Allergen ISS conjugates in allergic rhinitis

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.