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: 9143833
• 负责人: JOHN F MCDYER
• 金额: $ 95.91万
• 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/9143833
• 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; 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; Sampling; Schedule; Secure; Solid; Staging; Study Subject; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Translational trial; Transplant Recipients; Transplantation; Universities; Withdrawal; abstracting; airway epithelium; base; 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）是原发性免疫缺陷患者的一种治疗方法