title: A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease.
abstract: Targeted immune tolerance is a coveted therapy for the treatment of a variety of autoimmune diseases, as current treatment options often involve nonspecific immunosuppression. Intravenous (iv) infusion of apoptotic syngeneic splenocytes linked with peptide or protein autoantigens using ethylene carbodiimide (ECDI) has been demonstrated to be an effective method for inducing peripheral, antigen-specific tolerance for treatment of autoimmune disease. Here, we show the ability of biodegradable poly(lactic-co-glycolic acid) (PLG) nanoparticles to function as a safe, cost-effective, and highly efficient alternative to cellular carriers for the induction of antigen-specific T cell tolerance. We describe the formulation of tolerogenic PLG particles and demonstrate that administration of myelin antigen-coupled particles both prevented and treated relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a CD4 T cell-mediated mouse model of multiple sclerosis (MS). PLG particles made on-site with surfactant modifications surpass the efficacy of commercially available particles in their ability to couple peptide and to prevent disease induction. Most importantly, myelin antigen-coupled PLG nanoparticles are able to significantly ameliorate ongoing disease and subsequent relapses when administered at onset or at peak of acute disease, and minimize epitope spreading when administered during disease remission. Therapeutic treatment results in significantly reduced CNS infiltration of encephalitogenic Th1 (IFN-γ) and Th17 (IL-17a) cells as well as inflammatory monocytes/macrophages. Together, these data describe a platform for antigen display that is safe, low-cost, and highly effective at inducing antigen-specific T cell tolerance. The development of such a platform carries broad implications for the treatment of a variety of immune-mediated diseases.
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , 6-713 Tarry Building, 303 East Chicago Avenue, Chicago, Illinois 60611, United States.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Hunter
authors.forename: Derrick P
authors.initials: DP
authors.lastname: McCarthy
authors.forename: Woon Teck
authors.initials: WT
authors.lastname: Yap
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Harp
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.forename: Lonnie D
authors.initials: LD
authors.lastname: Shea
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D007165:Immunosuppression Therapy / Q000379:methods*; D019344:Lactic Acid / Q000737:chemistry / Q000378:metabolism; D008298:Maleates / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D011095:Polyethylenes / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012008:Recurrence; D012449:Safety; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000941:Antigens; D016207:Cytokines; D004337:Drug Carriers; D008298:Maleates; D010446:Peptide Fragments; D011095:Polyethylenes; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C043105:poly(methyl vinyl ether-co-maleic anhydride)