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Antigen-specific immune modulation with liver-targeting nanoparticles fosters immune protective regulatory T cells to delay Type 1 Diabetes

Written by Trophic Communications on . Posted in News, Publications.

Antigen-specific immune modulation with liver-targeting nanoparticles fosters immune protective regulatory T cells to delay Type 1 Diabetes

Poster Helmholtz Munich

Authors: Isabelle Serr, Daria Krzikalla, Barbara Metzler, Sabine Fleischer, Carolin Daniel

Summary

Type 1 Diabetes (T1D) is characterized by the loss of immune tolerance to beta-cells in the pancreas, resulting in their immune-mediated destruction. Restoring antigen-specific immune tolerance, thereby circumventing critical side effects of non-specific immunosuppression is a long-awaited goal for the prevention of T1D. We tested peptideconjugated nanoparticles developed by Topas Therapeutics that leverage the tolerogenic capacity of liver sinusoidal endothelial cells (LSECs) to restore antigen-specific immune tolerance in T1D

Antigen-specific tolerance and control of autoimmunity effected by liver sinusoidal endothelial cells is unimpaired in liver fibrosis

Written by Trophic Communications on . Posted in News, Publications.

Antigen-specific tolerance and control of autoimmunity effected by liver sinusoidal endothelial cells is unimpaired in liver fibrosis

Frontiers in Immunology

Authors: Cornelia Gottwick, Pia Averhoff, Christian Casar, Laura Anne Liebig, Sabrina Melanie Pilz, Victor Haas, Daria Krzikalla, Sabine Fleischer, Norbert Hübner, Lorenz Adlung, Dorothee Schwinge,  Christoph Schramm, Antonella Carambia, Johannes Herkel

Summary

Liver sinusoidal endothelial cells (LSECs) have a key role in maintaining organismal homeostasis by scavenging blood-borne molecules and inducing specific immune tolerance to ingested antigens. The scavenger and tolerance function of LSECs can be harnessed for specific treatment of autoimmune diseases by nanoparticle-mediated autoantigen delivery to LSECs. In liver fibrosis, which is a frequent condition in human populations, LSECs undergo changes promoting pro-fibrotic and pro-inflammatory activation of other hepatic cells, but it is unclear whether the scavenger and immune tolerance functions of LSECs are affected. Utilizing two mouse models of liver fibrosis, we explored the ability of LSECs to take up nanoparticles conjugated with antigen peptides, to present the ingested antigen peptides to T cells and to induce peptide-specific immune tolerance in vitro and in vivo in the context of autoimmune diseases. LSECs from fibrotic livers showed few distinct adaptations regarding immune functions; however, overall LSEC identity was largely maintained. Accordingly, endocytosis of nanoparticles by LSECs in vivo, as well as processing and presentation of nanoparticle-bound antigen peptides was not compromised by liver fibrosis. LSECs from fibrotic livers maintained the ability to effectively induce the generation of regulatory T cells from conventional CD4 T cells. Hence, targeted delivery of autoantigen peptides to LSECs in vivo effectively induced specific tolerance despite liver fibrosis, providing protection in two models of experimental autoimmune disease. Analysis of datasets from human subjects with or without liver cirrhosis confirmed that scavenger and tolerance pathways in LSECs were preserved in human liver fibrosis. Scavenger activity and antigen-specific tolerance induction by LSECs are preserved in liver fibrosis. Thus, LSECs remain reliable mediators of homeostasis and tolerance under fibrotic conditions, and particularly suitable targets for nanomedicine products.

Nanoparticles targeting liver sinusoidal endothelial cells improve tolerance to vector and transgene antigens through tolerance spreading

Written by Trophic Communications on . Posted in News, Publications.

Nanoparticles targeting liver sinusoidal endothelial cells improve tolerance to vector and transgene antigens through tolerance spreading

Journal: Molecular Therapy

Authors: Romain Hardet, Shu-Hung Wang, Sandrine Delignat, Marine Blandin, Reinaldo Digigow, Cornelia Gottwick, Markus Heine, Lígia Margarida Marques Mesquita, Marco Fanzutti, Anna-Lisa Vocaturo, Disha Mungalpara,  Olivier Boyer, Sébastien Lacroix-Desmazes, Sabine Fleischer, Sahil Adriouch

Summary

Liver sinusoidal endothelial cells (LSECs) naturally cross-present antigens and induce T cell tolerance. Targeting LSECs with peptide-coupled nanoparticles offers an efficient strategy to induce antigen-specific immune tolerance. Previous preclinical and clinical studies have shown that peptide-coupled nanoparticles can effectively inhibit T cell responses to the selected cognate peptide epitopes. However, clinical situations such as viral-vector-mediated gene therapy would benefit from simultaneous tolerance induction to multiple epitopes/antigens, posing a significant challenge. In this study, we used mouse models of adeno-associated virus (AAV)-mediated gene transfer to assess the in vivo effects of peptide-loaded nanoparticles designed to tolerize immune responses to transgene- or/and capsid-derived epitopes. We report here for the first time that LSEC-targeting nanoparticles coupled to a single peptide epitope promoted extension of tolerance to multiple relevant epitopes/antigens and simultaneously tolerized both CD4+ and CD8+ T cell responses. This tolerance spreading, which we termed “Tspread,” remained specific to the transgene- and capsid-derived antigens conveyed by the administered AAV vector and did not impair immune responses to an unrelated vaccine antigen. These findings delineate a novel LSEC-mediated tolerance spreading with important clinical implications for viral-vector gene therapy, where tolerance to multiple epitopes/antigens is essential for long-term expression of therapeutic genes.

Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice

Written by Trophic Communications on . Posted in Publications.

Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice

Journal: Journal of Hepatology

Authors: Antonella Carambia, Barbara Freund, Dorothee Schwinge, Oliver T Bruns, Sunhild C Salmen, Harald Ittrich, Rudolph Reimer, Markus Heine, Samuel Huber, Christian Waurisch, Alexander Eychmüller, David C Wraith, Thomas Korn, Peter Nielsen, Horst Weller, Christoph Schramm, Stefan Lüth, Ansgar W Lohse, Joerg Heeren, Johannes Herkel

Summary

It is well-known that the liver can induce immune tolerance, yet this knowledge could, thus far, not be translated into effective treatments for autoimmune diseases. We have previously shown that liver sinusoidal endothelial cells (LSECs) could substantially contribute to hepatic tolerance through their ability to induce CD4+ Foxp3+ regulatory T cells (Tregs). Here, we explored whether the Treg-inducing potential of LSECs could be harnessed for the treatment of autoimmune disease.

We engineered a polymeric nanoparticle (NP) carrier for the selective delivery of autoantigen peptides to LSECs in vivo. In the well-characterized autoimmune disease model of experimental autoimmune encephalomyelitis (EAE), we investigated whether administration of LSEC-targeting autoantigen peptide-loaded NPs could protect mice from autoimmune disease.

We demonstrate that NP-based autoantigen delivery to LSECs could completely and permanently prevent the onset of clinical EAE. More importantly, in a therapeutic approach, mice with already established EAE improved rapidly and substantially following administration of a single dose of autoantigen peptide-loaded NPs, whereas the control group deteriorated. Treatment efficacy seemed to depend on Tregs. The Treg frequencies in the spleens of mice treated with autoantigen peptide-loaded NPs were significantly higher than those in vehicle-treated mice. Moreover, NP-mediated disease control was abrogated after Treg depletion by repeated administration of Treg-depleting antibody.

Our findings provide proof of principle that the selective delivery of autoantigen peptides to LSECs by NPs can induce antigen-specific Tregs and enable effective treatment of autoimmune disease. These findings highlight the importance of Treg induction by LSECs for immune tolerance.

Nanoparticle platform preferentially targeting liver sinusoidal endothelial cells induces tolerance in CD4+ T cell-mediated disease models

Written by Trophic Communications on . Posted in News, Publications.

Nanoparticle platform preferentially targeting liver sinusoidal endothelial cells induces tolerance in CD4+ T cell-mediated disease models

Journal: Frontiers of Immunology

Authors: Shu-Hung Wang, Isabelle Serr, Reinaldo Digigow, Barbara Metzler, Alexey Surnov, Cornelia Gottwick, Muhammad Alsamman, Daria Krzikalla, Markus Heine, Miriam Zahlten, Agata Widera, Disha Mungalpara, Muharrem Şeleci, Marco Fanzutti, Lígia Margarida Marques Mesquita, Anna-Lisa Vocaturo, Johannes Herkel, Antonella Carambia, Christian Schröter, Dikran Sarko, Johannes Pohlner, Carolin Daniel, Cristina de Min, Sabine Fleischer

Summary

Treating autoimmune diseases without nonspecific immunosuppression remains challenging. To prevent or treat these conditions through targeted immunotherapy, we developed a clinical-stage nanoparticle platform that leverages the tolerogenic capacity of liver sinusoidal endothelial cells (LSECs) to restore antigen-specific immune tolerance.
In vivo efficacy was evaluated in various CD4+ T cell-mediated disease models, including preventive and therapeutic models of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), ovalbumin-sensitized delayed-type hypersensitivity (DTH), and the spontaneous type 1 diabetes model. Nanoparticle-induced antigen-specific immune responses were also analyzed through adoptive transfers of 2D2 transgenic T cells into wild-type mice, followed by nanoparticle administration.
The peptide-conjugated nanoparticles displayed a uniform size distribution (25–30 nm). Their coupling efficiency for peptides with unfavorable physicochemical properties was significantly enhanced by a proprietary linker technology. Preferential LSEC targeting of nanoparticles coupled with fluorescently labeled peptides was confirmed via intravital microscopy and flow cytometry. Intravenous nanoparticle administration significantly reduced disease severity and demyelination in EAE, independent of prednisone at maintenance doses, and suppressed target tissue inflammation in the DTH model. Furthermore, prophylactic administration of a mixture of nanoparticles coupled with five autoantigenic peptides significantly lowered the hyperglycemia incidence of the non-obese diabetic mice. Mechanistically, the tolerizing effects were associated with the induction of antigen-specific regulatory T cells and T cell anergy, which counteract proinflammatory T cells in the target tissue.
Our findings demonstrate that peptide-loaded nanoparticles preferentially deliver disease-relevant peptides to LSECs, thereby inducing antigen-specific immune tolerance. This versatile clinical-stage nanoparticle platform holds promise for clinical application across multiple autoimmune diseases.

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

Written by Trophic Communications on . Posted in Publications.

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

Journal: Immunology

Authors: Antonella Carambia, Cornelia Gottwick, Dorothee Schwinge, Stephanie Stein, Reinaldo Digigow, Muharrem Şeleci, Disha Mungalpara, Markus Heine, Fenja A Schuran, Carlotta Corban, Ansgar W Lohse, Christoph Schramm, Joerg Heeren, Johannes Herkel

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.

Safety, tolerability, pharmacokinetics and pharmacodynamic effects of desmoglein 3 peptide-coupled tolerizing nanoparticles in pemphigus

Written by Trophic Communications on . Posted in News, Publications.

Safety, tolerability, pharmacokinetics and pharmacodynamic effects of desmoglein 3 peptide-coupled tolerizing nanoparticles in pemphigus

Journal: British Journal of Dermatology

Authors: Dario Didona, Christoph Hudemann, Holger Garn, Daria Krzikalla, Shu-Hung Wang, Julia Hinterseher, Karolin Volkmann, Alexandra Polakova, Anna Zakrzewicz, Simon Feldhoff, Ritva Tikkanen, Reinaldo Digigow, Wolfgang Pfützner, Antonio Santos, Christine L Zimmer, Maik Hahmann, Susanne Harnisch, Siegfried Rösch, Sandra Huguenin, Rüdiger Eming, Matthias Hahn, Franziska Schauer, Emiliano Antiga, Stefano Senatore, Roberto Maglie, Jörg Täubel, Kamran Ghoreschi, Katharina Meier, Farzan Solimani, Michael Sticherling, Lukas Sollfrank, Claudia Günther, Kerstin Steinbrink, Nina Magnolo, Erno van Schaick, Veronica Asnaghi, Frank S Zollmann, Johannes Pohlner, Julia Hummel, Rupert Sandbrink, Cristina de Min, Sabine Fleischer, Christian Möbs, Michael Hertl

Summary

Pemphigus is a rare but potentially life-threatening disease. It causes blisters to form on the skin, mouth and genitals. It can lead to the loss of body fluids and proteins. It is also associated with severe infections. Blisters are caused by ‘autoantibodies’ (misguided defence proteins in the immune system) that bind to a component of the skin called Dsg3. The autoantibodies are produced by specialized immune cells known as ‘B cells’ with the help of another group of immune cells called ‘T cells’. These cells play an important role in starting autoimmune responses.

In this study, we tried to block the effects of T cells in pemphigus. We did this using ‘nanoparticles’ to deliver pieces of Dsg3 to the liver. These nanoparticles have the potential to inhibit (or stop) the misdirected immune response. We carried out a study in Germany, Italy and the UK and gave increasing doses of Dsg3-loaded nanoparticles to a group of 17 patients with the disease. We found that the treatment was well-tolerated by the patients. They did not experience any severe side effects. We also found changes in the patients’ blood. This provided the first hints that T cells and activated B cells that promote inflammation could be blocked, leading to a decrease in pemphigus autoantibodies.

Our study findings suggest that Dsg3-loaded nanoparticles should be further developed. The aim would be to treat pemphigus, and maybe even other autoimmune diseases, in a safe and specific way.