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.
Lung transplantation is the only effective treatment for patients with terminal lung diseases, such as pulmonary fibrosis, cystic fibrosis and emphysema, but the five year survival rate is still less than 50%. The proposed research is relevant to public health because the discovery of the immune mechanisms regulating chronic graft failure after lung transplantation is ultimately expected to provide new targets to develop therapies for lung transplant recipients. Thus the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human illness.
