title: Expanding antigen-specific regulatory networks to treat autoimmunity.
abstract: Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Clemente-Casares
authors.affiliation: Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Blanco
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Poornima
authors.initials: P
authors.lastname: Ambalavanan
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Santiswarup
authors.initials: S
authors.lastname: Singha
authors.affiliation: Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain.
authors.forename: Cesar
authors.initials: C
authors.lastname: Fandos
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Sue
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Jinguo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona 08028, Spain.
authors.forename: Nahir
authors.initials: N
authors.lastname: Garabatos
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona 08028, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Izquierdo
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Smriti
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Keough
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101-2795, USA.
authors.forename: Eddie
authors.initials: E
authors.lastname: James
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.|Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona 08028, Spain.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratmann
authors.affiliation: Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.affiliation: Julia McFarlane Diabetes Research Centre (JMDRC), and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.|Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D018845:CD11 Antigens / Q000276:immunology; D002454:Cell Differentiation; D016207:Cytokines / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D009928:Organ Specificity; D015995:Prevalence; D012995:Solubility; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D001324:Autoantigens; D018845:CD11 Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II