title: Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy.
abstract: Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.
authors: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy.
authors: Andrea
authors: A
authors: Farini
authors: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy; Department of Laboratory Medicine, University Milano Bicocca, Desio Hospital, Desio (MB), Italy.
authors: Clementina
authors: C
authors: Sitzia
authors: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.
authors: Barbara
authors: B
authors: Cassani
authors: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy.
authors: Letizia
authors: L
authors: Cassinelli
authors: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.
authors: Rosita
authors: R
authors: Rigoni
authors: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy.
authors: Federica
authors: F
authors: Colleoni
authors: Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy; Division of Pathology, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy.
authors: Nicola
authors: N
authors: Fusco
authors: Center for Surgical Research, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Stefano
authors: S
authors: Gatti
authors: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy.
authors: Pamela
authors: P
authors: Bella
authors: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy.
authors: Chiara
authors: C
authors: Villa
authors: Laboratorio di Chimica Clinica e Microbiologia, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors: Filomena
authors: F
authors: Napolitano
authors: Laboratorio di Chimica Clinica e Microbiologia, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors: Rita
authors: R
authors: Maiavacca
authors: Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy; Division of Pathology, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy.
authors: Silvano
authors: S
authors: Bosari
authors: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.
authors: Anna
authors: A
authors: Villa
authors: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy. Electronic address: yvan.torrente@unimi.it.
authors: Yvan
authors: Y
authors: Torrente
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007162:Immunoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000276:immunology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology
chemical_list: D007162:Immunoproteins; D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex