In vivo eosinophil chemotaxis

For IL-5 and the chemokine eotaxin, convincing evidence of in vivo activity as eosinophil chemotactic factors has been provided. Much higher concentrations of IL-5 were, however, required for eosinophil chemotaxis in vivo than in vitro. Neutralizing antibodies to IL-5 arc very effective at inhibiting eosinophil accumulation in blood and tissues in experimental models of allergic inflammation and helminth infection. Furthermore, mice transgenic for IL-5 have extremely high numbers of circulating eosinophils, yet show an otherwise normal pheno-type.

There are also interesting data on an in vivo synergism between IL-5 and eotaxin. Neither of the substances alone induced eosinophil accumulation after intradermal injection in guinea pigs. Low-dose intravenous IL-5, however, caused a rapid (within 1 h) and dramatic enhancing effect on eosinophil recruitment to sites of intradermal eotaxin injections. Thus, IL-5 acts systemically as a hormone to stimulate the release of a rapidly mobilizable pool of bone marrow eosinophils into the circulation and facilitates the eosinophil recruitment from blood microvessels by locally released eosinophil chemoattractants. This seems to hold also for other chemoattractants. Suhcutaneously injected PAF and LTB4 mediate eosinophil accumulation only in the presence of an IL-5-induced eosinophilia as well.

An important postulate for a truly eosinophil chemotactic factor is its demonstration in normal and/or pathologically altered tissue. This has so far been achieved for C5a, PAF, eicosanoids, IL-5, IL-8, MlP-la, RANTES and eotaxin, although the isolation of these factors has not been restricted to eosinophilic tissue. Although some eosinophil-specific chemoattractants have so far been identified, the mechanism by which eosinophils preferentially migrate into tissues are largely unknown. Extravasation of eosinophils involves a number of cell surface adhesion molecules, predominantly selectins for primary tethering and members of the 3,- and (32-integrin family for firm adhesion and transendo-thelial migration. There is much evidence that the interaction of VLA-4 (a4(31-integrin), expressed by eosinophils but not neutrophils, and vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells is a major adhesion pathway allowing selective migration of eosinophils. Blocking VLA-4 in vivo has been shown to reduce eosinophil accumulation in some models of allergic inflammation. In addition, antibodies to CD11/CD18 or intercellular adhesion molecule 1 (ICAM-1) (p2-integrins) reduced eosinophil accumulation in guinea pig skin. Recent studies have also demonstrated that these adhesion processes can be controlled by chemokines. RANTES, but not MlP-la or IL-8, is capable of stimulating eosinophil transendothelial migration via VLA-4/VCAM-depen-dent mechanisms in cells primed with IL-5.

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