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Summary Autoimmune diseases are caused by adaptive immune responses to self‐antigens. The development of antigen‐specific therapies that suppress disease‐related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC‐targeting nanoparticles provides effective protection from CD4 T‐cell‐driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen‐specific treatment of a CD8 T‐cell‐driven autoimmune disease. As a model for CD8 T‐cell‐mediated autoimmunity, we used OT‐1 T‐cell‐driven cholangitis in K14‐OVAp mice expressing the cognate MHC I‐restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide‐conjugated nanoparticles were administered intravenously one day before transfer of OT‐1 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide‐conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross‐presented the delivered peptide on MHC I molecules. Intriguingly, K14‐OVAp mice receiving SIINFEKL‐loaded nanoparticles manifested significantly reduced liver damage compared with vehicle‐treated K14‐OVAp mice. Mechanistically, treatment with LSEC‐targeting SIINFEKL‐loaded nanoparticles significantly reduced the number of liver‐infiltrating OT‐1 T cells, which up‐regulated expression of the co‐inhibitory receptor PD‐1 and down‐regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross‐present nanoparticle‐bound peptides on MHC I molecules. Therefore, nanoparticle‐mediated autoantigen peptide delivery to LSECs might serve the antigen‐specific treatment of CD8 T‐cell‐driven autoimmune disease., We show that CD8 T‐cell‐mediated bile duct damage can be prevented by targeting the specific epitope peptides to liver sinusoidal endothelial cells in vivo using nanoparticles. These cells effectively cross‐present the received peptides and induce CD8 T‐cell tolerance.

Purpose To assess the feasibility of a 7 Tesla (T) MR cholangiopancreatography (MRCP) protocol to image the morphology and detect and intraindividually monitor pathological changes of the biliopancreatic tract in a mouse model of primary sclerosing cholangitis (PSC). Materials and Methods Six female Mdr2(Abcb)−/− mice, a well-established model of PSC, were imaged five times during weeks 10–19. Three wild-type controls were imaged at age 15 weeks. MRCP acquisition with three-dimensional fast recovery fast spin echo sequences (3D-FRFSE) was performed using three sequences with different resolutions, repetition times (TR), and with/without respiration-gating in a 7T preclinical MRI system. Image quality and visualization of five biliopancreatic structures were evaluated by three independent readers. Results Image quality was rated diagnostically sufficient in 86% of the datasets acquired without gating and in 100% for the respiration-gated sequences. Intrahepatic ducts were well visualized (≥97%) in Mdr2−/− mice. Stenoses and dilatations of the biliary ducts were intraindividually monitored. Progression and regression of bile duct pathologies were sufficiently assessed during the observation time. Conclusion High-quality respiration-gated MRCP of the Mdr2−/− PSC model at 7T allows for in vivo imaging of murine biliopancreatic tract and monitoring of bile duct pathologies, permitting longitudinal intraindividual studies in murine models of inflammatory bile duct diseases. J. Magn. Reson. Imaging 2014;40:1355–1364. © 2013 Wiley Periodicals, Inc.