title: Modulation of Th2 responses by peptide analogues in a murine model of allergic asthma: amelioration or deterioration of the disease process depends on the Th1 or Th2 skewing characteristics of the therapeutic peptide.
abstract: Allergen-specific CD4+ Th2 cells play an important role in the immunological processes of allergic asthma. Previously we have shown that, by using the immunodominant epitope OVA323-339, peptide immunotherapy in a murine model of OVA induced allergic asthma, stimulated OVA-specific Th2 cells, and deteriorated airway hyperresponsiveness and eosinophilia. In the present study, we defined four modulatory peptide analogues of OVA323-339 with comparable MHC class II binding affinity. These peptide analogues were used for immunotherapy by s.c. injection in OVA-sensitized mice before OVA challenge. Compared with vehicle-treated mice, treatment with the Th2-skewing wild-type peptide and a Th2-skewing partial agonistic peptide (335N-A) dramatically increased airway eosinophilia upon OVA challenge. In contrast, treatment with a Th1-skewing peptide analogue (336E-A) resulted in a significant decrease in airway eosinophilia and OVA-specific IL-4 and IL-5 production. Our data show for the first time that a Th1-skewing peptide analogue of a dominant allergen epitope can modulate allergen-specific Th2 effector cells in an allergic response in vivo. Furthermore, these data suggest that the use of Th1-skewing peptides instead of wild-type peptide may improve peptide immunotherapy and may contribute to the development of a successful and safe immunotherapy for allergic patients.
authors.affiliation: Institute of Infectious Diseases, Department of Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: Janssen
authors.forename: A J
authors.initials: AJ
authors.lastname: van Oosterhout
authors.forename: A J
authors.initials: AJ
authors.lastname: van Rensen
authors.forename: W
authors.initials: W
authors.lastname: van Eden
authors.forename: F P
authors.initials: FP
authors.lastname: Nijkamp
authors.forename: M H
authors.initials: MH
authors.lastname: Wauben
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000628:therapy*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005434:Flow Cytometry; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007136:Immunoglobulins / Q000096:biosynthesis; D016130:Immunophenotyping; D007279:Injections, Subcutaneous; D007399:Interphase / Q000276:immunology; D008081:Liposomes / Q000008:administration & dosage; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; C111391:HA 126-138; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007136:Immunoglobulins; D008081:Liposomes; C111390:OVA 323-339; D010446:Peptide Fragments; D010047:Ovalbumin