Tolerance induction by liver sinusoidal endothelial cells is preserved in liver fibrosis

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Background Liver sinusoidal endothelial cells (LSECs) are major inducers of immune tolerance. Previously, we have shown that targeting of autoantigen peptides to LSECs using nanoparticles (NP) can be used for therapy of autoimmune diseases. In liver fibrosis, LSECs capillarize and are believed to acquire enhanced immunogenicity. Here, we explore whether in fibrosis, LSECs maintain their ability to induce tolerance to ingested autoantigen peptides. Methods To investigate LSEC tolerance induction in liver fibrosis, the CCl4 and Mdr2KO mouse models were used. Targeting of NP to liver cells was examined by injection of Cy5-labelled NP, and the ability of LSECs to cross-present antigens was tested using an antibody recognising SIINFEKL-peptide on MHC-I molecules. Furthermore, Treg conversion assays were performed using LSECs from fibrotic livers as antigen presenting cells. Treatment of autoimmune diseases with autoantigen-coupled NP in the context of liver fibrosis was tested in two mouse models: experimental autoimmune encephalomyelitis (EAE) and autoimmune cholangitis. Results In liver fibrosis, autoantigen-coupled NP were predominantly targeted to LSECs with similar efficacy as in non-fibrotic controls. LSECs from fibrotic livers had similar abilities to cross-present antigen and to induce Tregs as normal LSECs. Furthermore, NP-mediated targeting of autoantigen-peptide to LSECs in mice with established liver fibrosis was effectively preventing CD4+T cell-driven EAE and CD8+T cell-driven autoimmune cholangitis. Conclusion The ability of LSECs to induce specific immune tolerance to autoantigen peptides was not impaired by liver fibrosis, indicating that their tolerance-inducing function is less susceptible to fibrotic changes than previously thought. Publication History Article published online: 20 January 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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