title: Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens.
abstract: Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease. We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens. The fusion constructs consist of a recombinant protein containing repeat sequences derived from the S-antigen protein (SAg) of Plasmodium falciparum linked to a CD4 T cell epitope of myelin. They were tested for their efficacy to control the development of experimental autoimmune encephalomyelitis (EAE), In addition, we used the DO11.10 transgenic mouse model to study the immune mechanisms involved in tolerance induced by SAg fusion proteins. We found that repeated sequences of P. falciparum SAg protein linked to self-epitopes markedly protected mice from EAE. These fusion constructs were powerful tolerizing agents not only in a preventive setting but also in the treatment of ongoing disease. The tolerogenic effect was shown to be antigen-specific and strongly dependent on the physical linkage of the T cell epitope to the parasite structure and on the action of anti-inflammatory cytokines like IL-10 and TGF-β. Other mechanisms include down-regulation of TNF-α accompanied by increased numbers of FoxP3+cells. This study describes the use of repetitive structures from parasites linked to defined T cell epitopes as an effective method to induce antigen-specific tolerance with potential applicability for the treatment and prevention of autoimmune diseases.
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany. f.puentes@qmul.ac.uk.|Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Neuroimmunology Unit. 4 Newark Street, London, E1 2AT, UK. f.puentes@qmul.ac.uk.
authors: Fabiola
authors: F
authors: Puentes
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors: Katharina
authors: K
authors: Dickhaut
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors: Maria
authors: M
authors: Hofstätter
authors: Experimental Rheumatology, Deutsches Rheuma-Forschungszentrum, Berlin and Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Jennifer
authors: J
authors: Pfeil
authors: Experimental Rheumatology, Deutsches Rheuma-Forschungszentrum, Berlin and Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Uta
authors: U
authors: Lauer
authors: Experimental Rheumatology, Deutsches Rheuma-Forschungszentrum, Berlin and Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Alf
authors: A
authors: Hamann
authors: Experimental Rheumatology, Deutsches Rheuma-Forschungszentrum, Berlin and Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors: Ute
authors: U
authors: Hoffmann
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors: Kirsten
authors: K
authors: Falk
authors: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.|Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors: Olaf
authors: O
authors: Rötzschke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D007114:Immunization / Q000379:methods; D056747:Immunomodulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010271:Parasites / Q000235:genetics / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics / Q000276:immunology*
chemical_list: D001324:Autoantigens
keywords: EAE; Immunomodulation; Multiple sclerosis; Repetitive antigens; Self-antigens