Synthetically glycosylated antigens induce antigen-specific tolerance and prevent the onset of diabetes

• Published in: Nature biomedical engineering Vol. 3; no. 10; pp. 817 - 829
• Main Authors: Wilson, D. Scott, Damo, Martina, Hirosue, Sachiko, Raczy, Michal M., Brünggel, Kym, Diaceri, Giacomo, Quaglia-Thermes, Xavier, Hubbell, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2019; Nature Publishing Group
• Subjects: 13/1; 13/2; 13/21; 45/29; 631/61/24/590/1962; 631/61/54/152; 64/60; Acetylgalactosamine - immunology; Acetylgalactosamine - pharmacology; Acetylglucosamine - immunology; Acetylglucosamine - pharmacology; Adoptive Transfer; Anergy; Animals; Antigen presentation; Antigen Presentation - drug effects; Antigen Presentation - immunology; Antigen-presenting cells; Antigens; Autoantigens; Autoantigens - pharmacology; Autoimmune diseases; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; CD4 antigen; CD4-Positive T-Lymphocytes; CD8 antigen; CD8-Positive T-Lymphocytes; Clonal deletion; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - immunology; Disease Models, Animal; Female; Immune Tolerance - drug effects; Immunological tolerance; Immunology; Immunoregulation; Liver; Liver - drug effects; Liver - immunology; Liver diseases; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; N-Acetylgalactosamine; N-Acetylglucosamine; Peptides; Spleen; T-Lymphocytes - drug effects
• ISSN: 2157-846X; 2157-846X
• DOI: 10.1038/s41551-019-0424-1

Homeostatic antigen presentation by hepatic antigen-presenting cells, which results in tolerogenic T-cell education, could be exploited to induce antigen-specific immunological tolerance. Here we show that antigens modified with polymeric forms of either
N
-acetylgalactosamine or
N-
acetylglucosamine target hepatic antigen-presenting cells, increase their antigen presentation and induce antigen-specific tolerance, as indicated by CD4
+
and CD8
+
T-cell deletion and anergy. These synthetically glycosylated antigens also expanded functional regulatory T cells, which are necessary for the durable suppression of antigen-specific immune responses. In an adoptive-transfer mouse model of type-1 diabetes, treatment with the glycosylated autoantigens prevented T-cell-mediated diabetes, expanded antigen-specific regulatory T cells and resulted in lasting tolerance to a subsequent challenge with activated diabetogenic T cells. Glycosylated autoantigens targeted to hepatic antigen-presenting cells might enable therapies that promote immune tolerance in patients with autoimmune diseases.
Glycosylated peptides targeting hepatic antigen-presenting cells induce antigen-specific immune tolerance, preventing T-cell-mediated diabetes in mice.