title: Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes.
abstract: BACKGROUND
  The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes.
  
  
  OBJECTIVE
  To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes.
  
  
  METHODS
  A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides.
  
  
  RESULTS
  We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion.
  
  
  CONCLUSIONS
  We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases.
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Irma
authors.initials: I
authors.lastname: Pujol-Autonell
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Serracant-Prat
authors.affiliation: Catalan Institute of Nanoscience and Nanotechnology, Bellaterra, Spain.
authors.forename: Mary
authors.initials: M
authors.lastname: Cano-Sarabia
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Ampudia
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rodriguez-Fernandez
authors.affiliation: Statistics Department, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Sanchez
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Izquierdo
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratmann
authors.affiliation: Endocrinology and Nutrition Service, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Puig-Domingo
authors.affiliation: Catalan Institute of Nanoscience and Nanotechnology, Bellaterra, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Maspoch
authors.affiliation: Immunology Unit, Department of Experimental Medicine, University of Lleida and IRBLleida, Lleida, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Verdaguer
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vives-Pi
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology*; D007167:Immunotherapy; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000627:therapeutic use; D008081:Liposomes; D016688:Mice, Inbred NOD; D010641:Phenotype; D010718:Phosphatidylserines / Q000627:therapeutic use*
chemical_list: D001324:Autoantigens; D016207:Cytokines; D007328:Insulin; D008081:Liposomes; D010718:Phosphatidylserines