T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in development of allograft rejection in an established MHC-II mismatched (bm12 into B6) model of chronic cardiac allograft rejection and vasculopathy (CAV). Intriguingly, and in contradistinction to IFN-?-/- mice that are protected from CAV, T-bet-/- recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17 producing CD4 T cells. Concurrently, T-bet-/- mice exhibit a Th1-deficient environment characterized by profound IFN-? deficiency, a Th2 switch characterized by increased production of IL-4, IL-5, IL-10, and IL-13 cytokines, and increased production of the proinflammatory cytokines IL-6, IL-12p40 and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection in T-bet-/- mice. Interestingly, CD4 but not CD8 T cell deficiency in T-bet-/- mice affords dramatic protection from vasculopathy and facilitates long-term graft acceptance. This is the first report establishing that in the absence of Th1 mediated alloimmune responses, CD4 Th17 cells mediate a proinflammatory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for development of novel therapies to target this intractable problem in clinical solid organ transplantation. Based on published and our preliminary data, T-bet by affecting T helper cell differentiation plays an important role in inhibiting a proinflammatory Th17 type immune response. Our central hypothesis is that Th17 immunity plays a critical role in mediating aggressive alloimmune responses, allograft rejection and resistance to tolerance induction, particularly in the absence of Th1 immunity. The main goal of this proposal is to define the functions and mechanisms of action of Th17 cells in mediating alloimmune responses in vivo and identifying targets for inhibition of Th17 immunity as a means of developing novel strategies to achieve durable and reproducible tolerance in murine transplant models to translate to non-human primates and ultimately to humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI080836-05
Application #
8427360
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$126,169
Indirect Cost
$9,346
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Sarraj, Bara; Ye, Junsheng; Akl, Ahmed Ibrahim et al. (2014) Impaired selectin-dependent leukocyte recruitment induces T-cell exhaustion and prevents chronic allograft vasculopathy and rejection. Proc Natl Acad Sci U S A 111:12145-50
D'Addio, Francesca; Ueno, Takuya; Clarkson, Michael et al. (2013) CD160Ig fusion protein targets a novel costimulatory pathway and prolongs allograft survival. PLoS One 8:e60391
D'Addio, Francesca; Boenisch, Olaf; Magee, Ciara N et al. (2013) Prolonged, low-dose anti-thymocyte globulin, combined with CTLA4-Ig, promotes engraftment in a stringent transplant model. PLoS One 8:e53797
Abadja, Farida; Sarraj, Bara; Ansari, Mohammed J (2012) Significance of T helper 17 immunity in transplantation. Curr Opin Organ Transplant 17:8-14
D'Addio, Francesca; Yuan, Xueli; Habicht, Antje et al. (2010) A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model. Transplantation 90:260-9
Yuan, Xueli; Ansari, M Javeed; D'Addio, Francesca et al. (2009) Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. Proc Natl Acad Sci U S A 106:10734-9
Yuan, Xueli; Paez-Cortez, Jesus; Schmitt-Knosalla, Isabela et al. (2008) A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med 205:3133-44