Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes TH1 cytokine expression while downregulating TH2 cytokine expression in PBMCs from human patients with ragweed allergy

Abstract

Background: Recent studies have demonstrated that bacterially derived immunostimulatory sequences (ISSs) of DNA can activate the mammalian innate immune system and promote the development of TH1 cells. Promotion of TH1 immunity by means of immunotherapy in allergic patients has led to the alleviation of symptoms that result from allergen-specific TH2 responses. Objective: Our purpose was to investigate whether the TH1-enhancing properties of ISSs could be used to alter the TH2-dominated immune response of allergic PBMCs in vitro. Methods: Ragweed protein-linked ISS (PLI) was generated from a specific, highly active 22-base ISS and Amb a 1, the immunodominant allergen in ragweed pollen, to combine the TH1-enhancing properties of ISSs with allergen selectivity, and its activity was investigated in PBMC cultures from subjects with ragweed allergy. Results: PLI was markedly successful at reversing the dominant allergen-induced TH2 profile while greatly enhancing IFN-γ production. Delivering ISSs in a linked form proved to be much more effective at modulating the resulting cytokine profile than delivering free ISSs in a mixture with unlinked Amb a 1. PLI also demonstrated cytokine-modulating properties, even when used to stimulate cells that had already been primed for 6 days with Amb a 1. The antigen specificity of the action of PLI was confirmed by the observations that PLI enhances Amb a 1–specific T-cell proliferation. Conclusion: These data indicate that delivery of ISSs within an antigen-specific context exhibits potent cytokine-modulating activity and, combined with its reduced allergenicity, makes this molecule a strong candidate for use in improved immunotherapy applications. (J Allergy Clin Immunol 2001;108:191-7.)