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World Allergy Organization
WAO's mission: To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

World Allergy Forum: Immune Intervention

Immunostimulatory DNA (ISS) Challenging Traditional Allergen Immunotherapy

Eyal Raz

Immunostimulatory DNA sequence (ISS or a CpG motif) can inhibit an ongoing Th2 response and induce de novo a Th1 response. Their ability to modulate the immediate and late phases of the allergic inflammation was evaluated in two related animal models. In a mouse model of ragweed (RW)-induced allergic conjunctivitis, systemic or mucosal (eye drops) administration of ISS oligonucleotide (ODN) after RW/alum sensitization and before (pre-priming) or with RW challenge inhibited both the immediate hypersensitivity response and the late phase cellular infiltration. ISS-ODN administration suppressed the subsequent RW specific Th1 response. Mechanistically, the ISS-induced anti-inflammatory and immunomodulatory effects were abolished when mice were treated with anti-IL-12 neutralizing antibodies, suggesting a pivotal role for type 1 cytokines in the inhibition of both the immediate hypersensitivity response and the late phase cellular infiltration. In a mouse model of ovalbumin induced airway hyper-responsiveness ISS delivered prior (pre-priming) or with ovalbumin challenge significantly inhibits airway eosinophilia and reduces responsiveness to inhaled methacholine. The onset of the ISS effect on reducing the number of tissue eosinophils was for at least lasted 6 days. ISS was effective in inhibiting eosinophilic airway inflammation when administered either systemically (intraperitoneally), or mucosally (i.e. intranasally or intratracheally), to induce allergen specific IFN-g and to inhibit allergen specific IL-5 production. In both models ISS administration was more effective that dexamethasone in inhibiting the allergic responses. Thus, ISS-ODN is a novel anti-inflammatory and immunomodulatory agent that may provide an alternative to the current standard care of allergy.

References

  1. Roman M, Martin-Orozco E, Goodman J, Nguyen MD, Sato Y, Romaghy A, Kornbluth R, Richman DD, Carson DA, Raz E: Immunostimulatory DNA sequences function as Th1 promoting adjuvants. Nature Medicine 1997;3:849- 854.
  2. Broide D, Schwartz J, Tighe H, Gifford T, Nguyen M-D, Malek S, Van Uden J, Martin-Orozco E, Gelfand EW, Raz E. Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation and airway hyper-responsiveness in mice. J. Immunol 1998;161:7054-7062.
  3. Van Uden J, and Raz E. Immunostimulatory DNA and applications to allergic disease. J All Clin Immunol 1999;104:902-910.
  4. Kobayashi H, Horner A, Takabayashi K, Nguyen M-D, Huang E, Cinman N, Raz E. Immunostimulatory DNA pre-priming: A novel approach for prolonged Th-1 biased immunity. Cell Immunol 1999;198:69-75.
  5. Magone MT, Chan CC, Witcup SM, Raz E. Systemic or topical administration of immunstimulatory DNA inhibits early and late phase murine allergic conjunctivitis. Submitted 1999.

Slide presentation

 

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