| Budget Amount *help |
¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1997: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1996: ¥4,500,000 (Direct Cost: ¥4,500,000)
|
|---|
| Research Abstract |
The roles of helper T (Th) cells and T cell cytokines, including especially IL-5, have been strongly implicated in the chronic eosinophilic inflammation of the bronchial mucosa. We recently reported that mice adoptively transferred IL-5-producing Th clones developed airway eosinophilic inflammation as well as bronchial hyperresponsiveness upon inhalation of the relevant antigen, clearly indicating the importance of Th cells as the source of IL-5. We have investigated IL-5 production by Th cells derived from asthmatic patients and obtained the following findings ; 1) IL-5 production by CD4^+ T lymphocytes in response to a specific allergen, D.f.mite extract, is enhanced in atopie asthmatics, compared to normal subjects. 2) IL-5 production in response to nonspecific stimulus, phorbol ester plus calcium ionophore, is enhanced in both atopic and nonatopic asthmatics compared to normal subjects, whereas IL-2,3,4, GM-CSF and IFN-g production was not significantly different among the three gr
… More
oups. 3) Glucocorticoids and FK506 suppressed IL-5 synthesis in a dose dependent manner in vitro. 4) Administration of inhaled glucocorticoid clearly reduced IL-5 production by peripheral Th cells, in parallel with the improvement in clinical symptoms and pulmonary function tests. 5) Topical application of FK506 to severe atopic dermatitis patients resulted in a marked amelioration accompanied by a clear reduction in IL-5 synthesis by Th cells. It is, thus, suggested that enhanced IL-5 production by Th cells is characteristic of allergic diseases associated with eosinophilic inflammation, and its correction is an effective therapeutic target. To delineate molecular mechanisms of IL-5 production, Der f 2-specific Th clones and hybridomas were established from atopic subjects, and it was suggested that IL-5 synthesis of human Th cells is regulated at the transcriptional level. Construction of IL-5 gene-expressing and-nonexpressing hybridomas indicated that IL-5 gene transcription of human Th cells is differentially regulated from IL-2 and IL-4 gene transcription, and positively regulating transcription factor (s) operate through the 515 bp segment of human IL-5 promoter/enhancer (-511 to +4 relative to the transcription initiation site) for the activation-dependent gene transcription of IL-5 by Th cells. NF-AT,AP-1, NF-kB and Oct-1 binding activity were not different between IL-5-producing and-nonproducing Th clones. rIL-2 induced IL-5 gene transcription by Th clones without inducing NF-AT,AP-1, or NF-kB binding activity, suggesting that transcription factor (s) distinct from these involved in IL-2 and IL-4 gene transcription seenmed essential for human T cell IL-5 gene transcription. In the search for the inhibitor of IL-5 production, we have found an agent coined OM-01 that strongly suppresses protein production and gene transcription of IL-5 but not of IL-2 or IL-4. Our results collectively indicate that human T cell IL-5 synthesis seems to be controlled by unique Less
|
