Costimulatory pathways in transplantation

Abstract

Secondary, so-called costimulatory, signals are critically required for the process of T cell activation. Since landmark studies defined that T cells receiving a T cell receptor signal without a costimulatory signal, are tolerized in vitro, the investigation of T cell costimulation has attracted intense interest. Early studies demonstrated that interrupting T cell costimulation allows attenuation of the alloresponse, which is particularly difficult to modulate due to the clone size of alloreactive T cells. The understanding of costimulation has since evolved substantially and now encompasses not only positive signals involved in T cell activation but also negative signals inhibiting T cell activation and promoting T cell tolerance. Costimulation blockade has been used effectively for the induction of tolerance in rodent models of transplantation, but turned out to be less potent in large animals and humans. In this overview we will discuss the evolution of the concept of T cell costimulation, the potential of 'classical' and newly identified costimulation pathways as therapeutic targets for organ transplantation as well as progress towards clinical application of the first costimulation blocking compound.

Fig. 1

Costimulatory pathways relevant in transplantation. (a) Expression patterns of costimulatory molecules on T cells and APC are depicted. Categorization according to structure and function as positive or negative signalling pathway are indicated. (b) Costimulation blockers in (pre)clinical development and their ligands are depicted. Signals inhibited by these compounds are shown in grey.