Antagonistic peptides specifically inhibit proliferation, cytokine production, CD40L expression, and help for IgE synthesis by Der p 1-specific human T-cell clones

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Background:Allergic disorders are characterized by IgE antibody responses to a multitude of allergens as a result of the ability of these antibodies to specifically bind to high-affinity IgE receptors on mast cells and basophils. This interaction results in receptor activation and release of soluble mediators such as histamine and leukotrienes, which cause allergic reactions in various target organs. Because the synthesis of IgE is tightly regulated by cytokines and CD40 ligand (L) interactions, CD4+ helper T cells are obvious targets, with the aim to modulate allergen-induced IgE responses.Objectives:Because of the central role of allergen-specific T-helper type 2 (TH2) cells in the pathway leading to IgE synthesis in vitro and in vivo, we have evaluated the possibility of inhibiting allergen-induced activation of these cells by using allergen-derived peptides that have been modified by single amino acid substitutions.Methods:Three cloned human TH2-like CD4+ T-cell lines, specific for Der p 1, the major allergen in house dust, were used in this study. Upon activation with Der p 1 or specific Der p 1-dervived wild-type peptides, these T-cell clones produce high levels of IL-4 and IL-5 and low levels of interferon-γ and IL-2, respectively, and furthermore give help to B cells for the production of IgE in vitro. Modified synthetic peptides were generated by the introduction of single amino acid substitutions into two different T-cell activation-inducing epitopes on Der p 1. The effects of these modified peptides were studied in Der p 1-induced proliferation, cytokine production, and in vitro IgE production assays.Results:Several substituted Der p 1-derived peptides failed to induce T-cell proliferation, in contrast to the native peptides. In addition, some of these peptides acted as antagonists by strongly inhibiting wild-type peptide-induced proliferation as well as the production of interferon-γ, IL-2, IL-4, and IL-5, although the production of the latter two cytokines was less affected than that of interferon-γ, even at a 100-fold molar excess of the antagonistic peptides. In addition, the presence of an excess of each of the antagonistic peptides during the activation of Der p I-specific T-cell clones prevented induction of CD40L expression, resulting in a failure of these cells to give help to B cells for the production of IgE in vitro, even in the presence of exogenous IL-4.Conclusions:Substitution of certain amino acid residues in immunogenic Der p 1-derived peptides results in the generation of peptides that fail to induce proliferation of Der p 1-specific T-cell clones. In addition, these modified peptides have strong antagonistic activities on Der p 1-induced proliferation, cytokine production, and CD40L expression by allergen-specific T-cell clones as well as on T cell-mediated IgE production by B cells. These findings suggest that modified peptides interfere with allergen-induced activation of T cells, including the production of cytokines and the expression of surface molecules important for successful T cell-B cell interactions, and may therefore have therapeutic potential by inhibiting the expansion and function of allergen-specific TH2 cells.

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