title: Small molecule inhibitor of antigen binding and presentation by HLA-DR2b as a therapeutic strategy for the treatment of multiple sclerosis.
abstract: The strong association of HLA-DR2b (DRB1*1501) with multiple sclerosis (MS) suggests this molecule as prime target for specific immunotherapy. Inhibition of HLA-DR2b-restricted myelin-specific T cells has the potential to selectively prevent CNS pathology mediated by these MHC molecules without undesired global immunosuppression. In this study, we report development of a highly selective small molecule inhibitor of peptide binding and presentation by HLA-DR2b. PV-267, the candidate molecule used in these studies, inhibited cytokine production and proliferation of myelin-specific HLA-DR2b-restricted T cells. PV-267 had no significant effect on T cell responses mediated by other MHC class II molecules, including HLA-DR1, -DR4, or -DR9. Importantly, PV-267 did not induce nonspecific immune activation of human PBMC. Lastly, PV-267 showed treatment efficacy both in preventing experimental autoimmune encephalomyelitis and in treating established disease. The results suggest that blocking the MS-associated HLA-DR2b allele with small molecule inhibitors may be a promising therapeutic strategy for the treatment of MS.
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249;
authors.forename: Niannian
authors.initials: N
authors.lastname: Ji
authors.forename: Animesh
authors.initials: A
authors.lastname: Somanaboeina
authors.forename: Aakanksha
authors.initials: A
authors.lastname: Dixit
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kawamura
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Hayward
authors.forename: Christopher
authors.initials: C
authors.lastname: Self
authors.forename: Gary L
authors.initials: GL
authors.lastname: Olson
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Forsthuber
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D015802:HLA-DR2 Antigen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy; D004676:Myelin Basic Protein; D010455:Peptides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015802:HLA-DR2 Antigen; D004676:Myelin Basic Protein; D010455:Peptides