| In order to prevent allograft rejection, current regimens include potent panimmune suppression which non-specifically target T cell activation; however, such therapies often precipitate undesirable side-effects. On the horizon is a new generation of therapies aimed at inducing a state of donor-specific tolerance, with the potential to maintain graft survival in the absence of further treatment. The use of mixed allogeneic chimerism to induce donor-specific tolerance across full MHC barriers in animal models has demonstrated the effectiveness of such an approach. However, translation to the clinical setting has been slow. In this dissertation we take three approaches to examine the current state of experimental tolerance induction.; First, by examining the synergistic effects of blocking antibodies targeting costimulatory pathways we gain new insights into how these pathways act in priming an immune response. Early activity appears to be mediated by CD28 pathway and blockade leads to suppressed expansion as well as functional maturation. The role of the CD40 pathway however has proven to be more cryptic both in vitro and in vivo, and are only evident after the initial priming phase. In a second approach, the role of alternative costimulatory pathways in skin graft survival was explored. Strikingly, expression of the inhibitory molecule PD-1 was found to be closely associated with antigen-specific T cells under conditions of maintained peripheral tolerance. In vivo inhibition of PD-1 signaling lead to the rapid rejection of otherwise healthy allogeneic skin grafts intimately linking PD-1 expression with maintained peripheral tolerance towards donor grafts.; Finally, for such therapies to be realized, hematopoietic chimerism must effectively maintain protective immunity. However, during chronic or persistent infections mixed allogeneic chimeras show profound defects in the control of persisting viral pathogens. It appears that ineffective priming of a donor-restricted CTL response can lead to the persistence of virus and subsequent pan-T cell exhaustion as well as exacerbated pathology and morbidity. These studies, taken together demonstrate both hope and a call for caution in the development of clinically translated therapies. In order for patients to realize the utmost in terms of quality of life a new generation of tolerance inducing strategies is required. |
