Year: 2022
Type: article
Abstract: Type 1 diabetes is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been hampered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes, and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE with use of knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration, and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T-cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells.
Source: Diabetes
DOI: 10.2337/db22-0177
Authors: Sherman S. Leung, Danielle J. Borg, Domenica A. McCarthy, Tamar E. Boursalian, Justen Cracraft, Aowen Zhuang, Amelia K. Fotheringham, Nicole Flemming, Thomas Watkins, John J. Miles, Per-Henrik Groop, Jean L. Scheijen, Casper G. Schalkwijk, Raymond J. Steptoe, Kristen J. Radford, Mikael Knip, Josephine M. Forbes
Institutions: Translational Research Institute, The University of Queensland, Mater Research, Novo Nordisk (United States), Australian Institute of Tropical Health and Medicine, James Cook University, University of Helsinki, Baker Heart and Diabetes Institute, Helsinki University Hospital, Folkhälsans Forskningscentrum, Maastricht University, Helsinki Children's Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4283024265