Cytokine-directed therapies for asthma

Abstract

Increasing knowledge of the pathophysiologic roles of various cytokines in atopic diseases has provided the basis for the development of novel therapies. Strategic approaches for cytokine inhibition include the blocking of transcription factors that lead to their expression, blockade after their release, cytokine receptor antagonism, and the inhibition of signaling pathways that are activated after cytokine-receptor binding. The proinflammatory cytokines IL-5, IL-4, IL-13, and TNF-alpha are among the therapeutic targets. Results with a humanized anti-IL-5 have been disappointing. Although successful in markedly reducing circulating eosinophils and in preventing eosinophil accumulation in airways, the humanized anti-IL-5 was unable to affect early or late responses to allergen or to reduce airway reactivity to methacholine challenge in patients with asthma. On the other hand, a soluble IL-4 receptor antagonist has shown clinical benefits for patients with moderate asthma who require daily inhaled corticosteroids. Agents that target IL-13 and TNF-alpha remain to be evaluated in asthmatic inflammation. The use of cytokines with anti-inflammatory effects may also have therapeutic value. The evaluation of such agents in human beings, including IL-10, IL-12, and IFN-gamma, is at a preliminary stage, but so far results have not been encouraging.