Chronic rejection (CR) is the leading cause of late allograft loss, and is prevalent in cardiac, lung, renal, and to a lesser degree, liver transplantation. CR is a progressive, irreversible disease that is characterized by deteriorating graft function, interstitial fibrosis, and the formation of occlusive neointima, referred to herein as transplant associated vasculopathy (TAV). We have reported that CR in mouse cardiac allografts is also associated with cardiomyocyte hypertrophy. This has clinical relevance in that cardiac allograft hypertrophy has recently been identified as a prognostic marker for TAV, heart failure, and increased patient mortality following transplantation. Hence, interstitial fibrosis, TAV, and cardiac hypertrophy are manifestations of CR. Despite intense investigation, the etiology of CR and associated pathologies are very poorly understood. Hence, reliable therapeutic targets for the prevention and treatment of CR have not been identified and no effective therapies exist except re-transplantation. Due to its profibrotic activities, TGF? stands out as the cytokine most implicated in CR. However, there are many immunosuppressive activities of TGF? which are considered beneficial in the transplant setting. Indeed, we have reported a critical role for TGF? in suppressing graft-reactive T and B cell responses in mice that accept cardiac allografts following transient depletion of CD4+ cells. What is not known is how TGF? contributes to CR and whether fibrosis inducing elements downstream of TGF? may be targeted as therapies for CR. The overall hypothesis for this proposal is that profibrotic activities of TGF? may be selectively targeted as a therapy for CR while sparing the beneficial immunosuppressive qualities of TGF? which promote graft acceptance. We have recently identified IL-6, connective tissue growth factor (CTGF), and IL-17 as mediators of CR which lie downstream of TGF? and may serve as therapeutic targets for CR. We will test this possibility and will elucidate the interactions of TGF?, IL- 6, CTGF, and IL-17 in promoting CR. The individual and synergistic contributions of these cytokines to fibrosis, TAV, and hypertrophy will be elucidated and their hierarchy as therapeutic targets will be identified. These studies will be performed in the mouse cardiac allograft model where transient depletion of CD4+ cells prolongs graft survival yet all manifestations of CR develop.
Aim 1 will test the role of recipient vs. graft derived IL-6 in CR and will determine whether targeting the IL-6 trans-signaling pathway will ablate the CR inducing effects of IL-6 on the graft, but spare the protective effects of IL-6 required for productive immune responses. Since CTGF and IL-17 both lie downstream of TGF? and IL-6, Aim 2 will elucidate the individual and cooperative roles for CTGF and IL-17 in CR and determine the effectiveness of targeting these cytokines in tandem.
Aim 3 will test the hypothesis that CD4+ cells are critical for the induction of CR, but the progression of the disease may be prevented by targeting IL-6, CTGF, and/or IL-17. These studies will provide mechanistic insight for the development of novel therapies for preventing the induction and progression of CR.

Public Health Relevance

While transplantation is the treatment of choice for end-stage organ disease, chronic allograft rejection is the main barrier to long term graft acceptance. The cause of chronic rejection is not well understood and there are currently no effective treatments for this disease except re-transplantation. The proposed studies are aimed at elucidating the underlying mediators of chronic rejection with the goal of identifying new therapeutic targets for the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070613-11
Application #
8399026
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Shah, Monica R
Project Start
2002-06-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
11
Fiscal Year
2013
Total Cost
$370,090
Indirect Cost
$132,090
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Krill, Kenneth T; Csencsits-Smith, Keri; Wood, Sherri C et al. (2013) Glucocorticoid-induced TNFR-related protein stimulation reverses cardiac allograft acceptance induced by CD40-CD40L blockade. Clin Dev Immunol 2013:986859
Booth, Adam J; Wood, Sherri C; Cornett, Ashley M et al. (2012) Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis. J Pathol 226:609-18
Booth, Adam Jared; Grabauskiene, Svetlana; Wood, Sherri Chan et al. (2011) IL-6 promotes cardiac graft rejection mediated by CD4+ cells. J Immunol 187:5764-71
Burrell, Bryna E; Bishop, D Keith (2010) Th17 cells and transplant acceptance. Transplantation 90:945-8
Booth, Adam J; Bishop, D Keith (2010) TGF-beta, IL-6, IL-17 and CTGF direct multiple pathologies of chronic cardiac allograft rejection. Immunotherapy 2:511-20
Booth, A J; Csencsits-Smith, K; Wood, S C et al. (2010) Connective tissue growth factor promotes fibrosis downstream of TGFbeta and IL-6 in chronic cardiac allograft rejection. Am J Transplant 10:220-30
Faust, Susan M; Lu, Guanyi; Wood, Sherri C et al. (2009) TGFbeta neutralization within cardiac allografts by decorin gene transfer attenuates chronic rejection. J Immunol 183:7307-13
Faust, Susan M; Lu, Guanyi; Marini, Bernard L et al. (2009) Role of T cell TGFbeta signaling and IL-17 in allograft acceptance and fibrosis associated with chronic rejection. J Immunol 183:7297-306
Diaz, J A; Booth, A J; Lu, G et al. (2009) Critical role for IL-6 in hypertrophy and fibrosis in chronic cardiac allograft rejection. Am J Transplant 9:1773-83
Burrell, Bryna E; Lu, Guanyi; Li, Xian C et al. (2009) OX40 costimulation prevents allograft acceptance induced by CD40-CD40L blockade. J Immunol 182:379-90

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