Abstract
Since the discovery of regulatory T cells (Tregs) as crucial regulators of immune tolerance against self-antigens, these cells have become a promising tool for the induction of donor-specific tolerance in transplantation medicine. The therapeutic potential of increasing in vivoTreg numbers for a favorable Treg to Teff cell ratio has already been demonstrated in several sophisticated pre-clinical models and clinical pilot trials. In addition to improving cell quantity, enhancing Treg function utilizing engineering techniques led to encouraging results in models of autoimmunity and transplantation. Here we aim to discuss the most promising approaches for Treg-enhancing therapies, starting with adoptive transfer approaches and ex vivoexpansion cultures (polyclonal vs. antigen specific), followed by selective in vivostimulation methods. Furthermore, we address next generation concepts for Treg function enhancement (CARs, TRUCKs, BARs) as well as the advantages and caveats inherit to each approach. Finally, this review will discuss the clinical experience with Treg therapy in ongoing and already published clinical trials; however, data on long-term results and efficacy are still very limited and many questions that might complicate clinical translation remain open. Here, we discuss the hurdles for clinical translation and elaborate on current Treg-based therapeutic options as well as their potencies for improving long-term graft survival in transplantation.