Dextrorotatory Kynurenine Suppresses Acute Rejection

Background: Acute rejection (AR) remains a critical challenge to graft survival in kidney transplantation. Although dextrorotatory-amino acids (D-AAs) have been recognized as biologically active compounds, its role in mediating immunosuppression was poorly depicted. Methods: Serum samples from renal transplant recipients were analyzed via [d0]/[d5]-estradiol-3-benzoate-17ß-chloroformate (17ß-EBC) based ion mobility-mass spectrometry (IM-MS) to assess D-AAs levels. scRNA-seq data from GSE109564 dataset were analyzed. Additionally, murine skin and kidney transplantation models were utilized to assess the in vivo impact of d-kynurenine (D-Kyn) treatment on AR. Findings: Notable differences in the dextrorotatory composition of Val, Leu, Phe, Trp, Kyn and His were detected between AR and stable patients, with higher levels of D-Kyn linked to more stable graft function. Comparing to its chiral counterpart of L-Kyn, a higher concentration of D-Kyn effectively suppresses M1 macrophage inflammatory activity through the inhibition of transcription and secretion of inflammatory cytokines via the phosphoglycerate dehydrogenase (PHGDH)/TLR4/Caspase-1 pathway. In both murine skin and kidney transplantation models, D-Kyn displayed a more potent immunosuppressive potency than L-Kyn. Treatment with D-Kyn resulted in a reduction in macrophage-mediated inflammation and CD8 T cell activation, potentially through the regulation of macrophage-derived IL-23a. Interpretation: D-Kyn holds promising therapeutic potential for enhancing graft outcomes in transplant patients experiencing AR and lay the foundation for future clinical applications from the perspective of dextrorotatory amino acids.