Epitopes described in "Structure-based selection of small molecules to alter allele-specific MHC class II antigen presentation."

Article Authors:Aaron W Michels; David A Ostrov; Li Zhang; Maki Nakayama; Masanori Fuse; Kristen McDaniel; Bart O Roep; Peter A Gottlieb; Mark A Atkinson; George S Eisenbarth
Article Title:Structure-based selection of small molecules to alter allele-specific MHC class II antigen presentation.
Reference Detail
Reference ID:1022595
Abstract:Class II major histocompatibility molecules are the primary susceptibility locus for many autoimmune disorders, including type 1 diabetes. Human DQ8 and I-A(g7), in the NOD mouse model of spontaneous autoimmune diabetes, confers diabetes risk by modulating presentation of specific islet peptides in the thymus and periphery. We used an in silico molecular docking program to screen a large "druglike" chemical library to define small molecules capable of occupying specific structural pockets along the I-A(g7) binding groove, with the objective of influencing presentation to T cells of the autoantigen insulin B chain peptide consisting of amino acids 9-23. In this study we show, using both murine and human cells, that small molecules can enhance or inhibit specific TCR signaling in the presence of cognate target peptides, based upon the structural pocket targeted. The influence of compounds on the TCR response was pocket dependent, with pocket 1 and 6 compounds inhibiting responses and molecules directed at pocket 9 enhancing responses to peptide. At nanomolar concentrations, the inhibitory molecules block the insulin B chain peptide consisting of amino acids 9-23, endogenous insulin, and islet-stimulated T cell responses. Glyphosine, a pocket 9 compound, enhances insulin peptide presentation to T cells at concentrations as low as 10 nM, upregulates IL-10 secretion, and prevents diabetes in NOD mice. These studies present a novel method for identifying small molecules capable of both stimulating and inhibiting T cell responses, with potentially therapeutic applications.
Affiliations:Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045, USA. aaron.michels@ucdenver.edu.
Reference Type:Literature
PubMed ID:22043012
Journal:J Immunol
Journal Volume:187
Article Pages:5921-30
Journal ISSN:0022-1767
Article Chemical List:Autoantigens;Histocompatibility Antigens Class II;Insulin;Organophosphorus Compounds;Peptide Fragments;Receptors, Antigen, T-Cell;Small Molecule Libraries;insulin B (9-23);glyphosphine;Glycine
Article MeSH List:Alleles; Animals; Antigen Presentation(immunology); Autoantigens(genetics; immunology); Diabetes Mellitus, Type 1(genetics; immunology); Enzyme-Linked Immunosorbent Assay; Glycine(analogs & derivatives; immunology; pharmacology); Histocompatibility Antigens Class II(genetics; immunology); Humans; Insulin(genetics; immunology); Lymphocyte Activation(genetics; immunology); Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Models, Molecular; Organophosphorus Compounds(immunology; pharmacology); Peptide Fragments(genetics; immunology); Receptors, Antigen, T-Cell(genetics; immunology); Small Molecule Libraries; Structure-Activity Relationship
Curation Last Updated:2016-05-11 20:10:24