Cyclosporine Inhalation Solution (CIS) treatment of Bronchiolitis Obliterans

闭塞性细支气管炎是肺的小气道的阻塞性疾病，其可在造血干细胞或肺移植后发展。它与长期移植存活者的相当大的发病率和死亡率相关，因此代表了这些治疗成功的主要障碍。在移植后3至5年内通常发生这种并发症的患者中，超过55%的患者可能发生闭塞性细支气管炎相关呼吸衰竭导致的死亡。造血干细胞移植和肺移植中闭塞性细支气管炎的发病机制似乎具有共同的最终途径，即免疫介导的气道上皮和上皮下结构的损伤和炎症，导致肉芽组织和纤维增殖。在造血干细胞移植后，由于移植的T细胞靶向受体呼吸道上皮上表达的同种异体抗原，慢性炎症过程发展。相反，在移植肺中发生的炎性损伤是由同种异体免疫依赖性和独立性机制引起的。这些基于免疫的炎性损伤的其他附加因素包括病毒感染和微抽吸。 治疗主要是基于增加全身免疫抑制，这导致感染和发病的风险增加。因此，闭塞性细支气管炎的常规治疗没有改善这种疾病的长期结局。 最近，环孢霉素吸入溶液（CIS：由APT制药公司制造）与丙二醇的溶液已显示出改善肺移植患者的总体存活率和慢性无排斥存活率。 这些发现表明，靶向递送免疫抑制治疗的病变器官值得进一步调查，因为这可能会减少与全身免疫抑制相关的发病率。 然而，吸入性环孢素在造血干细胞移植后BO的治疗中还没有研究。 该计划代表了NHLBI血液学分支、NIH临床中心重症监护医学部和马里兰州大学肺医学部之间的合作。 马里兰州大学肺移植项目的医学主任Aldo Iacono博士正在进行研究。Iacono博士率先开发了用于肺移植的吸入性环孢素。我们的小组被授予了一个床旁奖，以研究吸入环孢素治疗BO的安全性和有效性。 本临床方案将招募两个不同的患者人群：来自马里兰州大学的BO造血移植受者和BO肺移植受者。患者将接受吸入性环孢素的剂量滴定，最大剂量为300 mg，每周三次。 除了在血液和支气管肺泡灌洗液中测量的CIS抗炎反应的实验室标志物外，还将测量包括肺功能检查在内的临床参数。 将记录与治疗相关的不良事件。 主要目的是评估吸入性环孢素作为一种新的治疗方法在已确诊BO的造血移植患者和肺移植患者中的安全性和有效性，并促进更好地了解这两个移植组中BO的发病机制。本研究正在积极招募在第一个接受治疗的患者队列中已观察到疗效初步证据的患者

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. This study is actively accruing patients with prelimnary evidence for efficacy having already been observed in the first cohort of patients treated