Lung transplantation (LTx) is a treatment option for end-stage pulmonary parenchymal and vascular diseases. However, long-term survival of the lung allograft is limited by the development of bronchiolitis obliterans syndrome (BOS), a condition unresponsive to therapy and often fatal. Using a newly developed anti-MHC induced model of obliterative airway disease (OAD) and LTx model, we have obtained evidence for a seminal role for alloMHC antibodies (Abs) in inducing autoimmunity, leading to the pathogenesis of OAD. Further, using a sendai viral infection, we have demonstrated an important role for post- transplant viral infection in epithelial destruction and fibroproliferation which parallels BOS following respiratory infections in LTx recipients. The goals of this project are to: 1) define the immunopathology of OAD induced by Abs to MHC class I. Towards this, we will determine: a) kinetics of auto-Ab production to collagen V and K-11 tubulin, b) define the role of T regulatory cells in the production of auto-Abs, c) analyze BAL fluid for their cytokine content, d) determine the phenotype of infiltrating cells and their cytokine, d) define the specificity of infiltrating T cells to autoantigens collagen V and K-11 tubulin, and e) determine the autoantigenic epitopes for helper T cell stimulation and Ab production. 2) Determine the mechanism of OAD development following the administration of anti-MHC class I. Towards this, we will determine;a) role of autoreactive T cellls or Abs to K-11 tubulin alone to cause OAD in native lung and in the transplanted lung, b) the role of Abs to MHC to augment OAD development together with self reactive T cells and Abs, c) mechanism by which Abs to MHC induce autoimmunity including the role of IL17 in this process, and d) the signaling cascades following ligation of autoantigen K-11 tubulin with its specific Ab in airway epithelial cells. 3) Define the role of viral infection in augmenting the development of OAD induced by anti-MHC class I. Towards this we will;a) determine the kinetics and strength of auto-Ab production and cellular infiltration, and b) determine the mechanism by which T regulatory cells are deleted following viral infection. The overall goal of this proposal is to employ unique preclinical murine models of OAD and viral infections to define the cellular and molecular mechanisms leading to autoimmunity in the pathogenesis of BOS following clinical LTx.

Public Health Relevance

The overall goal of this proposal is to employ unique preclinical murine models of obliterative airway disease and viral infections to define the cellular and molecular mechanisms leading to the pathogenesis of bronchiolitis obliterans syndrome following clinical lung transplant.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Kim, J J; Balasubramanian, R; Michaelides, G et al. (2014) The clinical spectrum of de novo donor-specific antibodies in pediatric renal transplant recipients. Am J Transplant 14:2350-8
Tiriveedhi, Venkataswarup; Banan, Babak; Deepti, Saini et al. (2014) Role of defensins in the pathogenesis of chronic lung allograft rejection. Hum Immunol 75:370-7
Subramanian, V; Ramachandran, S; Banan, B et al. (2014) Immune response to tissue-restricted self-antigens induces airway inflammation and fibrosis following murine lung transplantation. Am J Transplant 14:2359-66
Sarma, Nayan J; Tiriveedhi, Venkataswarup; Mohanakumar, T (2013) Detection of antibodies to self-antigens (K-alpha 1 tubulin, collagen I, II, IV, and V, myosin, and vimentin) by enzyme-linked immunosorbent assay (ELISA). Methods Mol Biol 1034:335-41
Angaswamy, Nataraju; Tiriveedhi, Venkataswarup; Sarma, Nayan J et al. (2013) Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection. Hum Immunol 74:1478-85
Witt, Chad A; Gaut, Joseph P; Yusen, Roger D et al. (2013) Acute antibody-mediated rejection after lung transplantation. J Heart Lung Transplant 32:1034-40
Tiriveedhi, Venkataswarup; Takenaka, Masashi; Sarma, Nayan J et al. (2013) Anti-major histocompatibility complex-induced obliterative airway disease: selective role for CD4 and CD8 T cells in inducing immune responses to self-antigens. J Heart Lung Transplant 32:714-22
Basha, Haseeb Ilias; Ramachandran, Sabarinathan; Tiriveedhi, Venkataswarup et al. (2013) Critical role for IL-17A/F in the immunopathogenesis of obliterative airway disease induced by Anti-MHC I antibodies. Transplantation 95:293-300
Weber, Joseph; Tiriveedhi, Venkataswarup; Takenaka, Masashi et al. (2012) Inhibition of renin angiotensin aldosterone system causes abrogation of obliterative airways disease through inhibition of tumor necrosis factor-?-dependant interleukin-17. J Heart Lung Transplant 31:419-26
Tiriveedhi, V; Angaswamy, N; Brand, D et al. (2012) A shift in the collagen V antigenic epitope leads to T helper phenotype switch and immune response to self-antigen leading to chronic lung allograft rejection. Clin Exp Immunol 167:158-68

Showing the most recent 10 out of 16 publications