集的安全监控、里程碑驱动的方案，以及 安全报告和终点分析的严格数据收集和管理。计划的集合 每项研究的基础研究的血液、支气管肺泡灌洗(BAL)和支气管刷样本患者将 与常规临床监测相吻合。在目标2中，我们将检验串联螺栓/BMT恢复的假设 和/或在研究患者中保留病原体特异性T细胞粘膜/系统宿主免疫。我们将表演 基于流式细胞术的检测病原体特异性系统/肺粘膜T细胞对KEY的反应 条件致病菌，如CMV、EBV、曲霉菌、假单胞菌、葡萄球菌、RSV、流感和使用RNA 序列分析以评估呼吸道转录组。在目标3中，我们将检验以下假设 Bolt/BMT将导致足以建立长期肺移植/BMT耐受的嵌合体水平， 从而为IST的退出提供便利。我们将使用超敏感技术评估嵌合体，并执行 全面的混合淋巴细胞反应研究，以测试同种异体反应性和评估不同的机制 在整个研究过程中，预期免疫耐受的目标是完全退出IST。私人投资促进局 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PI形式 对于这个U01项目。Szbolcs博士、McDyer博士和他们的团队高度致力于推动目前 对于患有弥漫性肺炎/终末期肺部疾病的患者，治疗选择有限。这个新颖的U01项目的成功将是 代表着肺移植和骨髓移植领域的范式转变，以及Tandem的概念验证 Bolt/BMT有可能扩展到其他固体候选器官，以努力实现耐受性。

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.