This study aims to identify the events responsible for lung injury in lung transplant recipients at the cellular level. The broad long-term objective of this application is to define the events which incite lung injury. We believe that recruitment of a population of T cells with immediate effector function is a crucial event leading to lung injury. We also hypothesize that multiple distinct triggers provoke the influx of these cells into the transplanted lung. Demonstrating how distinct inciting events give rise to similar or disparate levels of lung injury will be an important step in understanding the pathogenesis of ultimate graft failure. Further it will provide targets for early intervention. The approach taken here is to analyze the cells recovered from the lung lavages of transplant recipients and correlate these findings with function assays which elucidate the mechanisms mediating injury. There are three specific aims to this study.
Aim 1 is to demonstrate that lung injury from multiple etiologies (primary graft dysfunction, gastroesophageal reflux, viral infection) leads to influx of armed effector T cells.
We aim to show that these triggers provoke influx of cells which have specificity against donor MHG epitopes.
In aim 2 we will explore the kinetics of the CMV specific T cell response in relationship with the emergence of CMV infection in the lung. We will directly track CMV specific cells that emerge in the setting of CMV infection to determine if particular subsets of CMV specific T cells are associated with distinct CMV related pathology.
In aim 3 we will assess the supporting environment within the lung associated with an influx of armed effector cells. In particular we are interested in the relationship between macrophage activation, the elaboration of chemokines by these macrophages, and the associated recruitment of armed effector T cells in the setting of various injurious stimuli. Finally, we will explore the correlation between injury signals detected in lung lavage fluid with the transcriptional signal of injury detected within the lung tissue itself.
Lung transplantation while often life saving is complicated by episodes of lung injury which ultimately reduce the effectiveness of the transplanted lung(s). In this proposal we will determine the events which precipitate lung injury in hopes of highlighting new therapeutic strategies to help patients with transplanted lungs live longer.
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