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 #
1R01HL092514-01A2
Application #
7737001
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Reynolds, Herbert Y
Project Start
2009-08-06
Project End
2013-05-31
Budget Start
2009-08-06
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$380,000
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sharma, Monal; Ravichandran, Ranjithkumar; Bansal, Sandhya et al. (2018) Tissue-associated self-antigens containing exosomes: Role in allograft rejection. Hum Immunol 79:653-658
Nayak, Deepak K; Mendez, Oscar; Bowen, Sara et al. (2018) Isolation and In Vitro Culture of Murine and Human Alveolar Macrophages. J Vis Exp :
Gunasekaran, Muthukumar; Sharma, Monal; Hachem, Ramsey et al. (2018) Circulating Exosomes with Distinct Properties during Chronic Lung Allograft Rejection. J Immunol 200:2535-2541
Scozzi, Davide; Wang, Xingan; Liao, Fuyi et al. (2018) Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance. Am J Transplant :
Bansal, Sandhya; Sharma, Monal; R, Ranjithkumar et al. (2018) The role of exosomes in allograft immunity. Cell Immunol 331:85-92
Sharma, Monal; Liu, Wei; Perincheri, Sudhir et al. (2018) Exosomes expressing the self-antigens myosin and vimentin play an important role in syngeneic cardiac transplant rejection induced by antibodies to cardiac myosin. Am J Transplant 18:1626-1635
Lama, Vibha N; Belperio, John A; Christie, Jason D et al. (2017) Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop. JCI Insight 2:
Bharat, Ankit; Mohanakumar, T (2017) Immune Responses to Tissue-Restricted Nonmajor Histocompatibility Complex Antigens in Allograft Rejection. J Immunol Res 2017:6312514
Nayak, Deepak K; Zhou, Fangyu; Xu, Min et al. (2017) Zbtb7a induction in alveolar macrophages is implicated in anti-HLA-mediated lung allograft rejection. Sci Transl Med 9:
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

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