Immunomodulation of allergic disease

Abstract

This review focuses on sublingual immunotherapy (SLIT), toll-like receptor-9 (TLR-9) vaccines using cytosine phosphorothioate guanosine (CpG)-allergen conjugates, and anti-IL-5 as novel immunomodulating therapies in allergy. At present, all three approaches are investigational in the United States and require further study to determine their safety and effectiveness. SLIT provides a novel oral route of administering an allergen to induce tolerance to inhaled allergens. Studies of SLIT in allergic rhinitis demonstrate that it reduces symptoms and medication use and is associated with a low incidence of systemic allergic reactions. Initial phase II studies with TLR-9 vaccines conjugated to a ragweed allergen demonstrate that they reduce symptoms of allergic rhinitis during the ragweed season. Anti-IL-5 is effective as a corticosteroid-sparing agent in the hypereosinophilic syndrome. It has not shown benefit in moderate asthmatics with persistent symptoms but may reduce aspects of airway remodeling in asthma.

Figure 1A. CpG DNA

CpG DNA is a six base pair sequence of non-coding DNA that comprise a central cytosine (C) linked to a guanosine (G) through a phosphorothioate linkage (abbreviated p in CpG). To have immunodulating properties the CpG sequence must be flanked on the 5¹ end by two purines, and on the 3¹ end by two pyrimidine base pairs.

Figure 1B. B. Amb a1 conjugated to CpG DNA

A ragweed based TLR-9 vaccine was constructed by chemically linking the major ragweed protein allergen Amb a I to four strands of DNA. Each of the four strands of DNA contain two CpG sequences. The CpG sequences bind to TLR-9 receptors expressed intracellulary by cells of the innate immune system such as dendritic cells which take up injected allergens.