Emerging immune targets for the therapy of allergic asthma

Despite the existence of effective therapies, allergic asthma and related atopic syndromes have recently emerged as epidemic diseases and important public health concerns. A remarkable collaboration has since ensued between basic researchers, clinicians and the pharmaceutical industry in an effort to develop more effective therapeutic and preventative strategies.Studies from human and rodent models provide evidence that allergic asthma has an immune basis, involving antibodies such as immunoglobulin E and its receptor, FcɛRI, and T-helper type 2 (TH2)-cell-derived cytokines such as interleukin-4 (IL-4), IL-5 and IL-13.Therapeutic strategies now being developed focus on interrupting IgE and TH2 effector pathways. These include anti-IgE antibodies, molecules directly associated with TH2 cells (co-stimulatory molecules, homing molecules, tyrosine kinases, transcription factors and CD4) or secreted TH2 cytokines, chemokines and intermediates in their signalling pathways. Other molecules that might suppress IgE and TH2 function include Toll-like receptors (TLRs), IL-12 and other cytokines.Several potential immune targets seem to have limited therapeutic potential in allergic asthma either because they are relatively ineffective or because their general importance in immunity and other functions precludes safe targeting. These molecules include IL-5, the more widely shared cytokine-receptor signalling moieties, many transcription factors, including nuclear factor-κB (NF-κB) and most of the signal transducer and activator of transcription (STAT) factors, and the Janus-associated kinase (JAK) family of tyrosine kinases.Molecules with more potential as therapeutic targets include: IgE and its receptor, FcɛRI; molecules that control TH2 homing, such as putative TH2-specific homing integrins, chemokines and chemokine receptors; and intermediates in the signalling pathways that involve IL-4, IL-13, the α-subunit of the IL-4 receptor (IL-4Rα) and TLR9. Although likely to be effective, approaches that target these molecules could be plagued by rapid disease recurrence with cessation of therapy.The most promising approaches might be those that selectively remove or inactivate TH2 cells through the targeting of cell surface molecules such as T1, chemokine (C-C) motif receptor 8 (CCR8) and CCR4. Alternatively, molecules that prevent TH2 activation could be targeted. For example: IL-2-inducible tyrosine kinase (ITK); the co-stimulatory molecules CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); the transcription factor GATA-binding protein 3 (GATA3); or CD4.In addition to these new molecules, new approaches to blocking them will be developed, including soluble receptors, immunotoxin antibodies and gene therapy.