IL-4: Allergic Disease Drug Target in Cytokines & Growth factors

Introduction of IL-4 as a Cytokine

Interleukin (IL)-4 is a key cytokine in the development of allergic inflammation. It is associated with induction of the e isotype switch and secretion of IgE by B lymphocytes. IgE-mediated immune responses are further enhanced by IL-4 through its ability to upregulate IgE receptors on the cell surface: the low-affinity IgE receptor (FceRII; CD23) on B lymphocytes and mononuclear phagocytic cells and the high-affinity IgE receptor (FceRI) on mast cells and basophils. IgE-dependent mast cell activation induced by IL-4 has a pivotal role in the development of immediate allergic reactions. An additional mechanism by which IL-4 contributes to airway obstruction in asthma is through the induction of mucin gene expression and the hypersecretion of mucus. IL-4 increases the expression of eotaxin and other inflammatory cytokines from fibroblasts that might contribute to inflammation and lung remodelling in chronic asthma.

The Role of Drug Target IL-4 in Allergic Disease

1) An important activity of IL-4 in promoting cellular inflammation in the asthmatic lung is the induction of vascular cell adhesion molecule (VCAM)-1 on vascular endothelium. Through the interaction of VCAM-1, IL-4 is able to direct the migration of T lymphocytes, monocytes, basophils, and eosinophils to inflammatory loci. In addition, IL-4 inhibits eosinophil apoptosis and promotes eosinophilic inflammation by inducing eosinophil chemotaxis and activation through the increased expression of eotaxin.
2) An essential biological activity of IL-4 in the development of allergic inflammation is the ability to drive the differentiation of naive T helper type 0 (TH0) lymphocytes into TH2 lymphocytes. These TH2 cells are able to secrete IL-4, IL-5, IL-9 and IL-13 but lose the ability to produce interferon-g. Using human cells, administration of IL-4 generates TH2-like lymphocyte clones, whereas incubation with anti- IL-4 blocks this differentiation. The induction of TH2-like lymphocytes is a unique biological activity of IL-4 because IL-4 receptors and not IL-13 receptors are expressed on T cells. IgE production and the induction of VCAM-1 are activities shared with the related cytokine IL-13.
3) In addition to driving the differentiation of TH0 lymphocytes into the TH2 phenotype, IL-4 is important in allergic immune responses owing to its ability to prevent apoptosis of T lymphocytes. Activation of these cells results in rapid proliferation and secretion of cytokines. In the absence of an appropriate signal, activated T helper lymphocytes rapidly become apoptotic and are eliminated. Several cytokines, including IL-2, IL-4, IL-7, and IL-15, are effective in preventing the death of activated T cells. Of these, IL-4 and IL-15 are the most effective. Inhibition of apoptosis by IL-4 might be mediated partly by the ability of this cytokine to maintain levels of the survival-promoting protein Bcl-2 in T cells.

Targeting IL-4 in Allergic Disease Therapy

Soluble recombinant human IL-4 receptor (rhuIL-4R; Nuvance™; Immunex) is the extracellular portion of human IL-4Ra, the gene encoding which has been cloned and its product expressed in a mammalian expression system. Because the amino acid and carbohydrate or glycosylation sequences are identical to those of human IL-4R, soluble receptors are relatively nonimmunogenic.
This is in contrast to chimerized or humanized monoclonal antibodies antibodies, which retain some murine sequences, or IL-4 muteins that are not authentic. The promising results in preclinical studies led to preliminary investigations in which rhuIL-4R proved safe and effective in the treatment of patients with asthma.

IL-4 as Drug Target in Allergic Disease: Conclusion

Interleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma is a complex genetic disorder that has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. We report the results of initial clinical trials, which demonstrate clinical efficacy of this naturally occurring IL-4 antagonist as a therapeutic agent in asthma.

IL-4: Allergic Disease Drug Target in Cytokines & Growth factors Reference

Steinke JW, et al. Th2 cytokines and asthma — Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respiratory Research. 2001;2(2):66-70.