Targeting T cell modulation with novel bile acid derivatives in autoimmunity 2982

Abstract Description Recent research identified derivatives of lithocholic acid (LCA) as immunomodulators of T cell differentiation. Specifically, 3-oxoLCA and isoLCA inhibit Th17 cells, while isoalloLCA promotes Treg cells in the absence of antigen-presenting cells. Using the steroid nucleus gonane and hydroxy/oxo groups at position three, a 64-bile acid library was designed by altering oxidation states, functional groups, and stereochemistry. In single-dose screening under Th17- or Treg-differentiating conditions, nine and two bile acids outperformed or matched their positive controls, respectively. Subsequent dose-response assays revealed that sarsasapogenin (BA26) consistently outperformed both positive controls at 20 µM, inhibiting Th17 cells and promoting Treg cells. An androstan-17-one derivative (BA59) surpassed 3-oxoLCA in single-dose and showed similar trends than the positive control in dose-response screening. In experimental autoimmune encephalomyelitis (EAE) mice, oral treatment with 5 mg/kg BA26 or 25 mg/kg BA59 for three weeks (initiated when clinical scores reached ≥1) resulted in a lower AUC of clinical scores for BA59-treated mice (34.48 ± 13.98 vs. 45.85 ± 14.47 for vehicle, p = 0.078, n = 12 animals/group). BA59 increased regulatory T cells, elevated central memory CD8+ T cells, and reduced the CD4/CD8 ratio in the periphery. Ongoing experiments are evaluating higher doses of BA26, combinations of both bile acids, and are also confirming previous data with BA59. Funding Sources This work was supported by the Weill Cornell Startup Fund and by the “Agència de Gestió d’Ajuts Universitaris i de Recerca” (AGAUR; Generalitat de Catalunya) through Consolidated Research Groups 2021SGR00002 and 2017SGR527. Topic Categories Therapeutic Approaches to Autoimmunity (THER)