Outcomes after lung transplantation remain significantly worse than after transplantation of other organs. Ischemia reperfusion injury is the leading cause for early morbidity and mortality after lung transplantation and has also been shown to be a risk factor for chronic lung rejection demonstrating its long-term effect on allografts. However, the role of ischemia reperfusion injury in regulating lung allograft rejection is not clear largely due to a lack of physiological mouse model of lung transplantation. New data from our laboratory has shown that prolonging cold ischemia from 1 hour to 18 hours induces the acute rejection of mouse lung allografts in recipients treated with perioperative blockade of CD154-CD40 and CD28-B7 pathways. This acute rejection is associated with an altered balance of regulatory and effector T cells in the allografts.
The aim of this proposal is to perform mechanistic studies in the orthotopic mouse lung transplant model to investigate how ischemia reperfusion injury-associated signals regulate adaptive immune responses that lead to allograft rejection.
The first aim of this grant will examine how Toll-like receptor signaling regulates lung allograft rejection after prolonged ischemia.
The second aim will evaluate how downstream inflammatory signals associated with ischemia reperfusion injury regulate the balance between effector and regulatory T cells after lung transplantation and control lung allograft rejection. We observed the expansion of regulatory T cells after co-culture with airway epithelial cells.
The third aim will examine how signals associated with ischemia reperfusion injury regulate the ability of airway epithelial cells to expand regulatory T cells and whether regulatory T cells, expanded through co-culture with airway epithelial cells can prevent ischemia reperfusion injury-mediated lung allograft rejection.

Public Health Relevance

Lung transplantation has become an established therapy for patients suffering from end stage lung disease. The survival after lung transplantation remains considerably worse as compared to other organs such as the heart and the liver. A major obstacle to the success of lung transplantation is ischemia reperfusion injury. We propose to study how ischemia reperfusion injury impacts lung graft survival utilizing a novel mouse model.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094601-04
Application #
8307762
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Eu, Jerry Pc
Project Start
2009-09-02
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$376,200
Indirect Cost
$128,700
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Scozzi, Davide; Wang, Xingan; Liao, Fuyi et al. (2018) Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance. Am J Transplant :
Li, Wenjun; Luehmann, Hannah P; Hsiao, Hsi-Min et al. (2018) Visualization of Monocytic Cells in Regressing Atherosclerotic Plaques by Intravital 2-Photon and Positron Emission Tomography-Based Imaging-Brief Report. Arterioscler Thromb Vasc Biol 38:1030-1036
Hsiao, Hsi-Min; Fernandez, Ramiro; Tanaka, Satona et al. (2018) Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1?. J Clin Invest 128:2833-2847
Ibrahim, Mohsen; Scozzi, Davide; Toth, Kelsey A et al. (2018) Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-?-Mediated Tumor Immune Evasion. J Immunol 200:847-856
Takahashi, T; Hsiao, H M; Tanaka, S et al. (2018) PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction. Am J Transplant 18:216-225
Gauthier, Jason M; Li, Wenjun; Hsiao, Hsi-Min et al. (2017) Mechanisms of Graft Rejection and Immune Regulation after Lung Transplant. Ann Am Thorac Soc 14:S216-S219
Scozzi, Davide; Ibrahim, Mohsen; Menna, Cecilia et al. (2017) The Role of Neutrophils in Transplanted Organs. Am J Transplant 17:328-335
Hsiao, Hsi-Min; Scozzi, Davide; Gauthier, Jason M et al. (2017) Mechanisms of graft rejection after lung transplantation. Curr Opin Organ Transplant 22:29-35
Gelman, Andrew E; Fisher, Andrew J; Huang, Howard J et al. (2017) Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 36:1114-1120
Puyo, Carlos A; Peruzzi, Daniela; Earhart, Alexander et al. (2017) Endotracheal tube-induced sore throat pain and inflammation is coupled to the release of mitochondrial DNA. Mol Pain 13:1744806917731696

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