Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes.

5 years ago

Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes.

Viral N Shah, Samuel Ellis, Erin E Baschal, Peter A Gottlieb, Bernadette Pöllinger, Aaron W Michels, Aimon Alkanani, Stephanie Case, Kristen A McDaniel, Satish K Garg, Katherine J Seidl, Mark A Atkinson, David A Ostrov, Laura Pyle

Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes, the DQ8 molecule is common, confers significant disease risk and is involved in disease pathogenesis. We hypothesized blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen-binding cleft. A limited number of the predicted compounds inhibited DQ8 antigen presentation in vitro with one compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug of similar structure, methyldopa, specifically blocked DQ8 in recent-onset patients with type 1 diabetes along with reducing inflammatory T cell responses toward insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity.

Publisher URL: http://doi.org/10.1172/JCI97739

DOI: 10.1172/JCI97739