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（适用提供）：肺移植接受者的中位移植物存活率仍然约5年，是所有实体器官移植中最糟糕的。移植后第一年后的主要死亡原因是慢性排斥反应，这表明主要是支气管炎闭塞综合征（BOS）。因此，对于防止或限制BOS进展的新治疗策略的至关重要的需要，从而有效地延长了草的生存。体外光寄生虫在BOS的治疗中表现出了希望，但是它通常被用作打捞疗法，仅在常规方法失败后才开始。最初开发用于治疗皮肤T细胞淋巴瘤的ECP也已成功地用于治疗多种疾病，包括同种异体干细胞移植后心脏同种异体移植排斥和慢性移植物与宿主疾病。但是，由于缺乏机械理解，我们最佳利用这种治疗的能力受到了严重阻碍。该提案的主要目标是在肺移植中开发ECP的鼠模型，并确定ECP调节免疫反应的机制。为此，我们开发了体外和体内模型系统，这些系统概括了ECP的关键作用以及细支气管炎的基本特征。在特定的目标1中，我们将使用由华盛顿大学研究人员开创的已建立的鼠矫形肺移植模型，以确定ECP的有效性，以防止客观气道疾病的发展。该系统将是第一个研究肺移植中ECP的动物模型。在特定的目标2中，我们将使用体外和体内方法剖析ECP调节效应T细胞功能的机制。如果成功的话，我们将建立第一个在ECP中对慢性肺同种异体移植排斥反应的治疗的体内鼠模型系统，从而使我们能够探索机制，最重要的是，确定如何最好地在肺移植者接受者预防和治疗BOS方面最好地使用ECP。从该试点项目获得的数据将提供基本信息 这将指导在小鼠和人类中的未来研究，并可能为早期使用ECP预防细支气管炎的闭塞性提供关键的支持证据。