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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Allergy & Clinical Immunology-1 (AITC)
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Prograis, Lawrence J
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Neujahr, D C; Uppal, K; Force, S D et al. (2014) Bile acid aspiration associated with lung chemical profile linked to other biomarkers of injury after lung transplantation. Am J Transplant 14:841-8
Sueblinvong, Viranuj; Neujahr, David C; Mills, S Todd et al. (2012) Predisposition for disrepair in the aged lung. Am J Med Sci 344:41-51
Neujahr, D C; Perez, S D; Mohammed, A et al. (2012) Cumulative exposure to gamma interferon-dependent chemokines CXCL9 and CXCL10 correlates with worse outcome after lung transplant. Am J Transplant 12:438-46
Force, Seth D; Kilgo, Pat; Neujahr, David C et al. (2011) Bilateral lung transplantation offers better long-term survival, compared with single-lung transplantation, for younger patients with idiopathic pulmonary fibrosis. Ann Thorac Surg 91:244-9
Neujahr, David C; Larsen, Christian P (2011) Regulatory T cells in lung transplantation--an emerging concept. Semin Immunopathol 33:117-27
Grove, Daniel A; Xu, Jianguo; Joodi, Robert et al. (2011) Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation. J Heart Lung Transplant 30:341-50
Mohammed, A; Ulukpo, O; Lawrence, E C et al. (2011) Cumulative exposure to CD8+ granzyme Bhi T cells is associated with reduced lung function early after lung transplantation. Transplant Proc 43:3892-8
Neujahr, David C; Mohammed, Aminu; Ulukpo, Onome et al. (2010) Surgical correction of gastroesophageal reflux in lung transplant patients is associated with decreased effector CD8 cells in lung lavages: a case series. Chest 138:937-43
Mohammed, Aminu; Neujahr, David C (2010) Gastroesophageal reflux disease and graft failure after lung transplantation. Transplant Rev (Orlando) 24:99-103
Shah, N; Force, S D; Mitchell, P O et al. (2010) Gastroesophageal reflux disease is associated with an increased rate of acute rejection in lung transplant allografts. Transplant Proc 42:2702-6

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