Lung transplantation is the only definitive treatment for many end stage lung diseases, but the lung is more prone to rejection episodes that other solid organ allografts. This is believed to be due to the presence of large number of dendritic cells in the lung that can stimulate host T-lymphocytes resulting in graft destruction. The ability of lung DC's to induce immune responses is dependent on their state of maturation: immature DC's are poor stimulators whereas, mature DC's are potent inducers of allogeneic T cells. Based on expression of the homodimer of CD8alpha+, lung DC's can be divided further into two groups: immature DC's do not express CD8alpha, whereas mature DC's are both CD8alpha+ and CD8alpha-. The inability of immature lung DC's to induce allogeneic cellular immune responses has been attributed to low level expression of MHC class II, and co-stimulatory molecules required to activate T cells. Our data shows that immature lung DC's actually suppress T cell responses by activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades the amino acid tryptophan required for T cell proliferation. In addition, the function of IDO in CD8alpha+ and CD8alpha- DC's may vary. T cell recognition of allogeneic major histocompatibility molecules expressed on DC's is believed to be the stimulus for the rejection response. This may occur either by direct allorecognition or indirect allorecognition. Unlike direct allorecognition, the role of indirect allorecognition in lung allograft rejection has not been characterized. The soluble signals from macrophages or other cells in the lung that induce DC maturation are unknown, and the differential function of mature CD8alpha+ and CD8alpha- lung DC's in regulating alloimmune responses in the lung has not been investigated. The relationship of CD8alpha expression to production of functional IDO in lung DC's has not been reported. This proposal tests the hypothesis that lung DC's mediate lung allograft rejection by examining the following specific aims:
Aim 1. To determine the role of CD11c+CD8alpha- and CD11c+CD8alpha+ DC's in regulating cellular alloimmune responses in the lung, IDO function and expression will be examined in mature compared to immature DC's, and the effect of DC-derived IDO on T cell-induced DC activation investigated. By expressing mutated and full-length CD8alpha molecules in mice genetically deficient in CD8alpha, the role of CD8alpha in DC will be established.
Aim 2. To determine the interactions between donor lung macrophages and dendritic cells and the microenvironment of the lung that lead to upregulated alloimmune responses in the allograft, soluble signals produced locally in response to the instillation of allogeneic macrophages and dendritic cells in recipient lungs will be examined for their role in facilitating rejection.
Aim 3. To determine the role of indirect allorecognition in the pathogenesis of lung allograft rejection, lung DC's will be examined for their ability to phagocytose allogeneic donor cells followed by an assessment of their ability to express donor antigens that stimulate alloimmune responses in vitro and in vivo. The contribution of """"""""empty class II"""""""" molecules on lung DC's in stimulating alloimmune responses will also be investigated.
Aim 4. To determine the role of IDO in prevention of lung allograft rejection, IDO activity will be abrogated in rats made tolerant to lung allografts. Gene therapy will also be utilized to over express IDO in allograft donor lungs prior to transplantation followed by an assessment of the rejection response.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ALTX-1 (02))
Program Officer
Reynolds, Herbert Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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
Wilkes, David S (2011) Chronic lung allograft rejection and airway microvasculature: is HIF-1 the missing link? J Clin Invest 121:2155-7
Shilling, Rebecca A; Wilkes, David S (2011) Role of Th17 cells and IL-17 in lung transplant rejection. Semin Immunopathol 33:129-34
Braun, Ruedi K; Molitor-Dart, Melanie; Wigfield, Christopher et al. (2009) Transfer of tolerance to collagen type V suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection. Transplantation 88:1341-8
Shilling, R A; Wilkes, D S (2009) Immunobiology of chronic lung allograft dysfunction: new insights from the bench and beyond. Am J Transplant 9:1714-8
Yamada, Yoshito; Sekine, Yasuo; Yoshida, Shigetoshi et al. (2009) Type V collagen-induced oral tolerance plus low-dose cyclosporine prevents rejection of MHC class I and II incompatible lung allografts. J Immunol 183:237-45
Iwata, Takekazu; Philipovskiy, Alexander; Fisher, Amanda J et al. (2008) Anti-type V collagen humoral immunity in lung transplant primary graft dysfunction. J Immunol 181:5738-47
Chiyo, M; Iwata, T; Webb, T J et al. (2008) Silencing S1P1 receptors regulates collagen-V reactive lymphocyte-mediated immunobiology in the transplanted lung. Am J Transplant 8:537-46
Bobadilla, Joseph L; Love, Robert B; Jankowska-Gan, Ewa et al. (2008) Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation. Am J Respir Crit Care Med 177:660-8
Iwata, Takekazu; Chiyo, Masako; Yoshida, Shigetoshi et al. (2008) Lung transplant ischemia reperfusion injury: metalloprotease inhibition down-regulates exposure of type V collagen, growth-related oncogene-induced neutrophil chemotaxis, and tumor necrosis factor-alpha expression. Transplantation 85:417-26

Showing the most recent 10 out of 30 publications