Invited Symposium: Novel Cellular and Molecular Mechanisms in Allergic Inflammation
Hogan, SP (Division of Biochemistry & Molecular Biology, Australian National University, Australia)
Young, IG (Division of Biochemistry & Molecular Biology, Australian National University, Australia)
Matthaei, KI (Division of Biochemistry & Molecular Biology, Australian National University, Australia)
The cytokines interleukin-4 and –5 (IL-4, -5) play central roles in initiating and sustaining an asthmatic response by regulating the effector function of airways mast cells and eosinophils. IL-4 plays an essential role in the development of naive CD4+ T cells into Th2 type cells, which upon antigen stimulation, elicit signals through IL-4 and IL-5 for the regulation of IgE production and eosinophilia, respectively. The asthmatic response may therefore be regulated by IgE dependent release of inflammatory mediators from activated mast cells. Similarly, activated airways eosinophils may degranulate to mediators that have the potential to cause local tissue damage and bronchial hyperreactivity. An obligatory role for IL-5 in the development of allergic airways disease was demonstrated in IL-5 deficient mice of the C57BL/6 strain. Eosinophilia, morphological changes to the airways and bronchial hyperreactivity normally resulting from aeroallergen (OVA) challenge were abolished in these mice and could be totally reconstituted by the administration of recombinant IL-5. Moreover, IL-5 secreted from allergen specific CD4+ Th-2 cells plays a pivotal role in the pathophysiology of allergic airways disease by regulating eosinophilia and bronchial hyperreactivity in response to allergen inhalation. Blocking the actions of IL-4 may also provide an effective mechanism since inhibition or deletion of IL-4 during allergic airways inflammation attenuated eosinophilia, IgE production and bronchial hyperreactivity. Interestingly, a sub-population of CD4+ T-cells which develops into the Th-2 phenotype independently of IL-4 and can provide enough IL-5 during allergic inflammation to induce eosinophilia, bronchial hyperreactivity and morphological changes to the airways. Thus, two CD4+ T-cell pathways exist for the immune system to regulate IL-5 production and eosinophilia in response to inhaled allergens; one dependent on IL-4 and the other independent of this factor. Directly targeting T-cell activation may also alleviate bronchial hyperreactivity. A novel CD4+ T-cell pathway in BALB/c mice can modulate allergen-induced airways hyperreactivity independently of the collective actions of IL-4 and IL-5. Thus, a number of pathways exist that can act independently to induce airways hyperreactivity. This may account for the dissociation of airways eosinophilia from the development of airways hyperreactivity in some cases of asthma and in animal models of this disease. Hence, while a number of molecules can contribute to the mechanisms underlying the regulation of bronchial hyperreactivity in mice, only CD4+ T-cells have been shown to exclusively regulate disease pathogenesis.
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|Foster, PS; Hogan, SP; Young, IG; Matthaei, KI; (1998). The Modulation of Allergic Airways Disease by Interleukin-4 and -5: Studies using Cytokine Deficient Mice. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/denburg/foster0232/index.html|
|© 1998 Author(s) Hold Copyright|