title: Multimerized T cell epitopes protect from experimental autoimmune diabetes by inducing dominant tolerance.
abstract: Immunotherapy by using multimerized self-peptides has demonstrated a clear protective effect on experimental models of autoimmune diseases. However, the mechanisms involved remain ill-defined. Here we have evaluated the therapeutic efficacy of multimerized self-peptides at the effector phase of autoimmune diabetes and examined their mechanisms of action. Diabetes was induced in rat insulin promoter-hemagglutinin (HA) mice expressing HA in pancreatic beta-cells by adoptive transfer of HA(110-119)-specific T helper 1 cells. Complete protection was provided by low doses of the HA 4-mer consisting of four covalently linked linear HA(107-119) peptides. In vivo, the 4-mer appeared to act directly on the pathogenic HA-specific T helper 1 cells and indirectly by activation/recruitment of lymphocytes with regulatory properties so that mice became resistant to a second transfer of diabetogenic T cells. This effect was associated with a recruitment of Foxp3(+) CD4 T cells around islets. Moreover, we show that dominant protection from autoimmunity was transferable by spleen cells, and that development of this regulatory population was crucially dependent on the lymphocytes from treated rat insulin promoter-HA mice. Thus, immunotherapy using multimerized epitopes emerges as a promising strategy in view of the current identification of self-epitopes that are major targets of the pathogenic CD4 T cell response in autoimmune diseases.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
authors.forename: Lennart T
authors.initials: LT
authors.lastname: Mars
authors.forename: Cécile
authors.initials: C
authors.lastname: Cassan
authors.forename: Julie
authors.initials: J
authors.lastname: Cabarrocas
authors.forename: Maria
authors.initials: M
authors.lastname: Hofstätter
authors.forename: Sabine
authors.initials: S
authors.lastname: Desbois
authors.forename: Emilie
authors.initials: E
authors.lastname: Bergereau
authors.forename: Olaf
authors.initials: O
authors.lastname: Rötzschke
authors.forename: Kirsten
authors.initials: K
authors.lastname: Falk
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
mesh_terms: D000818:Animals; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology*; D006388:Hemagglutinins / Q000494:pharmacology; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006388:Hemagglutinins; D010446:Peptide Fragments