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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092514-04
Application #
8269926
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Eu, Jerry Pc
Project Start
2009-08-06
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
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
Chiu, Stephen; Fernandez, Ramiro; Subramanian, Vijay et al. (2016) Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity. J Immunol 197:51-7
Nayak, D K; Zhou, F; Xu, M et al. (2016) Long-Term Persistence of Donor Alveolar Macrophages in Human Lung Transplant Recipients That Influences Donor-Specific Immune Responses. Am J Transplant 16:2300-11
Bharat, Ankit; Chiu, Stephen; Zheng, Zhikun et al. (2016) Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation. Am J Respir Cell Mol Biol 55:532-541
Xu, Z; Ramachandran, S; Gunasekaran, M et al. (2016) B Cell-Activating Transcription Factor Plays a Critical Role in the Pathogenesis of Anti-Major Histocompatibility Complex-Induced Obliterative Airway Disease. Am J Transplant 16:1173-82
Xu, Zhongping; Nayak, Deepak K; Benshoff, Nicholas et al. (2015) De novo-developed antibodies to donor MHC antigens lead to dysregulation of microRNAs and induction of MHC class II. J Immunol 194:6133-43
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
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
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
Banan, Babak; Xu, Zhongping; Gunasekaran, Muthukumar et al. (2013) Role of alloimmunity and autoimmunity in allograft rejection. Clin Transpl :325-32

Showing the most recent 10 out of 30 publications