Indoleamine 2,3-dioxygenase protective role in lung transplantation

吲哚胺2,3-双加氧酶在肺移植中的保护作用

• 批准号: 7392417
• 负责人: GARY A VISNER
• 金额: $ 39.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-02 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392417
• 关键词: Acute; Allografting; Anti-Infective Agents; Antigen-Presenting Cells; Antioxidants; Blood; Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Cell Line; Cell surface; Cells; Chronic; Collagen; Complication; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Enzymes; Epithelial Cells; Fibroblasts; Fibrosis; Flow Cytometry; Generations; Goals; Graft Survival; Growth Factor; Histology; Immune; Immunohistochemistry; Immunophenotyping; In Vitro; Inflammatory; Injury; Interferons; Interleukin-10; Interleukin-12; Interleukin-4; Interleukin-6; Interleukins; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Measures; Mediating; Methods; Mission; Mixed Lymphocyte Culture Test; Modeling; Organ Survival; Organ Transplantation; Patients; Phase; Phenotype; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Process; Property; Protein Overexpression; Public Health; Rattus; Relative (related person); Research Personnel; Respiratory physiology; Role; Sleeping Beauty; Solid; Staging; Structure of parenchyma of lung; System; T-Cell Proliferation; T-Lymphocyte; Technology; Therapeutic; Time; Transforming Growth Factors; Transplant Recipients; Transplantation; Transposase; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral Genes; base; chemokine; cytokine; cytotoxic; cytotoxicity; day; gene delivery system; human TNF protein; improved; in vivo; killings; lung allograft; lymph nodes; pathogen; prevent; programs; protective effect; response; success; transgene expression

DESCRIPTION (provided by applicant): The overall goal of this proposal is to improve long-term survival of organ transplants with particular emphasis on lung transplantation. This is particularly relevant to the mission of the agency since 5 year survival (40-50%) of lung transplants is far below what is seen for other solid organ transplants. Acute and chronic rejection/bronchiolitis obliterans (BO) are major limiting factors for long-term lung allograft survival with chronic rejection coming from progression of the profibroproliferative process and the lung's relative inability for developing transplant tolerance. We have recently shown that indoleamine 2,3-dioxygenase (IDO) results in protection against acute rejection using a rat orthotopic lung allograft model. IDO is an inducible enzyme of tryptophan metabolism with immune modulating and potentially anti-fibrotic properties that may provide long-term graft survival effects. In this proposal, we plan to further evaluate IDO's role in protecting not only against an acute rejection, but also against the development of transplant mediated fibrosis as an indicator of chronic rejection. There are two major aims for this proposal. The first aim will determine whether the non-viral gene system (Sleeping Beauty transposon/transposase) generates long term IDO expression and protection of rat lung transplants. We will examine if IDO's graft survival properties are mediated by non-immune mechanisms in preventing transplant associated fibrosis through its interaction with profibrotic cytokines and inhibiting fibroblast proliferation. The second aim will determine whether IDO inhibits the alloimmune phase of rejection by promoting transplant tolerance. We will examine if augmented IDO in lung allografts 1) results in a tolerant phenotype in vivo 2) maintains dendritic cells in an immature/tolerant state 3) promotes the development of T regulatory/suppressive cells 4) if target cells with IDO expression are protected against cytotoxic T cells. Lung transplantation is an accepted therapy for patients with end-stage lung disease. Unfortunately its success has been limited by the development of chronic rejection. This project has significant relevance to public health since IDO with its ability to prevent transplant-associated fibrosis and promote acceptance (tolerance) of the lung transplant in which both would enhance long-term survival makes it a potential therapeutic option in lung transplantation.

描述（由申请人提供）：该提案的总体目标是提高器官移植的长期生存，并特别强调肺移植。这与该机构的任务特别相关，因为5年生存（40-50％）的肺移植物远低于其他固体器官移植物所见。急性和慢性排斥/支气管炎闭塞性（BO）是长期肺同种异体移植生存的主要限制因素，慢性排斥反应来自于果蛋白果局果果局的过程的进展，并且肺对发展移植耐受的相对无能。我们最近表明，使用大鼠原位肺同种异体移植模型，吲哚胺2,3-二加氧酶（IDO）可防止急性排斥。 IDO是色氨酸代谢的诱导酶，具有免疫调节和潜在的抗纤维化特性，可能会提供长期的移植生存作用。在该提案中，我们计划进一步评估IDO在保护急性排斥反应中的作用，还可以免受移植介导的纤维化的发展，以此作为慢性排斥反应的指标。该提案有两个主要目标。第一个目标将确定非病毒基因系统（睡美人转座子/转座酶）是否会产生长期的IDO表达和大鼠肺移植物的保护。我们将检查IDO的移植物生存特性是否是通过与纤维化细胞因子相互作用并抑制成纤维细胞增殖来防止移植相关纤维化方面的非免疫机制介导的。第二个目标将确定IDO是否通过促进移植耐受性抑制了同种免疫阶段。我们将检查肺同种异体移植中的增强IDO是否会导致体内耐受的表型2）在不成熟/耐受状态下保持树突状细胞3）促进T调节/抑制细胞的发展4）如果具有IDO表达的靶细胞对胞毒性T细胞进行保护。肺移植是针对末期肺部疾病患者的公认疗法。不幸的是，它的成功受到了慢性拒绝的发展限制。自IDO以来，该项目具有与公共卫生的重要相关性，其能够防止移植相关的纤维化并促进肺移植的接受（耐受性），在这种肺移植中，这两者都可以增强长期生存，从而使其成为肺移植中潜在的治疗选择。