title: Vaccinelike and prophylactic treatments of EAE with novel I-domain antigen conjugates (IDAC): targeting multiple antigenic peptides to APC.
abstract: The objective of this work is to utilize novel I-domain antigenic-peptide conjugates (IDAC) for targeting antigenic peptides to antigen-presenting cells (APC) to simulate tolerance in experimental autoimmune encephalomyelitis (EAE). IDAC-1 and IDAC-3 molecules are conjugates between the I-domain protein and PLP-Cys and Ac-PLP-Cys-NH(2) peptides, respectively, tethered to N-terminus and Lys residues on the I-domain. The hypothesis is that the I-domain protein binds to ICAM-1 and PLP peptide binds to MHC-II on the surface of APC; this binding event inhibits the formation of the immunological synapse at the APC-T-cell interface to alter T-cell differentiation from inflammatory to regulatory phenotypes. Conjugation of peptides to the I-domain did not change the secondary structure of IDAC molecules as determined by circular dichroism spectroscopy. The efficacies of IDAC-1 and -3 were evaluated in EAE mice by administering iv or sc injections of IDAC in a prophylactic or a vaccinelike dosing schedule. IDAC-3 was better than IDAC-1 in suppressing and delaying the onset of EAE when delivered in prophylactic and vaccinelike manners. IDAC-3 also suppressed subsequent relapse of the disease. The production of IL-17 was lowered in the IDAC-3-treated mice compared to those treated with PBS. In contrast, the production of IL-10 was increased, suggesting that there is a shift from inflammatory to regulatory T-cell populations in IDAC-3-treated mice. In conclusion, the I-domain can effectively deliver antigenic peptides in a vaccinelike or prophylactic manner for inducing immunotolerance in the EAE mouse model.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Simons Research Laboratories, 2095 Constant Avenue, Lawrence, Kansas 66047, United States.
authors.forename: Barlas
authors.initials: B
authors.lastname: Büyüktimkin
authors.forename: Prakash
authors.initials: P
authors.lastname: Manikwar
authors.forename: Paul K
authors.initials: PK
authors.lastname: Kiptoo
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Badawi
authors.forename: John M
authors.initials: JM
authors.lastname: Stewart
authors.forename: Teruna J
authors.initials: TJ
authors.lastname: Siahaan
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000941:Antigens; C556062:IL10 protein, mouse; D018796:Immunoconjugates; D020381:Interleukin-17; D018991:Myelin Proteolipid Protein; D010455:Peptides; C047516:Plp1 protein, mouse; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10