Cadaveric Donor Lung and Bone Marrow Transplantation in Immunodeficiency Diseases

尸体供体肺和骨髓移植治疗免疫缺陷疾病

• 批准号: 9310373
• 负责人: JOHN F MCDYER
• 金额: $ 96.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-06 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310373
• 关键词: Adherence; Age; Allograft Tolerance; Aspergillus; Bilateral; Biological Assay; Biological Preservation; Blood; Blood specimen; Bone Marrow Transplantation; Bronchoalveolar Lavage; CD19 gene; CD3 Antigens; CD8B1 gene; Cadaver; Chimerism; Chronic; Clinical; Clinical Protocols; Clinical Trials; Clonal Deletion; Collection; Complication; Cytomegalovirus; Data; Data Collection; Defect; Dendritic Cells; Disease; Education; Enrollment; Exhibits; FDA approved; Flow Cytometry; Goals; Human; Human Herpesvirus 4; Human Subject Research; Immune; Immune Tolerance; Immune system; Immunity; Immunocompetence; Immunologic Deficiency Syndromes; Immunosuppression; In Vitro; Infection; Laboratories; Life; Lung; Lung Transplantation; Lung diseases; MHC Class I Genes; Measures; Mixed Lymphocyte Culture Test; Monitor; Mucous Membrane; National Institute of Allergy and Infectious Disease; Online Systems; Organ; Organ Donor; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Phase; Play; Production; Protocols documentation; Pseudomonas; RNA Sequence Analysis; Recruitment Activity; Recurrence; Regimen; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Respiratory physiology; Risk; Role; Safety; Safety Management; Sampling; Savings; Schedule; Secure; Solid; Statistical Data Interpretation; Study Subject; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Translational trial; Transplant Recipients; Transplantation; Universities; Withdrawal; airway epithelium; base; bone marrow allograft; central tolerance; conditioning; congenital immunodeficiency; curative treatments; cytokine; cytotoxicity; data management; electronic data; experience; fighting; flu; high risk; human subject; indexing; lung allograft; mortality; multidisciplinary; novel; pathogen; peripheral blood; programs; reconstitution; response; restoration; success; systems research; transcriptome; transcriptome sequencing; Adherence; Age; Allograft Tolerance; Aspergillus; Bilateral; Biological Assay; Biological Preservation; Blood; Blood specimen; Bone Marrow Transplantation; Bronchoalveolar Lavage; CD19 gene; CD3 Antigens; CD8B1 gene; Cadaver; Chimerism; Chronic; Clinical; Clinical Protocols; Clinical Trials; Clonal Deletion; Collection; Complication; Cytomegalovirus; Data; Data Collection; Defect; Dendritic Cells; Disease; Education; Enrollment; Exhibits; FDA approved; Flow Cytometry; Goals; Human; Human Herpesvirus 4; Human Subject Research; Immune; Immune Tolerance; Immune system; Immunity; Immunocompetence; Immunologic Deficiency Syndromes; Immunosuppression; In Vitro; Infection; Laboratories; Life; Lung; Lung Transplantation; Lung diseases; MHC Class I Genes; Measures; Mixed Lymphocyte Culture Test; Monitor; Mucous Membrane; National Institute of Allergy and Infectious Disease; Online Systems; Organ; Organ Donor; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Phase; Play; Production; Protocols documentation; Pseudomonas; RNA Sequence Analysis; Recruitment Activity; Recurrence; Regimen; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Respiratory physiology; Risk; Role; Safety; Safety Management; Sampling; Savings; Schedule; Secure; Solid; Statistical Data Interpretation; Study Subject; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Translational trial; Transplant Recipients; Transplantation; Universities; Withdrawal; airway epithelium; base; bone marrow allograft; central tolerance; conditioning; congenital immunodeficiency; curative treatments; cytokine; cytotoxicity; data management; electronic data; experience; fighting; flu; high risk; human subject; indexing; lung allograft; mortality; multidisciplinary; novel; pathogen; peripheral blood; programs; reconstitution; response; restoration; success; systems research; transcriptome; transcriptome sequencing

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.

摘要：骨髓移植（BMT）可以是原发性免疫缺陷患者的治疗疗法 （PID）综合症，但是患有终肺疾病的患者不符合BMT或双侧的资格 原位肺移植（螺栓）。因此，针对PID/末期肺部疾病患者的明确治疗 代表未满足的临床需求。该U01项目提出了一项单个中心临床试验以评估安全性 和执行螺栓的功效，然后是CD3+/CD19+耗尽的BMT，该BMT来自同一尸体，部分部分 HLA匹配的供体，患有PID/终末期肺部疾病的患者。我们假设串联螺栓/BMT PID/末期肺部疾病的患者将导致基础PID纠正，肺正常化 病原体特异性免疫的功能，恢复/保存以及免疫耐受性的建立 这将允许戒断免疫抑制疗法（IST）。为了检验我们的假设，我们提出了3个目标。在 AIM 1，我们将对8例PID/终端肺患者进行I/II期串联螺栓/BMT临床试验 疾病。该试验将在两个共同私程的指导下进行，并具有互补的专业知识：Paul博士 Szabolcs（联系PI； BMT）和John McDyer博士（Co-Pi;肺移植）。关键的监督机构将包括 NIAID DSMB，一个由NIAID任命的显示器和匹兹堡大学教育与合规办公室 用于人类研究。该试验包含密集的安全监控，一个里程碑驱动的协议，以及 严格的数据收集和管理安全报告和端点分析。 Scheduled collection of 每个研究患者的血液，支气管肺泡灌洗（BAL）和支气管刷样品用于基础研究 与常规临床监测一致。在AIM 2中，我们将测试串联螺栓/BMT恢复的假设 和/或研究患者中病原体特异性T细胞粘膜/全身宿主免疫。我们将表演 基于流式细胞仪的测定法，以询问病原体特异性的全身/肺粘膜T细胞对密钥的反应 机会性病原体，例如CMV，EBV，曲霉，假单胞菌，葡萄球菌，RSV，流感，并使用RNA 序列分析以评估气道转录组。在AIM 3中，我们将测试串联的假设 螺栓/BMT将导致一定水平的嵌合体，足以建立长期的同种异体移植/BMT耐受性， 从而促进IST的撤离。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，以测试同种反应性并评估差异机制 在整个研究中，预期的免疫耐受性旨在完全撤回IST的目标。 pis 已经组建了一个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 对于这个U01项目。博士。 Szabolcs，McDyer及其团队非常致力于前进 PID/终末期肺病患者的治疗选择有限。这个小说U01项目的成功将是 代表肺移植和BMT领域的范式转移，以及串联的概念证明 螺栓/BMT可能会扩展到其他固体器官候选物，以实现公差。