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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 Peptide¹

Edith M. Janssen^*,, Antoon J. M. van Oosterhout, Annemiek J. M. L. van Rensen, Willem van Eden^*, Frans P. Nijkamp and Marca H. M. Wauben^*,2

^* Institute of Infectious Diseases and Immunology, Department of Immunology, Faculty of Veterinary Medicine, and Departments of Pharmacology and Pathophysiology and Pharmaceutics, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

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 OVA_323–339, 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 OVA_323–339 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.

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