Animal models have helped define the significance of IL-5 and the eosinophil in the disease process. IL5 administered to mice results in an increase of eosinophils (458). Experiments with IL-5-deficient and IL-5-transgenic mice confirm a role for this cytokine in controlling eosinophilia (459,460).In IL-5 knockout mice, no eosinophils are produced in response to parasite infection or sensitization with ovalbumin, and there is minimal development of lung inflammation or tissue damage. When IL-5 expression is reconstituted in these mice, pulmonary eosinophilia, tissue destruction, and airflow limitation can be observed after allergen challenge (459).
Transgenic mice that have constitutive expression of IL-5 with detectable levels of IL-5 in the serum and persistent eosinophilia have also been described (461). These mice are described as normal, which may suggest that activation and degranulation of eosinophils may be necessary for disease pathology.
9.4.2 IL-5 Modulators/Clinical Data. Modu lation of IL-5 can occur by inhibiting its production and synthesis, or through direct binding to IL-5 receptor or ligand. Cytokines can regulate IL-5 levels by inhibiting production. For example, IFNy and IL-10 have demonstrated they can inhibit IL-5 production in vitro (462), whereas IL-12 indirectly modulates IL-5 by biasing toward a Thl subset population (463).
Small molecule antagonists such as CsA, and rapamycin all inhibit IL-5 production (464,465). Glucocorticoids, in addition to decreasing bronchial hyperresponsiveness, can also downregulate IL-5 production (466468). OM-01 suppresses IL-5 protein production, mRNA expression, and transcriptional activity in PBMCs with no effect on either IL-2 or IL-4 (469, 470). (The structure for OM-Ol has not been disclosed.)
A fusion protein of human IL-5R a-chain and human IgG Cy3 chain (hIL5Ra-hy3) was used for screening a library of low molecular weight compounds, and the isothiazolone (79)
was identified as an IL-5R antagonist. By use of radiolabeled isothiazolone, it was determined that association of (79) with the receptor occurs through covalent modification of a sulfhydryl group on a free cysteine (Cys66) in IL5Ra (471,472).
In a separate study aimed at finding small molecule antagonists, the soluble form of the ligand binding a-chain of hIL-5 receptor was used to identify (80) and (81)as inhibitors of
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