title: PS80 interferes with the antiallergic effect of Cry-consensus peptide, a novel recombinant peptide for immunotherapy of Japanese cedar pollinosis, at very low concentration through modulation of Th1/Th2 balance.
abstract: Polysorbate 80 (PS80 or Tween-80) is often used as an additive to promote the rapid solubilization of pharmaceuticals in aqueous solutions. We investigated whether coinjection of a minimal amount of PS80 had a modulatory effect on the immunotherapeutic effects of Cry (Cryptomeria)-consensus peptide, a novel peptide developed for the therapeutic management of Japanese cedar pollinosis, using a Cry j 1-sensitized mouse model with experimental allergic rhinitis. Subcutaneous challenge with Cry-consensus peptide plus 50 microg/ml of PS80 did not affect the antigen-specific proliferation of splenocytes, but decreased the potency of Cry-consensus peptide to inhibit antigen-specific interleukin (IL)-5 production by the cells significantly in comparison with challenge with Cry-consensus peptide alone. However, there was no significant difference between the effect of Cry-consensus peptide administration on interferon (IFN)-gamma production in the presence and absence of PS80, indicating that PS80 interfered with the T helper 1 (Th1)-dominant T helper balance induced by Cry-consensus peptide challenge. Moreover, the increase in the level of antigen-specific immunoglobulin G2a (IgG2a) induced by Cry-consensus peptide challenge was inhibited slightly but unambiguously by PS80 coinjection. These in vitro experiments indicated that PS80 induces Th2-type differentiation of T helper cells through preferential inhibition of IFN-gamma expression relative to IL-5 expression in splenocytes in a concentration-dependent manner. In naïve mice, sensitization by Cry-consensus peptide with PS80 induced antigen-specific IL-5 production more potently than sensitization by Cry-consensus peptide alone, and when PS80 was added to bone marrow-derived dendritic cells, the endocytosis of fluorescence-labelled Cry-consensus peptide was dramatically inhibited in a concentration-dependent manner. Therefore, we conclude that PS80 has an immunomodulatory effect on the antigen-specific response resulting in a shift towards Th2 predominance with respect to the antigen recognition stage. Taken together, our findings suggest that PS80 might decrease the efficacy of Cry-consensus peptide through modulation of the efficiency of antigen endocytosis and/or of the direction of successive T helper cell differentiation.
authors.affiliation: Research and Development Section, Pharmaceuticals Development Department, Meiji Dairies Corporation, Kanagawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kozutsumi
authors.forename: Masako
authors.initials: M
authors.lastname: Tsunematsu
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamaji
authors.forename: Rika
authors.initials: R
authors.lastname: Murakami
authors.forename: Minehiko
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kino
mesh_terms: D000485:Allergens / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D000818:Animals; D052179:Antigens, Plant; D002478:Cells, Cultured; D032485:Cryptomeria / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D003888:Desensitization, Immunologic / Q000379:methods; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007155:Immunologic Factors / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D010940:Plant Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D011136:Polysorbates / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D052179:Antigens, Plant; C065290:Cry j I protein, Cryptomeria japonica; C065291:Cry j II protein, Cryptomeria japonica; D018984:Epitopes, T-Lymphocyte; D007155:Immunologic Factors; D015848:Interleukin-5; D010940:Plant Proteins; D011136:Polysorbates; D011994:Recombinant Proteins; C518796:cry-consensus peptide; D007371:Interferon-gamma