Person:

D'Addio, Francesca

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-γ−/− 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-γ 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.

Heart transplantation was performed for the first time 40 years ago and it is now universally considered the “gold standard” treatment for individuals suffering from end-stage heart failure. The increased understanding of the molecular mechanisms and of the role of the immune system in allograft rejection led to an overall improvement of graft survival, which is now around 10 years. The introduction of novel immunosuppressive drugs reduced the rate of acute allograft rejection but did not improve significantly the long-term graft survival. In addition, adverse effects (e.g. infections, cancer and renal failure) associated with immunosuppressive drugs are increasing over time and may affect post-transplantation outcomes. An immunosuppression-free protocol based on tolerance induction is the Holy Grail for heart transplant recipients, but it is still far beyond our reach. In this review, we discuss the landscape of immunological challenges that heart transplanted individuals face and we critically review the novel immunological approaches available to overcome these remaining issues. Some of the novel approaches, successfully tested in preclinical and clinical models, may lead to a prolongation of patient’s and heart allograft survival.