ITN - Allergy & Asthma Trial Information



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Allergen ISS conjugates in allergic rhinitis

Principal Investigators:
David H. Broide, University of California San Diego
Peter Creticos, Johns Hopkins University

Abstract
Allergic rhinitis is a common manifestation of allergy to airborne allergens. It is well suited to investigations of the effectiveness of immunomodulatory agents because nasal challenges with allergen can objectively demonstrate whether the immunomodulatory agent being tested induces a protective response to allergen challenge. The efficacy of current protein based immunotherapy (IT) for allergic rhinitis is limited, in large part, by the small amounts of allergen that can be given safely without causing severe allergic reactions. Based on studies in vitro and animal models of allergy in vivo, Immunostimulatory sequence DNA (ISS) may provide a means to inhibit pro-allergic Th2 mediated immune responses more effectively than current protein based IT. ISS inhibits the production of Th2 pro-allergic cytokines from murine splenocytes and human mononuclear cells, and prevents allergic responses in several animal models of allergic disease. In mice, rabbits, and monkeys, a chemical conjugate of Amb a I, the major ragweed (RW) allergen and ISS (termed AIC ; Amb a I Immunostimulatory DNA Conjugate) has proven to be more immunogenic then Amb a I, and more effective in the inhibition and reversal of Th2 biased allergic responses. In vitro studies demonstrate that conjugation of Amb a I to ISS reduces its allergenic potential up to 100 fold in basophil degranulation studies in vitro, and in skin testing of RW allergic patients in vivo. Safety studies in mice suggest that AIC has no significant toxicity. This improved immunogenicity, and decreased allergenicity, makes AIC potentially an improved therapy for allergen IT.

The goals of the proposed investigations are to evaluate the safety and efficacy of AIC IT and its mechanisms of tolerance induction. Patients with RW hypersensitivity and allergic rhinitis will be recruited at Johns Hopkins University and at the University of California San Diego and randomly assigned in separate blinded studies to receive AIC, or placebo. Patients will be monitored for safety (local and systemic reactions to AIC; routine chemistries, blood counts, ds DNA Ab titers), immune response to AIC, and clinical response to RW nasal challenge. Studies in Baltimore will also determine whether AIC reduces allergic rhinitis symptoms during the RW season. Studies at the University of California San Diego will focus on different AIC dosing schedules, alternative AIC formulations, and follow subjects for 2 years off of AIC to determine the duration of any immune and clinical responses observed.

Mechanistic Studies: Mechanisms of tolerance induction will be assessed using specimens derived from the target mucus membrane (nasal mucosa) as well as peripheral tissues (skin and blood). The mechanistic studies will explore whether AIC induces T cell tolerance, immune deviation, or induction of regulatory T lymphocytes. Studies will investigate RW induced T cell proliferation and cytokine profiles in culture and by intracellular cytokine staining. In situ hybridization and TaqMan PCR will be utilized to assess T cell cytokine profiles in nasal mucosa.

Participating Investigators

	David H. Broide, University of California San Diego
	Peter Creticos, Johns Hopkins Asthma & Allergy Ctr
	Eyal Raz, University of California San Diego
	Terance Davidson, University of California San Diego
	Gary Firestein, University of California San Diego
	Robert G Hamilton, Johns Hopkins Asthma & Allergy Ctr
	Anthony A. Horner, University of California San Diego
	Alfredo Jalowayski, University of California San Diego
	Anne Kagey-Sobotka, Johns Hopkins Asthma & Allergy Ctr
	Lawrence M. Lichtenstein, Johns Hopkins Asthma & Allergy Ctr
	Philip S. Norman, Johns Hopkins Asthma & Allergy Ctr
	Joe Ramsdell, University of California San Diego
	John Thomas Schroder, Johns Hopkins Asthma & Allergy Ctr
	Kenji Takabayashi, University of California San Diego

Study News & Recent Developments

	New Positive Data from Phase II ITN Study of Ragweed Immunotherapy Product (AIC) [open]
	Dynavax, Johns Hopkins University and NIH-Sponsored Immune Tolerance Network Present New Positive Data from Phase II Study of Ragweed Immunotherapy Product (AIC) - DynaVax [go]

Background Articles

	ISS oligodeoxynucleotide-based vaccination and immunomodulation - J Allergy Clin Immunol [Abstract]
	Immunostimulatory DNA and applications to allergic disease - J Allergy Clin Immunol [go]
	Immunostimulatory DNA Sequences Inhibit IL-5, Eosinophilic Inflammation, and Airway Hyperresponsiveness in Mice - J Immunol [go]
	DNA-based immunization for asthma [Abstract]

Resources & Interesting Links

Dynavax Technologies ISS overview [go

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Study Publications

	Creticos,P.S., Schroeder,J.T., Hamilton,R.G., Alcer-Whaley,S.L., Bhattignavong,A.P., Lindblad,R., Hoffman,R., Seyfert,V., Eiden,J.J., Broide,D., and Immune Tolerance Network Group (2006): Immunotherapy with a Ragweed–Toll-Like Receptor 9 Agonist Vaccine for Allergic Rhinitis. NEJM 355: 1445-1455, 2006. [PubMed] [Reprint]
	Creticos PS, Lighvani SS, Bieneman AP, Balcer-Whaley SP, Norman PS, Lichtenstein LM, Schroeder JY. Enhanced IL10 Secretion by PBMC During the Ragweed Season: Effects of AIC Immunotherapy vs Placebo. J. Allergy Clin. Immunol. Vol. 111, S201 (530), 2003. Presented at 60th Meeting AAAAI, Denver, CO. Mar 3-7, 2003. Abstract 530. [Abstract]
	Creticos PS, Eiden JJ, Broide D H, Balcer-Whaley, SL, Schroeder, JT, Khattignavong, A, Li H, Norman P, Hamilton, R. Immunotherapy with Immunostimulatory Oligonucleotides Linked to Purified Ragweed Amb a 1 Allergen: Effects on Antibody Production, Nasal Allergen Provocation, and Ragweed Seasonal Rhinitis. J. Allergy Clin. Immunol. 109, No 4, 743-44 (3) 2002. Presented at 2003 AAAAI, March 1-3, 2002. [Abstract]
	Creticos, PS, Eiden JJ, Broide DH, Balcer-Whaley SL, Schroeder JT, Khattignavong A, Li H. Norman P, Hamilton R. Immunotherapy with Immunostimulatory Oligonucleotides Linked to Purified Ragweed Amb a 1 Allergen: Effects on Nasal Allergen Provocation, Antibody Production, and Seasonal Rhinitis Endpoints. 24th Symposium of Collegium Internationale Allergoligicum, Bermuda. November 1, 2002 .