Immunomodulators in Asthma Therapy Vesselin V. Dimov, MD, Jeffrey R. Stokes, MD, and Thomas B. Casale, MD Corresponding author Thomas B. Casale, MD Department of Medicine, Division of Allergy/Immunology, Creighton University, 601 North 30th Street, Suite 5850, Omaha, NE 68131, USA. E-mail: tbcasale@creighton.edu Current Allergy and Asthma Reports 2009, 9:475–483 Current Medicine Group LLC ISSN 1529-7322 Copyright © 2009 by Current Medicine Group LLC New developments in the feld of allergy and immu- nology have yielded a variety of novel therapeutic approaches in recent years, and more agents are at the clinical trial stage. Among the therapeutic approaches discussed in this review are Toll-like receptor agonists, immunostimulatory oligodeoxy- nucleotides, orally and parenterally administered cytokine blockers, and specifc cytokine receptor antagonists. Transcription factor modulators target- ing syk kinase, peroxisome proliferator-activated receptor- γ, and nuclear factor- κB are also being evaluated in the treatment of asthma. The anti-IgE monoclonal antibody omalizumab has established effectiveness in patients with allergic asthma, but the criteria for selecting patients who are most likely to beneft from it are less clear. This review summarizes data from human clinical trials with immunomodu- lators to discuss the rationale for their use, their ef fcacy, and adverse events associated with them. Introduction New discoveries regarding the molecular mechanisms of allergic and immunologic diseases have led to a variety of novel therapeutic approaches in recent years, and more agents are at the human clinical trial stage [1]. This article is an in-depth review of some of these new and potential treatment modalities for patients with asthma. Asthma is a chronic infammatory disease that affects about 300 million people worldwide. Although most patients respond well to the currently available treatments, 5% to 10% have severe disease that responds poorly, and another subset of patients have steroid resistance or intoler- able side effects from currently available treatments. New therapeutic approaches reviewed in this article include Toll-like receptor (TLR) agonists, orally and parenterally administered cytokine blockers, specifc cytokine receptor antagonists, transcription factor modulators, and anti-IgE monoclonal antibodies (mAbs). These agents would be especially benefcial to patients who have poor control of their disease despite using guideline-recommended treat- ments. Moreover, if they could reverse airway remodeling or prevent it from occurring, a substantial therapeutic beneft would accrue. The risk–beneft ratio of these thera- peutic approaches is also discussed (Fig. 1). Toll-like Receptors TLRs play an important role in the activation of anti- gen-presenting cells for innate and adaptive immune responses. Agents targeting the TLRs can modify the T-helper type 1 (Th1)–Th2 cytokine balance and thus affect allergic diseases. Eleven TLRs have been identi- fed in humans to date. Agonists for TLR4 and TLR9 have been used in human clinical trials to treat allergic respiratory diseases. TLR4 binds lipopolysaccharides and endotoxins expressed on the cell surface. No TLR4 ago- nists are currently in development for treatment of asthma as monotherapy. However, TLR4 agonists combined with allergen immunotherapy are an effective strategy for the management of allergic rhinitis. Four preseasonal injections of monophosphoryl lipid A combined with glu- taraldehyde-modifed antigen adsorbed onto L-tyrosine depot adjuvant to enhance tolerability have been shown to reduce symptoms and rescue medication use in patients with seasonal allergic rhinitis [2]. TLR9 agonists (immunostimulatory oligonucleotides) TLR9 recognizes synthetic oligodeoxynucleotides contain- ing unmethylated deoxycytidyl-deoxyguanosine (CpG) motifs, which mimic the immunostimulatory activity of bacterial DNA. Innate and adaptive immune systems are activated through TLR9 signaling. TLR9 is the receptor for CpG DNA, which in humans is expressed in the high- est concentrations on B cells and plasmacytoid dendritic cells. Commonly referred to as CpG oligodeoxynucleo- tides, TLR9 agonists directly induce the activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. TLR9-activated plasmacytoid dendritic cells produce interferon (IFN)- α, leading to secondary activation of natural killer T cells, monocytes, and neutrophils. B cells activated by TLR9 produce interleukin (IL)-6 and IL-10