Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes
David A. Ostrov, … , Peter A. Gottlieb, Aaron W. Michels
David A. Ostrov, … , Peter A. Gottlieb, Aaron W. Michels
Published February 13, 2018
Citation Information: J Clin Invest. 2018;128(5):1888-1902. https://doi.org/10.1172/JCI97739.
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Research Article Autoimmunity Endocrinology

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

Abstract

Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes (T1D), the DQ8 molecule is common, confers significant disease risk, and is involved in disease pathogenesis. We hypothesized that 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 1 compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug with a similar structure, methyldopa, specifically blocked DQ8 in patients with recent-onset T1D and reduced inflammatory T cell responses to insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity.

Authors

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

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Figure 4

Methyldopa blocks DQ8 antigen presentation in vivo.

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Methyldopa blocks DQ8 antigen presentation in vivo. (A) Diagram of the a...
(A) Diagram of the assay used to monitor the potency of methyldopa to block DQ8 in Tg mice. (B) Adult DQ8-Tg mice were gavaged with vehicle or 200 mg/kg methyldopa 3 times per day for 4 days (n = 4/group). Ex vivo splenocytes were used as APCs to present different concentrations of the insulin B:13-23 peptide or a deamidated α-gliadin peptide to clone 5 or 489, respectively. No methyldopa was added to the in vitro culture. A dose of 200 mg/kg is equivalent to 1,000 mg 3 times per day in a human weighing 60 kg. Data represent the mean ± SEM and are representative of 3 independent experiments. (C) Percentages and (D) numbers of CD11b+ and CD11c+ cells in the spleens of treated mice. (E) MFI of DQ8 cell-surface staining on each cell population. Each dot represents an individual mouse.