To date, we completed a series of studies of cytokine responses to influenza A infection. We have studied local and circulating levels of IL-2, IFN- , IL-4, IL-6, IL-8. IL-10, TGF-, and TNF-. We have documented a reproducible and predictable course of cytokine responses particularly with significant elevations of IFN-, IL-6, IL-8, and TNF-. By obtaining specimens on a daily basis through the course of infection and documenting patient upper respiratory, lower respiratory and systemic symptoms as well as body temperature and quantity of virus shed in nasal secretions, we have correlated disease severity and virus yield with prompt rises in local and circulating IL-6, TNF- , while IL-8 elevations are somewhat delayed. IFN- elevations are seen locally as well. Recently, we have conducted challenge studies in which patients will receive, in a double-blind fashion, various doses of new synthetic neuraminidase inhibitors being developed by the Glaxo- Wellcome Company and by Gilead Sciences Inc. We used the opportunity of controlled trials to study local responses by additional cytokines IFN- and IL-10, and four chemokines: MIP- 1 , MIP-1 , MCP-1 and RANTES. In so doing, we defined the kinetics and magnitude of responses by each of these immune effector proteins. Significant rises by day 3 of infection in IFN-, and IL-10 reveal an orchestrated responses with counter- regulatory cytokines. Significant rises in all chemokines tested, except RANTES were also documented. The controlled therapeutic trials proved the high clinical potency and safety of zanamavir and of GS-4104. Not only did they greatly inhibit virus replication, but local and systemic responses were significantly ameliorated. The cytokine and chemocytokine responses well virtually abigated by treatment as well.
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