Amb a 1–immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response

Abstract

Background Amb a 1–immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) is a novel immunotherapeutic compound consisting of purified Amb a 1 from short ragweed proteins covalently linked to an immunostimulatory phosphorothioate oligodeoxyribonucleotide. In sensitized animals AIC can stimulate an Amb a 1–specific T H1 response and decrease pulmonary reactivity to ragweed challenge. Clinical trials have documented reduced allergic response to AIC in comparison with licensed ragweed extract. Objectives We sought to determine the in vivo effect of short-course immunotherapy with AIC on eosinophilia and cytokine mRNA expression in the nasal mucosa of ragweed-sensitive patients. Methods Ragweed-sensitive patients with allergic rhinitis were treated with 6 escalating doses of AIC (0.06-12 μg, n = 28) or placebo (n = 29) at weekly intervals immediately before the 2001 ragweed season. Symptom scores and medication use were recorded for the 2001 and 2002 ragweed seasons for all patients. A subset of patients (12 receiving AIC and 7 receiving placebo) consented to have nasal biopsy specimens taken before immunization and before and after the first ragweed season. The preseason and postseason biopsy specimens were taken 24 hours after ragweed allergen challenge and compared with the initial unchallenged biopsy specimen to assess cytokine and inflammatory cell responses by using immunocytochemistry and in situ hybridization. Results AIC was safe and well tolerated by all patients. There was no difference between the AIC and placebo groups in the number of allergen-induced major basic protein–, IL-4–, IL-5–, or IFN-γ–positive cells in the mucosa in the first weeks after AIC immunization. On rechallenge and rebiopsy after the end of the 2001 ragweed season, however, AIC-treated patients had a significantly reduced increase in eosinophils and IL-4 mRNA-positive cells and an increased number of IFN-γ mRNA-positive cells compared with placebo-treated patients. No difference between treatment groups was observed in symptom scores or medication use during the first ragweed season. During the second ragweed season, however, there was a significant decrease in chest symptoms and a trend toward reduced nasal symptoms in the AIC-treated group. Conclusion Short-course immunotherapy with AIC can modify the response of nasal mucosa to allergen challenge by increasing T H1 cytokine production and decreasing T H2 cytokine production and eosinophilia. This modification was not immediate but was observed 4 to 5 months after completion of immunotherapy and seasonal ragweed-pollen exposure. The T-cell subset shift after immunization and seasonal exposure was followed by evidence of clinical efficacy in the second ragweed season without additional AIC immunizations.