Eosinophils on trial

Although eosinophils constitute a minor population of blood granulocytes, they are recruited in significant numbers at tissue sites of worm infection and allergic reactions. These cells, distinguished by their cytoplasmic granules staining pink with eosin, have an impressive armamentarium of secretory products that are employed to combat parasitic helminths. These same products have been associated with tissue damage in allergic asthma, making them an attractive target for drug development. IL-5 has been the lead target in the development of drugs directed at eosinophils. This cytokine is important for eosinophil development and release from the bone marrow and eosinophil survival once the cells are in peripheral tissues. Deletion of the IL-5 gene or use of anti-IL-5 antibodies in animal models of allergic asthma results in low blood and lung eosinophil counts, which is associated with improved lung function. Hence, therapeutic anti-IL-5 antibodies have been developed which have proven efficacy in reducing some aspects of the disease. An alternative approach is to identify the molecules produced in the asthmatic lung that recruits eosinophils from small blood vessels to airway tissues. IL-5 is not thought to act in this way. IL-5 drives the chemokinesis of eosinophils, that is, an increased cell motility, but not chemotaxis, that is, directional migration along a chemical gradient. Initially, some non-selective chemoattractants were identified using in vitro chemotaxis assays, but these could not account for the enriched eosinophil accumulation observed in allergic reactions in vivo. Subsequently, a highly potent CC chemokine with high selectivity for eosinophils was discovered using a guinea-pig model of allergic airway disease, and named eotaxin. The sequence of eotaxin was subsequently used to determine eotaxins in several species, including human. The receptor for eotaxin, CCR3, was then identified and found to be highly expressed on eosinophils as well as on other cells involved in allergy, such as basophils and mast cells. Two more eotaxins were then discovered showing similar activity on eosinophils, but low sequence similarity. Hence, there are now known to be 3 eotaxins: eotaxin-1/CCL11, eotaxin-2/CCL24 and eotaxin-3/CCL26. All 3 eotaxins stimulate CCR3 as agonists, although they can exert inhibitory effects on other cells via additional chemokine receptors. These findings held out the promise of an orally available drug aimed at blocking CCR3 and thus preventing eosinophil effects by inhibiting access to airway tissues. From the mid-1990s, many biotechnology and pharmaceutical companies established programmes to identify such antagonists. The paper by Gauvreau et al in this issue describes a small, short-term safety study of a CCR3 antagonist, AXP1275, given to patients with allergic asthma and control subjects. At the doses used, there was no significant effect on allergen-induced early or late bronchoconstriction in the patient group. This was disappointing, but the authors point out that the serum levels of the compound did not reach the levels envisaged to have efficacy. Furthermore, there was no significant effect on the numbers of eosinophils in sputum, as was observed in another study using a chemically distinct CCR3 antagonist, GW766994. The lack of effect could be due to inadequate serum levels of drug (and therefore low receptor occupancy) or, as discussed by the authors, the involvement of other chemoattractants in vivo acting on receptors other than CCR3. Notable in this respect is the receptor CCR1 that has been shown to be expressed on the eosinophils of some individuals. Early studies in vitro explored the effects of a dual antagonist that blocked both CCR3 and CCR1. Interestingly, the study by Gauvreau and colleagues showed that the CCR3 antagonist suppressed airway hyperresponsiveness to methylcholine, an effect also observed in the previous study with GW766994. At first sight, this is difficult to reconcile with the lack of effect on sputum eosinophil numbers. However, the drug may affect the distribution of eosinophils in lung tissue. As the authors mention, there is evidence that eotaxin-1 can attract eosinophils to nerves and released major basic protein is able to block inhibitory M2 muscarinic receptors. Furthermore, the authors have previously put forward data which support the notion that CCR3 receptors and acetylcholine M3 receptors physically interact with one another, which may modulate their respective functions in eosinophils. These results are discouraging; but to some extent, they mirror the early results with a therapeutic antibody to IL-5. In this small study with mepolizumab, the antibody did not induce significant changes in lung function after allergen challenge, although eosinophil counts in blood and sputum were down. This study was followed by several detailed investigations over a longer period with larger, selected patient groups and optimized dosing. These studies demonstrated a clear effect in suppressing exacerbation rates in patients with severe, eosinophilic asthma and the ability to spare the glucocorticoid dose given to patients. An antibody to the IL-5 receptor, benralizumab, has also proved effective. There is additional evidence from studies using Mepolizumab that tissue remodelling in the airways is dependent on IL-5. It is possible that optimal dosing over longer periods in selected patient groups with CCR3 antagonists could also prove effective, but this raises broader issues which are discussed below. The exciting era of chemokine research, starting in the mid1980s, resulted in the discovery of approximately 50 chemokines and 20 receptors. The roles of these molecules were investigated The accompanying paper of this editorial has been published in Volume 48, Issue 4, April 2018, Pages 445–451 (https://onlinelibrary.wiley.com/doi/abs/10.1111/cea.13114). DOI: 10.1111/cea.13147