Ostrov, David A., Alkanani, Aimon , McDaniel, Kristen A. , Case, Stephanie , Baschal, Erin E. , Pyle, Laura, Ellis, Sam, Seidl, Katherine J., Shah, Viral N., Garg, Satish K., Atkinson, Mark A., Gottlieb, Peter A. and Michels, Aaron W. (2018) Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes. Journal of Clinical Investigation. ISSN 0021-9738

Abstract

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 will provide a treatment 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 antigen binding cleft. A number of 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. We discovered an existing drug, methyldopa, blocked DQ8 and treated recent onset type 1 diabetes patients having the DQ8 allele. Methyldopa specifically inhibited DQ8 antigen presentation along with reducing inflammatory T-cell responses toward insulin, highlighting the relevance of blocking disease specific MHC II antigen presentation to treat autoimmunity.

Item Type:	Article
Date Deposited:	09 Mar 2018 00:45
Last Modified:	09 Mar 2018 00:45
URI:	https://oak.novartis.com/id/eprint/33281