Histamine H4 antagonism: a therapy for chronic allergy?

Abstract

Chronic inflammatory diseases such as bronchial asthma, allergic gastrointestinal disease, and atopic dermatitis are characterized by the selective recruitment and activation of distinct subtypes of leukocytes, particularly eosinophils, into the tissue from peripheral blood (Rothenberg, 1998). Eosinophils, along with mast cells, are postulated to play a key role in the pathophysiology of these chronic diseases. The striking accumulation of eosinophils in allergic disease has stimulated intense scientific examination leading to the discovery of numerous molecular mechanisms responsible for this process. Eosinophils, like all leukocytes, migrate from the vascular lumen, across the endothelial cell surface into the appropriate tissue sites. This elaborate mechanism, known as transendothelial migration, has been shown to be a highly orchestrated process (Springer, 1994). The migratory pathway, or chemotaxis, of the leukocyte is directly influenced by soluble molecules known as chemoattractants. These molecules reside along a tissue gradient, and bind to and activate G-protein coupled receptors (GPCRs) on the leukocyte cell surface. Several eosinophil chemoattractants have been extensively studied. Some of these molecules, the classical chemoattractants, include the complement cleavage fragments, leukotrienes and platelet-activating factor (PAF). These chemoattractants have been shown to stimulate the recruitment of a wide variety of leukocyte subtypes, and are therefore nonselective. In contrast, chemotactic cytokines (or chemokines) such as eotaxin-1, -2, -3, and monocyte chemoattractant protein (MCP)-4 are more selective for the recruitment of leukocytes associated with allergic inflammation, such as eosinophils, mast cells, and basophils.