Immune Checkpoints in Solid Organ Transplantation.

Simple Summary: The immune system spontaneously recognizes and destroys foreign cells and organs when grafted into a genetically different individual. Organ transplantation is only successful because of the use of life-long immunosuppressive medications, which comes at the cost of severe toxicities. Thus, a major breakthrough in transplantation would be to be able to educate the immune system to accept grafted organs in the long term. A possible way to do that would be to exploit a physiological retro-control of the immune cells, which is based on the timely and coordinated expression of cell-surface receptors with inhibitory activities. In cancer, blocking these receptors (or Immune Checkpoints) boosts the anti-tumor functions of certain immune cells (the T-lymphocytes), with highly significant clinical benefits. Thus, it is likely that opposite actions, such as increasing the expression or the function of these receptors, would result in the dampening of the immune response against foreign organs. Further, this effect would be specific, sparing the protective immune response against pathogens. In this review, we will provide a summary of the current knowledge on the role of immune checkpoints in the context of organ transplantation and explain why and how these pathways could be manipulated to the benefit of patients. Allogenic graft acceptance is only achieved by life-long immunosuppression, which comes at the cost of significant toxicity. Clinicians face the challenge of adapting the patients' treatments over long periods to lower the risks associated with these toxicities, permanently leveraging the risk of excessive versus insufficient immunosuppression. A major goal and challenge in the field of solid organ transplantation (SOT) is to attain a state of stable immune tolerance specifically towards the grafted organ. The immune system is equipped with a set of inhibitory co-receptors known as immune checkpoints (ICs), which physiologically regulate numerous effector functions. Insufficient regulation through these ICs can lead to autoimmunity and/or immune-mediated toxicity, while excessive expression of ICs induces stable hypo-responsiveness, especially in T cells, a state sometimes referred to as exhaustion. IC blockade has emerged in the last decade as a powerful therapeutic tool against cancer. The opposite action, i.e., subverting IC for the benefit of establishing a state of specific hypo-responsiveness against auto- or allo-antigens, is still in its infancy. In this review, we will summarize the available literature on the role of ICs in SOT and the relevance of ICs with graft acceptance. We will also discuss the possible influence of current immunosuppressive medications on IC functions. [ABSTRACT FROM AUTHOR]