title: Routes of administration and dose optimization of soluble antigen arrays in mice with experimental autoimmune encephalomyelitis.
abstract: Soluble antigen arrays (SAgAs) were developed for treating mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. SAgAs are composed of hyaluronan with grafted EAE antigen and LABL peptide (a ligand of ICAM-1). SAgA dose was tested by varying injection volume, SAgA concentration, and administration schedule. Routes of administration were explored to determine the efficacy of SAgAs when injected intramuscularly, subcutaneously, intraperitoneally, intravenously, or instilled into lungs. Injections proximal to the central nervous system (CNS) were compared with distal injection sites. Intravenous dosing was included to determine if SAgA efficiency results from systemic exposure. Pulmonary instillation (p.i.) was included as reports suggest T cells are licensed in the lungs before moving to the CNS. Decreasing the volume of injection or SAgA dose reduced treatment efficacy. Treating mice with a single injection on day 4, 7, and 10 also reduced efficacy compared with injecting on all three days. Surprisingly, changing the injection site did not lead to a significant difference in efficacy. Intravenous administration showed efficacy similar to other routes, suggesting SAgAs act systemically. When SAgAs were delivered via p.i., however, EAE mice failed to develop any symptoms, suggesting a unique lung mechanism to ameliorate EAE in mice.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, 66047.
authors.forename: Sharadvi
authors.initials: S
authors.lastname: Thati
authors.forename: Christopher
authors.initials: C
authors.lastname: Kuehl
authors.forename: Brittany
authors.initials: B
authors.lastname: Hartwell
authors.forename: Joshua
authors.initials: J
authors.lastname: Sestak
authors.forename: Teruna
authors.initials: T
authors.lastname: Siahaan
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
authors.forename: Cory
authors.initials: C
authors.lastname: Berkland
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D005260:Female; D051379:Mice; D010446:Peptide Fragments / Q000008:administration & dosage*; D012995:Solubility
chemical_list: D000942:Antigens, Bacterial; D010446:Peptide Fragments
keywords: HPLC; SJL mice; biomaterials; experimental autoimmune encephalomyelitis; facilitated diffusion/transport; hyaluronan; immunology; peptides; polymeric drug delivery system