Interleukin-4 and interleukin-5 as targets for inhibition of eosinophilic inflammation and allergic airways hyperreactivity

Clinical and experimental investigations suggest that allergen-specific CD4+ T-cells, IgE and the cytokines IL-4 and IL-5 play central roles in initiating and sustaining an asthmatic response by regulating the recruitment and/or activation of airways mast cells and eosinophils. IL-5 plays a unique role in eosinophil development and activation and has been strongly implicated in the aetiology of asthma. The present paper summarizes our recent investigations on the role of these cytokines using cytokines knockout mice and a mouse aeroallergen model. Investigations in IL-5-/- mice indicate that this cytokines is critical for regulating aeroallergen-induced eosinophilia, the onset of lung damage and airways hyperreactivity during allergic airways inflammation. While IL-4 and allergen-specific IgE play important roles in the regulation of allergic disease, recent investigations in IL-4-/- mice suggest that allergic airways inflammation can occur via pathways which operate independently of these molecules. Activation of these IL-4 independent pathways are also intimately associated with CDA+ T-cells, IL-5 signal transduction and eosinophilic inflammation. Such IL-5 regulated pathways may also play a substantive role in the aetiology of asthma. Thus, evidence is now emerging that allergic airways disease is regulated by humoral and cell mediated pocesses. The central role of IL-5 in both components of allergic disease highlights the requirements for highly specific therapeutic agents which inhibit the production or action of this cytokines.

The role of interleukin-5 (IL-5) in vivo: studies with IL-5 deficient mice

Eosinophil recruitment is a characteristic feature of a number of pathological conditions and was the topic of the recent International Symposium on allergic inflammation, asthma, parasitic and infectious diseases (Rio de Janeiro, June 3-5, 1996). Since interleukin-5 (IL-5) is believed to regulate the gowth, differentiation and activation of eosinophils (Conffman et al. 1989, Sanderson 1992), the role of eosinophils and IL-5 are closely linked. Although IL-5 specifically regulates eosinophilia in vivo and this is its most well established activity, it is becoming clear that IL-5 also has other biological effects. The recent derivation of an IL-5 deficient mouse (Kopf et al. 1996), provides a model for exploring not only the role of IL-5 and eosinophils but also other novel activities of IL-5. Of note is that although the IL-5 deficient mice cannot elicit a pronounced eosinophilia in response of inflammatory stimulation following aeroallergen challenge or parasite infection they still produce basal levels of eosinophils that appear to be morphologically and functionally normal. However, the basal levels of eosinophils appear insufficient for normal host defense as IL-5 deficiency has been shown to compromise defence against several helminth infections. In addition, IL-5 deficient mice appear to have functional deficiencies in B-1 B lymphocytes and in IgA production.