Lung transplantation is the only definitive therapy for many forms of endstage lung disease, but chronic rejection remains the major impediment to the long term survival of the lung transplant recipient. Allthough anti-donor (allo-)T and B cell immunity is known to be involved in the rejection response, the co-POIs of this Program have reported that T cell-mediated autoimmunity to a minor collagen, type V collagen [col(V)], is the major risk factor for chronic rejection, known as obliterative bronchiolitis/bronchiolitis obliterans syndrome, which is the leading cause of death in lung transplant recipients. In addition, the co-PIs have reported that anti-col(V) humoral immunity is the major risk factor for primary graft dysfunction (PGD) which is the leading cause of early death post transplantation and a risk factor for acute rejection and OB/BOS. IL-17A produced by col(V)-reactive T cells and known to key roles in autoimmune disease, also has a key role in col(V)-reactive T cell-mediated OB and PGD. However, the role of IL-17A in stimulating anti-col(V) antibody responses, and the eptitopes recognized by these antibodies are unknown. In addition, the role of macrophages, reported to have a central role in IL-17A induction, is unknown. This application tests the hypothesis that IL-17A induced anti-col(V) humoral immunity contributes to the pathogenesis of acute rejection and OB by examining the following specific aims: 1. Determine the epitopes recognized by anti-col(V) producing B cells in patients post lung transplantation, as well as the pre-transplant conditions associated with this response.
Aim 2. Determine if anti-col(V) antibody production is 1L-17A dependent and if IL-17A facilitates anti-col(V) antibody mediated pathology in lung transplants.
Aim 3. Determine if macrophages are the antigen presenting cells responsible for stimulating anti-col(V) humoral immunity.
Aim 4. Determine if col(V)-induced tolerance will prevent 1L-17A production and anti-col(V) antibody synthesis.

Public Health Relevance

This application will determine the role of antibodies to col(V), an autoantigen, in the pathogenesis of lung transplant rejection. In addition, these studies will provide greater understanding of the role of autoimmunity to col(V) in the rejection response. The objective of these studies is to identify potential targets for therapeutic intervention to prolong the life of the lung transplant patient.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Muir, Alison M; Massoudi, Dawiyat; Nguyen, Ngon et al. (2016) BMP1-like proteinases are essential to the structure and wound healing of skin. Matrix Biol 56:114-131
Pandya, Pankita H; Fisher, Amanda J; Mickler, Elizabeth A et al. (2016) Hypoxia-Inducible Factor-1? Regulates CD55 in Airway Epithelium. Am J Respir Cell Mol Biol 55:889-898
Park, Arick C; Huang, Guorui; Jankowska-Gan, Ewa et al. (2016) Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance. J Biol Chem 291:3359-70
Agashe, Vrushali V; Burlingham, William J (2015) Autoimmune Reactivity in Graft Injury: Player or Bystander? Curr Transplant Rep 2:211-221
Wu, Qiang; Gupta, Pawan Kumar; Suzuki, Hidemi et al. (2015) CD4 T Cells but Not Th17 Cells Are Required for Mouse Lung Transplant Obliterative Bronchiolitis. Am J Transplant 15:1793-1804
Park, Arick C; Phillips, Charlotte L; Pfeiffer, Ferris M et al. (2015) Homozygosity and Heterozygosity for Null Col5a2 Alleles Produce Embryonic Lethality and a Novel Classic Ehlers-Danlos Syndrome-Related Phenotype. Am J Pathol 185:2000-11
Pandya, Pankita H; Wilkes, David S (2014) Complement system in lung disease. Am J Respir Cell Mol Biol 51:467-73
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
Sullivan, J A; Jankowska-Gan, E; Shi, L et al. (2014) Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses. Am J Transplant 14:1512-22
Gracon, Adam S A; Wilkes, David S (2014) Lung transplantation: chronic allograft dysfunction and establishing immune tolerance. Hum Immunol 75:887-94

Showing the most recent 10 out of 31 publications