Primary Graft Dysfunction (PGD) is severe acute lung injury after lung transplantation. PGD has a major impact on outcomes following lung transplantation, markedly increasing morbidity, mortality, and cost. Thus, reduction in the incidence of PGD would dramatically improve clinical and economic outcomes following lung transplantation. Despite the clear importance of PGD to lung transplantation, fundamental questions about mechanisms that increase PGD risk remain unanswered. Type V collagen [col(V)] is a native lung collagen that may become exposed and cause autoimmunity in the setting of lung inflammation. Recent work by our group suggests that both humoral and cellular immunity to col(V) are involved in PGD pathogenesis. Furthermore, our prior studies suggest that autoimmunity to col(V) is present in recipients prior to the transplant procedure and may thus be used to predict PGD. However, the pre-transplant lung diseases associated anti-col(V) immunity have not been defined, and the utility of this immune response as a predictor of PGD is unknown. Furthermore, the T cell subset involved in anti-col(V)-induced PGD is unknown, and mechanisms of anti-col(V) antibody mediated injury have not been reported. Utilizing a large prospective multicenter clinical study, and our rat lung transplant model that reproduces the clinical condition, we hypothesize that autoimmunity to col(V) influences the risk of PGD following lung transplantation in recipients, and can be utilized to predict PGD. This translational application combines the strengths of the two principal investigators whom were the first to define clinical PGD, and anti- col(V) immunity in the pathogenesis PGD. The application will leverage data collected as part of the Lung Transplant Outcomes Group, which is an ongoing 10 center cohort study of PGD pathogenesis, with Dr. Christie as PI. Laboratory aims will be expand prior discoveries by Dr. Wilkes at IU. The goals of our Aims are to provide insight into the mechanisms of PGD by anti-col(V) autoimmunity in human and laboratory models, to test the utility of anti-col(V) antibodies in prediction of clinical PGD, and to set the stage for clinical trials of tolerance strategies to col(V) in lung transplantation. To achieve these aims, both laboratory and clinical methods will be employed to provide a comprehensive, integrated body of knowledge on the role of col(V) autoimmunity in PGD pathogenesis. Clinical and biological aims will be fully integrated to apply mechanistic insight from laboratory to human populations, and to test the mechanistic underpinnings of clinical observations. The output of this application will provide needed data for potential clinical trials.

Public Health Relevance

Primary graft dysfunction (PGD) is a severe acute lung injury syndrome occurring in the days after lung transplantation, markedly increasing morbidity, mortality, and cost. Type V collagen [col(V)] is a native lung collagen that may become exposed and cause autoimmunity in the setting of lung inflammation, and recent work by our group suggests that auto-immunity to col(V) is involved in PGD pathogenesis. The goals of our highly translational Aims are to provide insight into the mechanisms of PGD by anti-col(V) autoimmunity in human and laboratory models, to test the utility of anti-col(V) antibodies in prediction of clinical PGD, and to conduct pre-clinical studies that set the stage for clinical trials of tolerance strategies to col(V) in lung transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096845-04
Application #
8469561
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2010-05-14
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$560,115
Indirect Cost
$85,485
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Eberlein, Michael; Reed, Robert M; Bolukbas, Servet et al. (2015) Lung size mismatch and primary graft dysfunction after bilateral lung transplantation. J Heart Lung Transplant 34:233-40
Cantu, Edward; Shah, Rupal J; Lin, Wei et al. (2015) Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation. J Thorac Cardiovasc Surg 149:596-602
Diamond, Joshua M; Akimova, Tatiana; Kazi, Altaf et al. (2014) Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med 189:567-75
Shah, Rupal J; Christie, Jason D (2014) Response. Chest 145:193
Pandya, Pankita H; Wilkes, David S (2014) Complement system in lung disease. Am J Respir Cell Mol Biol 51:467-73
Chatterjee, Shampa; Nieman, Gary F; Christie, Jason D et al. (2014) Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307:L668-80
Weber, Daniel J; Gracon, Adam S A; Ripsch, Matthew S et al. (2014) The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation. Sci Transl Med 6:252ra124
Gu, Hongmei; Mickler, Elizabeth A; Cummings, Oscar W et al. (2014) Crosstalk between TGF-?1 and complement activation augments epithelial injury in pulmonary fibrosis. FASEB J 28:4223-34
Shah, Rupal J; Emtiazjoo, Amir M; Diamond, Joshua M et al. (2014) Plasma complement levels are associated with primary graft dysfunction and mortality after lung transplantation. Am J Respir Crit Care Med 189:1564-7
Diamond, Joshua M; Lee, James C; Kawut, Steven M et al. (2013) Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med 187:527-34

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