World Allergy Forum: Immune Intervention
Chemokines in Chronic Allergic Inflammation:
Opportunities for Novel Therapeutic Intervention
Timothy J. Williams
There is increasing evidence that the family of chemokines is important in regulating the movement of leukocytes from the blood into sites of inflammation. There is particular interest in mechanism involved in eosinophil accumulation in the asthmatic lung, as these cells are thought to be important in tissue damage and lung dysfunction as a result of activation and degranulation in the lung tissue. Eotaxin was discovered as a highly potent eosinophil chemoattractant protein, purified and sequenced from BAL fluid taken from allergen-challenged sensitised guinea pig lung (1). Human eotaxin cDNA was subsequently cloned (2) as well as its 7-Tm receptor, designated CCR3 (3) CC-chemokines in addition to eotaxin are now known to signal via CCR3 eg. eotaxin-2, eotaxin-3 and MCP-4. Eotaxin is potent in inducing eosinophil accumulation in the lung and may also, be involved, together with IL-5 in releasing bone marrow eosinophils into the blood (4).
Evidence has come from several laboratories that cytokines secreted by Th2 lymphocytes, IL-4 and IL-13, can induce eotaxin production by other cells such as fibroblasts, endothelial cells and epitheliae cells. CCR3 is highly expressed on eosinophils but also on basophils and a subpopulation of Th2 lymphocytes. Eotaxin appears to be important in recruiting Th2 lymphocytes, particularly in the early stages of allergic inflammation in the lungs (5).
These observations provide the possibility that agents can be developed to inhibit the recruitment of eosinophils and other cell types involved in allergic inflammation into the asthmatic lung. Small molecules are in development that effectively block CCR3. Such compounds may form the basis of a new generation of therapeutic agents aimed at preventing the pathogenesis associated with leukocyte recruitment and subsequent activation.
- Jose PJ, Griffiths-Johnson DA, Collins PD, Walsh DT, Moqbel R, Totty NF, Truong O, Hsuan JJ, Williams TJ. Eotaxin: A potent eosinophil chemoattractant cytokine detected in a guinea-pig model of allergic airways inflammation. J Exp Med 1994;179:881-887.
- Ponath PD, Qin S, Ringler DJ, Clark-Lewis I, Wang J, Kassam N, Smith H, Shi X, Gonzalo J-A, Newman W, Gutierrez-Ramos J-C, Mackay CR. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest 1996;97:604-612.
- Ponath PD, Qin S, Post TW, Wang J, Wu L, Gerard NP, Newman W, Gerard C, Mackay CR. Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils. J Exp Med 1996;183:2437-2448.
- Palframan RT, Collins PD, Williams TJ, Rankin SM. Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow. Blood 1998;91:2240-2248.
- Lloyd CM, Delany T, Nguyen T, Tian J, Martinez-A C, Coyle AJ, Gutierrez-Ramos J-C. CC Chemokine receptor (CCR)3/Eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J Exp Med 2000;191:265-273.