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¹ Transplantation.Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School and ² Harvard School of Public Health and Harvard Medical School, Boston, MA 02115
³ Division of Nephrology and Division of Organ Transplantation. Northwestern University Feinberg School of Medicine, Chicago, IL 60611

CORRESPONDENCE Mohamed H. Sayegh: msayegh{at}rics.bwh.harvard.edu OR M. Javeed Ansari: jansari{at}northwestern.edu

T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in the development of allograft rejection in an established MHC class II–mismatched (bm12 into B6) model of chronic allograft vasculopathy (CAV). Intriguingly, and in contrast 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 T helper type 1 (Th1)–deficient environment characterized by profound IFN- deficiency, a Th2 switch characterized by increased production of interleukin (IL) 4, IL-5, IL-10, and IL-13 cytokines, as well as increased production of the proinflammatory cytokines IL-6, IL-12p40, and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection and vasculopathy 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 study establishing that in the absence of Th1-mediated alloimmune responses, CD4 Th17 cells mediate an aggressive proinflammatory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for the development of novel therapies to target this intractable problem in clinical solid organ transplantation.

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