Nanoparticle‐mediated targeting of autoantigen peptide to cross‐presenting liver sinusoidal endothelial cells protects from CD8 T‐cell‐driven autoimmune cholangitis

Abstract

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.

Nanoparticle-Based Drug Delivery Systems for Induction of Tolerance and Treatment of Autoimmune Diseases

“…Carambia showed that targeting LSECs with polymer-coated MBP-coupled NPs administration injection protected mice from CD4 + T cell-driven EAE by inducing Foxp3 + Treg cells ( Carambia et al, 2015 ). This team then used SIINFEKL peptide-loaded nanoparticles, which are high selectively, internalized by LSECs in vivo and prevent CD8 T-cell driven autoimmune cholangitis ( Carambia et al, 2021 ). Qi Liu et al used biodegradable PLGA polymers to encapsulate OVA, targeting LSECs to induce antigen-specific immune tolerance in allergic airway disease.…”

Harnessing the liver to induce antigen-specific immune tolerance

“…LSECs are also able to induce CD8 memory T cells, which remain non-responsive during steady-state and require strong signals for re-activation [ 59 , 60 ]. Accordingly, nanoparticle-mediated delivery of MHC I–restricted autoantigen peptide was found to induce antigen-specific CD8 T cell tolerance and protection from antigen-driven cholangitis [ 61 ]. Importantly, although it was found that LSECs acquire enhanced immunogenicity in liver fibrosis [ 62 ], it was also shown that tolerance induction by LSECs was robust when stimulated with inflammation inducers and overcome only by viral infection [ 31 ].…”

“…These LSEC-targeting nanoparticles have been reported to provide generation of regulatory T cells and antigen-specific protection from CD4 T cell–driven autoimmune neuroinflammation [ 56 ]. Moreover, owed to the ability of LSECs to cross-present peptides that were delivered with LSEC-targeting nanoparticles, this approach could also be used to induce antigen-specific CD8 T cell tolerance and protection from CD8 T cell–mediated cholangitis [ 61 ]. It is likely that also other types of nanoparticles, notably those that are small, can be taken up by LSECs [ 91 ], but thus far a high selectivity has not been reported.…”

Recent advances on drug delivery nanoplatforms for the treatment of autoimmune inflammatory diseases

“…The liver-protective effects of Se NPs seem promising because they can protect animals from liver damage induced by chemicals or pathogens through their antioxidant capacity. 121…”