Lung transplantation (LTx) is a viable treatment option for end-stage pulmonary diseases. Unfortunately long-term survival and function of lung allografts is limited by development of chronic rejection that is clinically diagnosed as bronchiolitis obliterans syndrome (BOS), an irreversible condition unresponsive to therapy and often fatal. Using newly developed models of obliterative airway disease (OAD), we demonstrated a seminal role for antibodies (Abs) to MHC and to lung self-antigens (Ags) (K?1 Tubulin (K?1T) and Collagen V (Col-V)) in inducing cellular and humoral immune responses to self-Ags and MHC leading to OAD. Passive administration of Abs resulted in induction of several important molecules involved in the activation of T helper cells (Zbtb7a), inflammatory cascade (Laptm5) and limiting regulatory T cell populations (Mt1). Our results using syngeneic and allogenic murine single LTx models have demonstrated that administration of Abs to lung Ags can lead to OAD. Further, we have evidence that Abs to MHC as well as Abs to K?1T or Col-V can break tolerance to lung allografts resulting in OAD in a MHC mismatch LTx model in which tolerance was established using co-stimulatory blockade. Administration of anti-K?1T resulted in not only cellular autoimmunity to K?1T but also cellular as well as humoral responses to Col-V and donor MHC indicating spreading of immune responses in lung allograft rejection. These results collectively demonstrate an important role for Abs to MHC and self-Ags in the pathogenesis of OAD. The goals of this project are to: 1) define the early events following administration of Abs that leads to activation of T helper cells, inflammatory cascade, and T regulatory cells using RNA interference based targeted gene knockdown, 2) to define the mechanisms by which anti-MHC and anti-lung self-Ags induce exosome formation and define the role of exosomes in the spreading of immune responses. We demonstrated that bronchoalveolar lavage (BAL) fluids from mice following administration of Abs as well as anti-MHC (DSA)+ human LTx recipients contain increased concentration of exosomes in the local milieu, which express lung self-Ags (K?1T, Col-V and Col-I). Our hypothesis is that these exosomes play an essential role in eliciting augmented immune responses leading to intermolecular spreading, breaking of tolerance and allograft rejection. Towards this we will isolate and characterize exosomes from BAL fluid and determine if immunization with exosomes regulates the polarization and switch in macrophage phenotypes that stimulates auto-immune and alloimmune responses, and 3) determine the role of neutrophils in the Ab induced exosome formation in murine LTx. The overall goal of this proposal is to employ unique preclinical murine models of OAD to delineate the molecular mechanisms leading to autoimmunity in the pathogenesis of BOS following human LTx and to develop new therapeutic strategies towards preventing and/or treating chronic lung allograft rejection.

Public Health Relevance

The overall goals of this proposal is to employ unique preclinical murine models of obliterative airway disease of native and transplanted lungs and to define the role of anti-MHC induced immune responses to self-antigens (autoimmunity) in the pathogenesis of chronic rejection following lung transplantation and to develop strategies to prevent it.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092514-08
Application #
9475299
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Craig, Matt
Project Start
2009-08-06
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
St. Joseph's Hospital and Medical Center
Department
Type
DUNS #
131606022
City
Phoenix
State
AZ
Country
United States
Zip Code
85013
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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