Immunostimulatory DNA inhibits IL-4–dependent IgE synthesis by human B cells

• Published in: Journal of allergy and clinical immunology Vol. 108; no. 3; pp. 417 - 423
• Main Authors: Horner, Anthony A., Widhopf, George F., Burger, Jan A., Takabayashi, Kenji, Cinman, Nadya, Ronaghy, Arash, Spiegelberg, Hans L., Raz, Eyal
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.09.2001; Elsevier
• Subjects: allergy; Anti-Allergic Agents - pharmacology; B lymphocytes; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Biological and medical sciences; Cells, Cultured; CpG motif; DNA - immunology; DNA - pharmacology; Human; Humans; Hypersensitivity - immunology; Hypersensitivity, Immediate - immunology; IFN-γ receptor; IL-4 receptor; immuno-stimulatory DNA; Immunoglobulin A - biosynthesis; Immunoglobulin E - biosynthesis; Immunoglobulin G - biosynthesis; Immunoglobulin M - biosynthesis; Immunopathology; Immunotherapy (general aspects); Interleukin-4 - immunology; isotype switching; Medical sciences; Oligodeoxyribonucleotides - immunology; Oligodeoxyribonucleotides - pharmacology; Thionucleotides - immunology; Thionucleotides - pharmacology; vaccination; Human; B lymphocytes; ISS-ODN; MFIR; IL-4 receptor; immuno-stimulatory DNA; allergy; IFN-γR; M-ODN; IL-4R; IFN-γ receptor; isotype switching; vaccination; CpG motif; Immunopathology; Allergy; Immunoglobulins; Immunostimulation; Immune response; Nucleotide sequence; IgE; Cytokine; Isotype; Switching; Interleukin 4; Treatment; DNA; Immunotherapy; Gamma interferon; Biological receptor
• ISSN: 0091-6749
• DOI: 10.1067/mai.2001.117795

Background: Immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) is a potent antiallergic immunomodulating agent in mice. However, few studies have addressed its antiallergic potential in human subjects. Objective: We sought to determine whether a phosphoro-thioate ISS-ODN could inhibit IL-4–dependent IgE synthesis by human B cells. Methods: Initially, nonatopic- and atopic-donor PBMCs were incubated with ISS-ODN or mutated oligodeoxynucleotide, and cytokine production and B-cell expression of IFN-γ receptor and IL-4 receptor were measured by using ELISA and flow cytometry, respectively. In subsequent studies atopic-donor PBMCs were incubated with IL-4 alone or with ISS-ODN or mutated oligodeoxynucleotide. After 14 days, IgE production and IgM, IgG, and IgA production were determined by using ELISA. In select IgE studies cytokines were neutralized with mAbs. Results: ISS-ODN induced IL-12, IFN-α, IFN-γ, IL-10, and IL-6 production from both nonatopic- and atopic-donor PBMCs. ISS-ODN also increased IFN-γ receptor and inhibited IL-4 receptor expression on B cells from both donor populations. Furthermore, ISS-ODN inhibited IL-4–dependent IgE production by atopic-donor PBMCs. Neutralization of IL-12, IFN-α, IFN-γ, and IL-10, but not IL-6, attenuated the inhibitory activity of ISS-ODN on IgE production. In contrast to its inhibition of IgE synthesis, ISS-ODN stimulated the production of IgM, IgG, and IgA. Conclusion: These in vitro studies demonstrate that phos-phorothioate ISS-ODN elicits an innate immune response by PBMCs, which inhibits IL-4–dependent IgE synthesis. In addition, these results provide further support for consideration of ISS-ODN therapy for the treatment of allergic disease in clinical practice. (J Allergy Clin Immunol 2001;108:417-23.)