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.

Biological effect of varying peptide binding affinity to the BoLA-DRB3*2703 allele

“…Various OVA and FMD-V peptides have previously been used as immunogenic epitopes to define antigen presentation, the kinetics of peptide-MHC binding, and assess antibody responses of cattle and mice [3,4,7,11,17,22,31]. FMD-VP2 and VP4, for example, were both demonstrated to bind with high affinity to BoLA-DRB3*1101 and BoLA-DRB3*0201, respectively.…”

“…This may not be surprising, since the peptides used in this study were ranked according to their binding affinity for the BoLA-DRB3*2703 molecule, alone. Other variables including, peptide degradation, binding affinity for the T-cell receptor, expression of co-stimulatory and adhesion molecules, T-cell receptor avidity, surface density of MHC class II-T-cell receptor complexes, cell-cycle and length of differentiation time have also been demonstrated to influence MHC class II-T-cell receptor mediated T-lymphocyte function [2,6,11,16,20,29,30]. Our initial interpretation of the decreased DNA synthesis in the FMD-VP4 (high binding) peptide-specific T-lymphocytes was that there might be a hole in the T-cell repertoire.…”

The Efficacy of Immunotherapy in an Experimental Murine Model of Allergic Asthma Is Related to the Strength and Site of T Cell Activation During Immunotherapy

“…In several clinical trials, however, it has been shown that, although some patients showed a reduction of airway symptoms and Th2-associated responses, Fel d I peptide immunotherapy elicited allergic symptoms and late asthmatic reactions in cat-allergic asthmatics (7,8). Moreover, we recently showed that in OVA-sensitized mice, s.c. immunotherapy with the immunodominant T cell epitope OVA 323-339 enhanced both airway hyperresponsiveness (AHR) 3 and eosinophilia upon OVA challenge (9), while an in vitro defined superagonistic analogue of this OVA 323-339 epitope had a beneficial effect (10).…”

“…The outcome of these forms of immunotherapy was related to the site of Ag-specific T cell activation, and the magnitude of the T cell response using an adoptive T cell transfer model (19). In this model, limited numbers of fluorescent labeled (CFSE) OVA 323-339 -specific DO11.10 T cells were transferred into naive BALB/c recipients, and T cell activation and division in various lymphoid organs were monitored at various days after immunotherapy with OVA, OVA 323-339 , or the peptide analogue of OVA 323-339 , OVA 336 E-A, which we defined previously as a superagonistic peptide with comparable MHC-binding affinity as OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] , but more potent in the induction of T cell proliferation and Th1 cytokine induction in DO11.10 T cells in vitro (10).…”

“…OVA 323-339 -specific DO11.10 T cells were obtained from TCR transgenic mice by negative selection, as described previously (10). Cells obtained after depletion were shown to be Ͼ90% OVA 323-339 -specific T cells, as demonstrated by FACS analysis using the clonotype-specific Ab KJ1.26 (22).…”