RORγt inverse agonist TF-S14 inhibits Th17 cytokines and prolongs skin allograft survival in sensitized mice

• Published in: Communications biology Vol. 7; no. 1; p. 454
• Main Authors: Fouda, Ahmed, Maallah, Mohamed Taoubane, Kouyoumdjian, Araz, Negi, Sarita, Paraskevas, Steven, Tchervenkov, Jean
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-04-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 631/250/127/1213; 631/250/1854/2812; 631/250/2520; 64/60; Allografts; Animals; Biomedical and Life Sciences; Cell differentiation; Cell proliferation; Class switching; Cytokines; Drug Inverse Agonism; Graft rejection; Helper cells; Humans; Immunoglobulin G; Infiltration; Inverse agonists; Leukocytes (neutrophilic); Life Sciences; Lymphocytes B; Lymphocytes T; Lymphoid tissue; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3; Skin; Th17 Cells
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06144-2

Chronic antibody mediated rejection (AMR) is the major cause of solid organ graft rejection. Th17 contributes to AMR through the secretion of IL17A, IL21 and IL22. These cytokines promote neutrophilic infiltration, B cell proliferation and donor specific antibodies (DSAs) production. In the current study we investigated the role of Th17 in transplant sensitization. Additionally, we investigated the therapeutic potential of novel inverse agonists of the retinoic acid receptor-related orphan receptor gamma t (RORγt) in the treatment of skin allograft rejection in sensitized mice. Our results show that RORγt inverse agonists reduce cytokine production in human Th17 cells in vitro. In mice, we demonstrate that the RORγt inverse agonist TF-S14 reduces Th17 signature cytokines in vitro and in vivo and leads to blocking neutrophilic infiltration to skin allografts, inhibition of the B-cell differentiation, and the reduction of de novo IgG3 DSAs production. Finally, we show that TF-S14 prolongs the survival of a total mismatch grafts in sensitized mice. In conclusion, RORγt inverse agonists offer a therapeutic intervention through a novel mechanism to treat rejection in highly sensitized patients.
In graft rejection, Th17 promotes tertiary lymphoid tissue, neutrophilic infiltration and DSAs. The RORγt inverse agonist TF-S14 inhibits Th17 cytokines, antibody class switching and prolongs allograft survival in sensitized mice.