MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN THE TREATMENT OF LUNG ALLOGRAFT REJECTION

体外光采术治疗同种异体肺排斥反应的机制

• 批准号: 9056994
• 负责人: Andrew Eric Gelman
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056994
• 关键词: Allogenic; Allografting; Animal Model; Antigens; Biological Models; Bronchiolitis Obliterans; CD28 gene; Cause of Death; Cell physiology; Cells; Chronic; Contact hypersensitivity; Cutaneous; Cyclosporine; Data; Development; Disease; Effectiveness; Effector Cell; Family; Functional disorder; Future; Goals; Graft Survival; Health; Histology; Human; Immune; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Injection of therapeutic agent; Institutes; Lesion; Lung; Lung Transplantation; Mediating; Methylprednisolone; Modeling; Mus; Observational Study; Operative Surgical Procedures; Organ; Organ Transplantation; Pathway interactions; Patients; Pharmaceutical Preparations; Photopheresis; Pilot Projects; Prevention; Refractory; Regimen; Regulatory T-Lymphocyte; Research Personnel; Salvage Therapy; Solid; Splenocyte; Stem cell transplant; Stem cells; Syndrome; System; T cell response; T-Cell Lymphoma; T-Lymphocyte; Techniques; Testing; Transplant Recipients; Transplantation; Universities; Washington; Work; allograft rejection; chronic graft versus host disease; effective therapy; heart allograft; immunosuppressed; improved; in vitro Model; in vivo; in vivo Model; lung allograft; mouse model; prevent; receptor; response; standard of care; therapy development; tool; treatment strategy

 DESCRIPTION (provided by applicant): Median graft survival for recipients of lung transplants remains approximately 5 years, the worst of all solid organ transplants. The major cause of death after the first year post-transplantation is chronic rejection, manifest primarily as bronchiolitis obliterans syndrome (BOS). Therefore, there is a critical unmet need for new treatment strategies that prevent or limit the progression of BOS and will thereby effectively prolong graft survival. Extracorporeal photopheresis has shown promise in the treatment of BOS, however it is typically used as a salvage therapy, instituted only after conventional approaches have failed. Initially developed for the treatment of cutaneous T cell lymphoma, ECP has also been successfully used to treat a number of diseases, including cardiac allograft rejection and chronic graft versus host disease following allogeneic stem cell transplantation. However, our ability optimally utilize this treatment is severely hampered by a lack of mechanistic understanding. The major goals of this proposal are to develop a murine model of ECP in lung transplantation, and to determine the mechanism by which ECP modulates the immune response. To accomplish this, we have developed in vitro and in vivo model systems which recapitulate the key effects of ECP, as well as the essential features of bronchiolitis obliterans. In specific aim 1, we will use an established murine orthotopic lung transplant model, pioneered by Washington University researchers, to determine the effectiveness of ECP to prevent the development of obliterative airways disease. This system will be the first, animal model to investigate ECP in lung transplantation. In specific aim 2, we will use both in vitro and in vivo approaches to dissect the mechanism by which ECP modulates effector T cell function. If successful, we will have established the first in vivo murine model system of the treatment of chronic lung allograft rejection with ECP, allowing us to explore mechanism, and most importantly, to determine how best to use ECP in the prevention and treatment of BOS in lung transplant recipients. The data obtained from this pilot project will provide essential information that will guide future studies in both mice and humans, and may provide critical supportive evidence for the early use of ECP to prevent bronchiolitis obliterans.

 描述（由申请人提供）：肺移植受者的中位移植物存活期约为5年，是所有实体器官移植中最差的。移植后第一年死亡的主要原因是慢性排斥反应，主要表现为闭塞性细支气管炎综合征（BOS）。因此，对于预防或限制BOS进展并从而有效延长移植物存活的新治疗策略存在关键的未满足的需求。体外循环血液分离术在治疗BOS方面显示出了希望，然而它通常被用作挽救治疗，仅在常规方法失败后才开始。ECP最初是为治疗皮肤T细胞淋巴瘤而开发的，也已成功用于治疗许多疾病，包括心脏同种异体移植物排斥反应和异基因干细胞移植后的慢性移植物抗宿主病。然而，我们最佳利用这种治疗的能力受到缺乏机械理解的严重阻碍。 本研究的主要目的是建立小鼠肺移植中ECP的模型，并确定ECP调节免疫应答的机制。为了实现这一点，我们已经开发了体外和体内模型系统，概括了ECP的关键作用，以及闭塞性细支气管炎的基本特征。在具体目标1中，我们将使用由华盛顿大学研究人员开创的已建立的小鼠原位肺移植模型来确定ECP预防闭塞性气道疾病发展的有效性。该系统将是第一个研究ECP在肺移植中的动物模型。在具体目标2中，我们将使用体外和体内方法来剖析ECP调节效应T细胞功能的机制。如果成功，我们将建立第一个用ECP治疗慢性肺移植排斥反应的体内小鼠模型系统，使我们能够探索机制，最重要的是，确定如何最好地使用ECP预防和治疗肺移植受者的BOS。从这一试验项目中获得的数据将提供基本信息 这将指导未来在小鼠和人类中的研究，并可能为早期使用ECP预防闭塞性细支气管炎提供关键的支持性证据。