IL-17 and Lung Transplant Obliterative Bronchiolitis

IL-17 与肺移植闭塞性细支气管炎

基本信息

批准号：
8675925
负责人：
Rebecca A. Shilling
金额：
$ 39.08万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675925
关键词：
Allografting Antigens Autoimmune Responses Autoimmunity Bone Marrow Bronchiolitis Bronchiolitis Obliterans Cells Chimera organism Chronic Collagen Complication Cystic Fibrosis Data Development Epithelial Fibrosis Goals Graft Rejection Human Immune Immunobiology Immunologist Immunology Immunosuppressive Agents Inflammatory Injury Interleukin-10 Interleukin-17 Interleukin-6 Knowledge Lesion Lung Lung Transplantation Lung diseases Mediating Mission Modeling Morbidity - disease rate Mus Obstruction Organ Outcome Pathologic Patients Pre-Clinical Model Principal Investigator Probability Process Production Public Health Pulmonary Emphysema Pulmonary Fibrosis Research Research Personnel Rodent Rodent Model Serum Signal Transduction Solid Source Survival Rate Syndrome T-Cell Immunologic Specificity T-Lymphocyte Testing Therapeutic Intervention Transplant Recipients Transplantation Work cell type clinically relevant cytokine effective therapy graft failure improved injured airway innovation lung allograft mortality mouse model novel prevent therapy development tool

项目摘要

DESCRIPTION (provided by applicant): The 5 year survival rate of 50% for lung transplant patients is much lower compared to other solid organs due to the late complication of bronchiolitis obliterans syndrome for which there is no effective treatment. Bronchiolitis obliterans syndrome (BOS) is characterized by obliterative bronchiolitis (OB) of the airways and is immune-mediated chronic rejection of the lung. The long-term goal is to develop novel therapies to treat patients with OB/BOS. Cellular and humoral autoimmune responses can induce OB in rodent models and are associated with BOS in humans. The T cells found to be mediating autoimmunity were CD4+ IL-17 producing T cells. These studies suggest autoreactive Th17 cells promote airway injury and OB. However, the mechanisms by which IL-17 mediates airway obliteration are not known. The objective of this application is to determine the mechanisms by which IL-17 promotes lung allograft obliterative bronchiolitis. Research has been significantly hampered by the lack of a clinically relevant murine model of OB. We have now developed a novel mouse model of orthotopic lung transplantation, which unlike other models of lung transplant in rodents, develops reproducible obliteration of the airways identical to the lesion found in humans. The central hypothesis of this application is that IL-17 produced by allograft reactive T cells promotes airway fibrosis. Our hypothesis has been formulated by our own preliminary data that IL-17 blockade prevents airway fibrosis and obliteration in allografts in our model. The specific aims are: 1) Determine the extent to which T cells and IL- 17A or IL-17F are required for the development of OB; 2) Determine mechanisms by which IL-17 blockade prevents development of OB. The rationale for the proposed research is that elucidating the mechanisms by which IL-17 promotes fibrosis and by which blockade of IL-17 prevents OB will identify novel targets for therapy for OB. The proposed research is significant because it is expected to expand understanding of how OB develops and can be prevented. In our opinion, the proposed research is innovative because we have developed a reproducible pre-clinical model of OB that has a high probability of identifying novel targets for therapeutic intervention.