1. Synthetically glycosylated antigens induce antigen-specific tolerance and prevent the onset of diabetes
- Author
-
Wilson, D. Scott, Damo, Martina, Hirosue, Sachiko, Raczy, Michal M., Bruenggel, Kym, Diaceri, Giacomo, Quaglia-Thermes, Xavier, and Hubbell, Jeffrey A.
- Subjects
c-type lectin ,asialoglycoprotein receptor ,regulatory t-cells ,kupffer cells ,rat-liver ,sinusoidal endothelial-cells ,growth-factor-beta ,in-vitro ,cross-presentation ,mannose receptor - Abstract
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 Tcells, 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.