Potential Impact of Extracorporeal Photopheresis on Trained Immunity and Organ Transplant Acceptance

Extracorporeal photopheresis (ECP) is a well-established, safe, and effective immunomodulatory therapy currently used in clinics to decrease T cell-mediated immunity in various disorders, including autoimmune diseases and chronic rejection in organ transplantation. Although the ECP procedure has been shown to induce apoptotic cells that are reintroduced into the patient at the end of the treatment, the precise tolerogenic mechanisms mediated by ECP are not fully understood. Previous in vitro studies have demonstrated that early apoptotic cells express annexins on their cell surface, which suppress myeloid cell activation on stimulation with bacterial lipopolysaccharide through Toll-like receptors. Mechanistically, annexins prevent the upregulation of costimulatory molecules (CD40 and CD86) and decrease the secretion of proinflammatory cytokines (tumor necrosis factor and interferon-γ) through nuclear factor kappa B signaling pathways, altogether inhibiting antigen-specific T-cell responses in vivo. In human and mouse bone marrow-derived macrophages, binding of annexin to Dectin-1, a c-type lectin receptor, promotes peripheral tolerance through the spleen tyrosine kinase signaling pathway and NADPH oxidase 2 downstream activation. In animal models, the synergistic activation of Dectin-1 and Toll-like receptor 4 by damage-associated molecular patterns in graft-infiltrating monocytes leads to the induction of trained immunity. Because trained immunity prevents long-term allograft survival in organ transplant recipients, we hypothesize pretreatment with ECP represents a potential unexplored therapeutic option to favor transplantation tolerance. Specifically, ECP may serve as a prophylactic therapy to prevent trained immunity in contexts involving the activation of the Dectin-1 pathway.