Human rIL-5 was found to selectively stimulate morphological changes and the function of human eosinophils. This molecule is thus a prime candidate for the selective eosinophilia and eosinophil activation seen in disease.

Experiments in vitro suggest that although interleukin 5 (IL-5) stimulates the late stages of eosinophil differentiation, other cytokines are required for the generation of eosinophil progenitor cells. In this study transgenic mice constitutively expressing the IL-5 gene were established using a genomic fragment of the IL-5 gene coupled to the dominant control region from the gene encoding human CD2. Four independent eosinophilic transgenic lines have thus far been established, two of which with 8 and 49 transgene copies, are described in detail. These mice appeared macroscopically normal apart from splenomegaly. Eosinophils were at least 65- and 265-fold higher in blood from transgenics, relative to normal littermates, and approximately two- or sevenfold more numerous relative to blood from mice infected with the helminth Mesocestoides corti. Much more modest increases in blood neutrophil, lymphocyte, and monocyte numbers were noted in transgenics, relative to normal littermates (less than threefold). Thus IL-5 in vivo is relatively specific for the eosinophil lineage. Large numbers of eosinophils were present in spleen, bone marrow, and peritoneal exudate, and were highest in the line with the greatest transgene copy number. Eosinophilia was also noted in histological sections of transgenic lungs, Peyer's patches, mesenteric lymph nodes, and gut lamina propria but not in other tissues examined. IL-5 was detected in the sera of transgenics at levels comparable to those seen in sera from parasite-infected animals. IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF) were not found. IL-5 mRNA was detected in transgenic thymus, Peyer's patches, and superficial lymph nodes, but not in heart, liver, brain, or skeletal muscle or in any tissues from nontransgenics. Bone marrow from transgenic mice was rich in IL-5-dependent eosinophil precursors. These data indicate that induction of the IL-5 gene is sufficient for production of eosinophilia, and that IL-5 can induce the full pathway of eosinophil differentiation. IL-5 may therefore not be restricted in action to the later stages of eosinophil differentiation, as suggested by earlier in vitro studies.

OSINOPHIL production can be induced in vitro by E interleukin-3 (IL-3), granulocyte-macrophage colonystimulating factor (GM-CSF), and IL-5. Both IL-3 and GM-CSF have activities on other hemopoietic lineages, whereas IL-5 is specific for the eosinophil/basophil lineage. The activity of IL-5 on basophils has been reviewed recently' and will not be discussed here. There is now good evidence that IL-5 is the major, and possibly the only, cytokine involved in the production of specific eosinophilia. Classically eosinophilia is observed in a restricted number of diseases, most notably helminth infections and allergic diseases. However, although the increase in eosinophil numbers is less spectacular, there is increasing evidence for an involvement of eosinophils in a wider spectrum of diseases.A study of experimental infection of volunteers by the hookworm Necator americanus gave clear evidence for an increase in eosinophils with no significant increase in other blood leucocytes,2 and infection of mice with the cestode Mesocestoides Corti causes a massive increase in blood and peritoneal eosinophils with little effect on the number of ne~trophils.~ This biologic specificity, the relatively restricted disease profile of eosinophilia, and the requirement for a functional T-lymphocyte ~y s t e m ~-~ suggested that the control of eosinophilia must be part of the immune response and based on a subset of T celk7Eosinophils are cytotoxic cells capable of killing helminths, parasitic protozoa, chicken erythrocytes, and tumor cells in vitro. For more general reviews and background see Spry,8 Dexter et a1,9 Thompson,'O and Smith and Cook.ll Time-lapse cinematography has shown that eosinophils phagocytose and regurgitate red blood cells very rapidly. This is in contrast to neutrophils and macrophages that retain them until they have been broken down.12 This explains why eosinophils appear to be less active in comparison to neutrophils in classical phagocytosis assays using yeast or bacteria. They do not retain the particles. It is unclear what this implies for the killing ability of the eosinophil, but it is possible that they are better adapted to attach to large parasites13 rather than to phagocytose small particles. IL-5 STRUCTUREIL-5 is unusual among the T-cell-produced cytokines in being a disulphide-linked homodimeric glycoprotein. It is highly homologous between species, as indicated by the high sequence homology between mouse and human 1L-5 and the cross-reactivity of the protein across a variety of mammalian species. Mature human IL-5 monomer comprises 115 amino acids (molecular weight [M,] of 12,000 and 24,000 for the dimer). The secreted material has an M, of 40,000 to 45,000, and thus nearly half the native material consists of carbohydrate, although this carbohydrate does not appear to be necessary for biologic activity in vitro.14 Studies with mouse IL-5 indicate that the monomer has no biologic activity and has no inhibitory activity, suggesting that they do not form high-affinity interactions with the IL-5 receptor...

No abstract

Interleukin (IL-5) was found to enhance the adhesion of eosinophils, but not neutrophils, to both microvascular and large vein endothelial cells in a dose-dependent manner. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) and platelet-activating factor (PAF) enhanced both eosinophil and neutrophil adhesion. Significant increases in eosinophil CR3 expression, but not LFA-1, were observed following pre-incubation with PAF, IL-3, IL-5 or GM-CSF. Neutrophil CR3 expression was increased significantly by pre-incubation with PAF or GM-CSF, but not IL-3 or IL-5. Enhanced adhesion to human microvascular endothelial cells (HMVEC) or human umbilical vein endothelial cells (HUVEC) was inhibited by (ranked in order of potency) anti-CR3α = common β-chain > LFA-1α. Anti-p 150,95α had no measurable effect. Basal expression of eosinophil CR3 with monoclonal antibody inhibited IL-5-induced eosinophil hyperadherence to HUVEC in a manner almost identical to inhibition in the presence of excess anti-CR3. Thus, a conformational or affíntiy change in adhesion receptors following activation seems more important than a simple increase in numbers. No inhibition of unstimulated eosinophil adhesion to HMVEC or HUVEC by CD11/18 monoclonal antibody was observed. These findings demonstrate that IL-5 enhances eosinophil, but not neutrophil, adherence reactions, by a mechanism dependent, at least in part, on the CD11/18 family of adhesion glycoproteins.