Cyclosporine Inhalation Solution (CIS) treatment of Bronchiolitis Obliterans

环孢素吸入溶液（CIS）治疗闭塞性细支气管炎

基本信息

批准号：
8344885
负责人：
RICHARD CHILDS
金额：
$ 47.54万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8344885
关键词：
Adverse event Affect Alveolar Anti-Inflammatory Agents Anti-inflammatory Antigens Award Biological Assay Blood Blood Cells Breathing Bronchiolitis Obliterans Bronchoalveolar Lavage Chronic Clinical Clinical Protocols Collaborations Complication Critical Care Cyclosporine Deposition Development Disease Dose Drug Kinetics Enrollment Epithelial Flow Cytometry Gene Expression Gene Expression Profiling Granulation Tissue Hematology Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Image Immune Immunosuppression Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Investigation Irrigation Label Laboratories Laboratory Markers Lung Lung Transplantation Maryland Measures Mediating Mediator of activation protein Medicine Morbidity - disease rate National Heart, Lung, and Blood Institute Obstructive Lung Diseases Organ Organ Transplantation Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Physician Executives Preparation Process Propylene Glycols Proteomics Pulmonary function tests Pulmonology Radio Resolution Respiratory Failure Respiratory physiology Risk Safety Solutions Staging Stem cell transplant Structure Structure of respiratory epithelium Survivors Symptoms T-Lymphocyte Therapeutic immunosuppression Time Tissue-Specific Gene Expression Titrations Transplant Recipients Transplantation United States National Institutes of Health Universities Virus Diseases X-Ray Computed Tomography airway epithelium base bench to bedside conventional therapy cytokine effective therapy functional genomics human data improved inflammatory marker injured airway insight mortality novel patient population programs safety study small airways disease success targeted delivery

项目摘要

ronchiolitis obliterans is an obstructive disease of the small airways of the lung that may develop after either hematopoietic stem cell or lung transplantation. It is associated with considerable morbidity and mortality in long-term transplant survivors and thus represents a major impediment to the success of these therapies Mortality due to bronchiolitis obliterans-associated respiratory failure may occur in more than 55% of patients developing this complication typically within 3 to 5 years following transplantation. The pathogenesis of bronchiolitis obliterans in hematopoietic stem cell and lung transplants appears to share a common final pathway of immune-mediated injury and inflammation to airway epithelium and sub-epithelial structures that results in granulation tissue and fibro-proliferation. Following hematopoietic stem cell transplantation, a chronic inflammatory process develops as a consequence of transplanted T cells targeting allo-antigens expressed on the respiratory epithelium of the recipient. In contrast, the inflammatory injury that develops in the transplanted lung results from alloimmune-dependent and independent mechanisms. Other additive factors to these immune-based inflammatory injuries include viral infections and micro-aspiration. Treatment is based primarily on increased systemic immunosuppression which results in attendant increased risk of infection and morbidity. As a consequence, conventional therapy for bronchiolitis obliterans has not improved long-term outcome of this disorder. Recently, cyclosporine inhalation solution (CIS: made by the APT pharmaceutical company) in solution with propylene glycol has been shown to improve overall survival and chronic rejection-free survival in lung transplant patients. These findings suggest targeted delivery of immunosuppressive therapy to the diseased organ warrants further investigation as this may minimize the morbidity associated with systemic immunosuppression. However, inhaled cyclosporine has not been studied in the treatment of BO following hematopoietic stem cell transplantation. This program represents collaboration between the Hematology branch of the NHLBI, The Critical Care Medicine Department of the NIH Clinical Center, and The Pulmonary Medicine Department at The University of Maryland. Studies are being done in association Aldo Iacono, MD, the Medical Director of the Lung Transplant Program at the University of Maryland. Dr. Iacono pioneered the development of inhaled cyclosporine for lung transplants. Our group was awarded a bench to bedside award to study the safety and efficacy of inhaled cyclosporine for the treatment of BO. Two distinct patient populations will be offered enrollment on this clinical protocol: hematopoietic transplant recipients with BO and lung transplant recipients with BO referred from the University of Maryland. Patients will undergo dose titration of inhaled cyclosporine to a maximum dose of 300mg, three times weekly. Clinical parameters, including pulmonary function tests, will be measured in addition to laboratory markers of the anti-inflammatory response to CIS measured in the blood and from bronchio-alveolar lavages. Adverse events associated with treatment will be recorded. The primary objective is assessing the safety and efficacy of inhaled cyclosporine as a new therapy in hematopoietic transplant patients and lung transplant patients with established BO and to promote a better understanding of the pathogenesis of BO in these two transplant groups.

ronchiolitis闭塞性是肺部小气道的阻塞性疾病，在造血干细胞或肺移植后可能发育。它与长期移植幸存者中的发病率和死亡率相关，因此代表了由于支气管炎闭塞剂相关的呼吸衰竭而导致这些疗法死亡率成功的主要障碍，可能会发生在55％以上的患者中，通常在移植后3至5年内发生这种并发症。造血干细胞和肺移植中支气管炎的发病机制似乎具有免疫介导的损伤和对气道上皮上皮结构的炎症和炎症的共同最终途径，从而导致肉芽组织和纤维增生。造血干细胞移植后，由于移植的T细胞靶向受体的呼吸性上皮表达的同种抗原的移植T细胞而形成慢性炎症过程。相反，在移植肺中发展的炎症损伤是由同种免疫依赖性和独立机制引起的。这些基于免疫的炎症性损伤的其他加性因素包括病毒感染和微抽动。治疗主要基于全身免疫抑制的增加，从而导致随之而来的感染风险增加。结果，闭塞性支气管炎的常规疗法尚未改善这种疾病的长期结局。最近，已证明环孢素吸入溶液（CIS：由APT Pharmaceutical Company制造的）用丙烯乙二醇溶液溶液可改善肺移植患者的整体生存和慢性抑制生存期。这些发现表明，针对患病器官的免疫抑制疗法的有针对性递送需要进一步研究，因为这可能最大程度地减少了与全身免疫抑制相关的发病率。然而，在造血干细胞移植后，尚未研究吸入环孢霉素的BO治疗。该计划代表了NHLBI的血液学分支，NIH临床中心的重症监护医学系与马里兰大学肺部医学系之间的合作。研究正在进行研究，马里兰州肺部移植计划的医学总监Aldo Iacono协会。 Iacono博士率先开发了吸入的环孢菌素进行肺移植。我们的小组被授予床旁奖，以研究吸入环孢菌素治疗BO的安全性和功效。该临床方案将提供两名不同的患者人群：造血移植受者，由BO和肺移植受者与马里兰州大学的BO转交。患者将每周三次，将吸入环孢霉素的剂量滴定为300mg的最大剂量。除了对血液和支气管 - 肺泡灌洗中测得的抗炎反应的实验室标记外，还将测量包括肺功能测试在内的临床参数。将记录与治疗相关的不良事件。主要目的是评估吸入环孢素作为造血移植患者的新疗法和具有BO的肺移植患者的新疗法，并在这两个移植组中更好地了解BO的发病机理。