New immunosuppressive strategies in transplantation

Immunosuppressive agents have enabled the rise of allogenic renal transplantation in the last 50 years. However, several issues remain to be solved. Calcineurin inhibitors, the cornerstone of immunosuppressive strategies, are associated with nephrotoxicity. Immunosuppressive regimens currently used do not specifically target the alto-immune response and thus favor cancers and infections. Most immunosuppressive agents target T cell activation and are not efficient enough to prevent alto-immunization in the long term. Finally, antibody mediated rejections favored by the emergence of anti-human leukocyte antigen donor specific antibodies strongly affect allograft survival. There are few validated treatments for antibody-mediated rejection (plasma exchange, intravenous immunoglobulin). The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade (lymphocyte activation). Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials. Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (Imlifidase), B cell and plasmablasts activation (anti-IL-6/IL-6R, anti-CD38...) and complement inhibition are in the pipeline, with the challenge of their evaluation in such an heterogeneous pathology. Lastly, innovative therapeutic strategies to enable transplant tolerance are being developed, based on stem cell transplantation, mesenchymal cells or regulatory cells. (C) 2022 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights reserved.