RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice.

The receptor for advanced glycation endproducts (RAGE) is involved in multiple inflammatory processes. RAGE participates in adaptive and innate immune responses but its role in human immune cell responses has not been directly tested in vivo. We treated humanized mice (NSG) with the small molecule antagonist of RAGE, azeliragon, (AZ), and measured effects on xenogeneic (B6) skin graft rejection. AZ delayed the median time to xenograft rejection (22 vs 56 days, P = 0.0001). PD-1 expression on CD4+ and CD8+ T cells was lower following AZ therapy. Transcriptome studies showed inhibition of pathways in splenocytes with AZ including IL-23, IL-17A and IL-1β signaling. The serum levels of IL-1β and IL-17A in AZ treated mice were reduced in mice that did not reject skin grafts. The RAGE antagonist prevented xenograft rejection by human immune cells in a murine model. A RAGE antagonist may be a useful inhibitor of adaptive human immune responses. • The receptor for glycation endproducts (RAGE) has been found to play an important role in innate and adaptive immune cell signaling and function largely in murine models • We show that a RAGE antagonist, azeliragon, modulated the rejection of xenogeneic skin grafts by human cells in in humanized mice • RAGE antagonism decreased expression of PD-1 on CD4 and CD8+ T cells and also reduces expression of genes associated with inflammatory pathways, particularly IL-17 production. • Blockade of RAGE may be an effective strategy for inhibiting unwanted adaptive and innate immune responses.