The Journal of Experimental Medicine
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Published online 28 November 2005 doi:10.1084/jem.20050631
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 11, 1563-1573
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ARTICLE

 Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction

Edith M. Hessel1, Mabel Chu1, Jennifer O. Lizcano1, Bonnie Chang1, Nancy Herman2, Sariah A. Kell1, Marsha Wills-Karp2, and Robert L. Coffman1

1 Dynavax Technologies, Berkeley, CA 94710
2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229

CORRESPONDENCE Edith M. Hessel: ehessel{at}dvax.com

A single treatment with a CpG-containing immunostimulatory DNA sequence (ISS) given before allergen challenge can inhibit T helper type 2 cell (Th2)–mediated airway responses in animal models of allergic asthma; however, the mechanism of this inhibition remains largely undefined. Here, we demonstrate that airway delivery of ISS before allergen challenge in Th2-primed mice acts in two distinct ways to prevent the allergic responses to this challenge. The first is to prevent induction of cytokines from allergen-specific Th2 cells, as demonstrated by the nearly complete inhibition of Th2 cytokine production, Th2-dependent functional responses, and gene induction patterns. ISS inhibits the Th2 response by rendering lung antigen-presenting cells (APCs) unable to effectively present antigen to Th2 cells, but not to Th1 cells. This loss of APC function correlates with a reduced expression of costimulatory molecules, including programmed cell death ligand (PD-L)1, PD-L2, CD40, CD80, CD86, and inducible T cell costimulator, and of major histocompatibility complex class II on CD11c+ APCs from the airways of ISS-treated mice. The second important action of ISS is inhibition of immunoglobulin E–dependent release of Th2 cytokines, especially interleukin 4, from basophils and/or mast cells in the airways of Th2-primed mice. Thus, inhibition by ISS of allergic responses can be explained by two novel mechanisms that culminate in the inhibition of the principal sources of type 2 cytokines in the airways.

Abbreviations used: APTI, airway pressure-time index; BAL, bronchoalveolar lavage; ICOS, inducible T cell costimulator; IDO, indoleamine 2,3-dioxygenase; ISS, immunostimulatory DNA sequence(s); M-trp, 1-methyl-DL-tryptophan; ODN, oligodeoxynucleotide; PD-1, programmed cell death protein 1; PDC, plasmacytoid dendritic cell; PD-L, programmed cell death ligand; RW, ragweed pollen extract; TLR, Toll-like receptor.


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