Combinatorial Contextualization of Peptidic Epitopes for Enhanced Cellular Immunity

• Published in: PloS one Vol. 9; no. 10; p. e110425
• Main Authors: Ito, Masaki, Hayashi, Kazumi, Adachi, Eru, Minamisawa, Tamiko, Homma, Sadamu, Koido, Shigeo, Shiba, Kiyotaka
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.10.2014; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adjuvants, Immunologic - pharmacology; AIDS; AIDS vaccines; Aluminum; Amino Acid Sequence; Animals; Antigen presentation; Antigen Presentation - drug effects; Antigen Presentation - immunology; Antigen-Presenting Cells - immunology; Antigenic determinants; Antigens; Biology and Life Sciences; Cancer; Cell Proliferation - drug effects; Cell-mediated immunity; Clone Cells; Cloning; Combinatorial analysis; Combinatorial Chemistry Techniques; Cross-Priming - drug effects; Cross-Priming - immunology; Dendritic cells; Emulsification; Endotoxins; Engineering; Epitopes; Epitopes - chemistry; Epitopes - drug effects; Epitopes - immunology; Freund's incomplete adjuvant; Immunity; Immunity, Cellular - drug effects; Immunity, Cellular - immunology; Immunogenicity; Libraries; Lipid A; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Malaria; Medical research; Medicine; Mice; Molecular Sequence Data; Monophosphoryl lipid A; Oncology; Ovalbumin; Ovalbumin - immunology; Peptides; Peptides - chemistry; Peptides - immunology; Pollutants; Poly I - pharmacology; Polymerization; Polysaccharides - pharmacology; Proteasome Endopeptidase Complex - metabolism; Proteins; Repetitive Sequences, Amino Acid; Salts; Scavenger Receptors, Class A - metabolism; Surfactants; T cells; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Terpenes; Vaccines; Vector-borne diseases; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110425

Invocation of cellular immunity by epitopic peptides remains largely dependent on empirically developed protocols, such as interfusion of aluminum salts or emulsification using terpenoids and surfactants. To explore novel vaccine formulation, epitopic peptide motifs were co-programmed with structural motifs to produce artificial antigens using our "motif-programming" approach. As a proof of concept, we used an ovalbumin (OVA) system and prepared an artificial protein library by combinatorially polymerizing MHC class I and II sequences from OVA along with a sequence that tends to form secondary structures. The purified endotoxin-free proteins were then examined for their ability to activate OVA-specific T-cell hybridoma cells after being processed within dendritic cells. One clone, F37A (containing three MHC I and two MHC II OVA epitopes), possessed a greater ability to evoke cellular immunity than the native OVA or the other artificial antigens. The sensitivity profiles of drugs that interfered with the F37A uptake differed from those of the other artificial proteins and OVA, suggesting that alteration of the cross-presentation pathway is responsible for the enhanced immunogenicity. Moreover, F37A, but not an epitopic peptide, invoked cellular immunity when injected together with monophosphoryl lipid A (MPL), and retarded tumor growth in mice. Thus, an artificially synthesized protein antigen induced cellular immunity in vivo in the absence of incomplete Freund's adjuvant or aluminum salts. The method described here could be potentially used for developing vaccines for such intractable ailments as AIDS, malaria and cancer, ailments in which cellular immunity likely play a crucial role in prevention and treatment.