Combination and Adjuvant Therapies to Facilitate the Efficacy of Costimulatory Blockade

Many drugs are used to prevent allograft rejection. Most target T cells but inhibit pathways that are not exclusive to T cells and thus evoke off-target side effects. Many, particularly calcineurin inhibitors, hinder T cell receptor (TCR) signaling and thus inhibit T cells in a non-antigen-specific manner. Recently, agents targeting T cell costimulation have been developed. Costimulation molecules supplement TCR signaling and are necessary for full T cell activation. Costimulatory molecule-specific monoclonal antibodies and fusion proteins have been shown to prevent rejection in preclinical settings, and by sparing the TCR, their effects have retained antigen specificity. The CD28-CD80/86 and CD40-CD154 pathways are the most studied targets, and agents inhibiting these pathways have reached clinical trials. However, these agents cannot by themselves prevent clinical rejection. This chapter will review costimulation blockade-based agents particularly in regard to their use in combination with adjuvant therapies, including conventional immunosuppressants and agents inhibiting adhesion molecule function.