IL-5: Allergic Disease Drug Target in Cytokines & Growth factors

Introduction of IL-5 as a Cytokine

IL-5 was originally found as ‘T-cell replacing factor’ that is secreted from T cells to stimulate antibody production from activated B cells. IL-5 is produced by Th2 cells after stimulation with Mycobacterium tuberculosis, Toxocara canis or with allergens and by mast cells upon stimulation with allergen–IgE complex. As an active form, IL-5 makes homodimer in that two molecules are coupled in ‘interdigitated’ fashion. IL-5 messenger RNA (mRNA) is also expressed in eosinophils, γδT cells, NK and NKT cells and non-hematopoietic cells. CD4− c-kit− CD3ε− IL-2Rα+ cells in the Peyer's patch produce high levels of IL-5 when stimulated with IL-2. IL-5 acts on target cells by binding to its specific receptor (IL-5R).

The Role of Drug Target IL-5 in Allergic Disease

The notion that IL-5-regulated eosinophilia plays a central role in the pathogenesis of asthma is based on extensive circumstantial evidence from clinical investigations that show a strong correlation between eosinophils, their secreted products and IL-5, with severity and exacerbation of disease. Once recruited to sites of allergic inflammation, eosinophils become activated and are thought to induce disease through the release of proinflammatory molecules and granular proteins. In particular, there is evidence that eosinophilic products damage the respiratory epithelium and induce AHR. Increased numbers of eosinophil and basophil colony forming units (progenitor cells) are also found in the blood of allergic individuals, and elevated numbers correlate with exacerbation of disease. Thus, severity and exacerbations of asthma are directly linked to eosinophil regulatory pathways, although no clear pathogenic mechanism has yet been identified.
The eosinophil paradigm identifies IL-5-regulated eosinophilia as a central pathogenic pathway, because of the proposed central role of this cytokine in eosinophil development and movement, and circumstantial evidence from clinical studies. For example, levels of IL-5 and cells expressing mRNA for this cytokine are elevated in blood and lung secretions of asthmatics. Furthermore, after allergen-induced late-phase asthmatic responses, levels of IL-5 increase in the lung and correlate with the degree of eosinophilic inflammation.
Inhibition of IL-5 function in animal models of asthma also results (although not always) in attenuation of hallmark features of disease, in particular eosinophilia and AHR.

Targeting IL-5 Signaling in Allergic Disease Therapy

The specificity of IL-5 for eosinophil-regulated processes in conjunction with data from animal models of asthma has led to the development of a humanized (IgG-k) monoclonal antibody to IL-5 (hmAb-IL-5) and a recent clinical trial to determine the therapeutic value of targeting this molecule in asthmatics. Importantly, this trial through the provision of a blocking agent, which specifically targets IL-5 in humans, has allowed the testing of the causal role of this cytokine, and indirectly, of eosinophils in human disease.
This trial was an extension of successful investigations in primates where hmAb-IL-5 was shown to be active on circulating and airway eosinophilia as well as blocking AHR, and was an important step in determining tolerability of such a targeted treatment in asthmatics. Although hmAb-IL-5 treatment reduced eosinophil numbers in the blood and , the lack of effect of treatment on allergen-induced changes in lung function are ambiguous.

IL-5 as Drug Target in Allergic Disease: Conclusion

Eosinophil trafficking is a complex process, and although IL-5 is a key regulator of eosinophil function, alternative pathways operate in conjunction with this cytokine to promote the accumulation of eosinophils in allergic tissues. Importantly, local chemokine systems play a central role independently of IL-5 in the recruitment of eosinophils into inflamed tissues. The contribution of IL-5-dependent and independent mechanisms for the recruitment of eosinophils into tissues in various allergic inflammatory disorders must be considered in therapeutic strategies designed to identify the role of this granulocyte in the induction, progression or exacerbation of disease.

IL-5-Allergic Disease Drug Target in Cytokines & Growth factors: Reference

Foster P S, et al. Interleukin-5 and eosinophils as therapeutic targets for asthma[J]. Trends in molecular medicine, 2002, 8(4): 162-167.
Blümchen K, et al. Interleukin-5: a novel target for asthma therapy[J]. Expert opinion on biological therapy, 2001, 1(3): 433-453.