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Biosecurity Briefing
Study Suggests that Inhibiting Immune Response May Not Protect Against H5N1 By Jennifer Nuzzo, July 20, 2007 A new article published ahead of print of the July 24, 2007, issue of the Proceedings of the National Academy of Sciences (PNAS) provides evidence against a commonly asserted hypothesis: that inhibition of host immune response may protect against lethal infection with influenza.1 It has been widely hypothesized in the scientific and clinical communities that a surge in the levels of cytokines, which are chemicals that are produced by the host’s immune system and are involved in triggoring the inflammatory (immune) response, may ultimately be the “main cause of pathology and ultimately of death” in those infected with H5N1 influenza, rather than the specific action of the virus itself. While cytokines normally prompt the host’s immune system to ward off an invading pathogen, a surge of cytokines, which is often referred to as a “cytokine storm,” results in an overactive immune response which may lead to an attack on the host’s own cells. This surge has been observed in both human and mouse cells following infection with H5N1. Because cytokines can produce both helpful and harmful cellular-level effects in mammals, the scientific and clinical communities have suggested that suppressing the action of cytokines may help reduce the lethal effects of H5N1 infection. To investigate the significance of cytokines in H5N1-induced morbidity and mortality in mammals, a research team led by Dr. Robert Webster of St. Jude’s Children’s Research Hospital completed a two-part investigation involving mice that had been inoculated with lethal doses of a highly pathogenic H5N1 influenza strain. In the first part of the investigation, the researchers looked at whether genetic deficiencies in production of specific cytokines protect mice from lethal doses of H5N1. To test this hypothesis, they compared survival rates among groups of mice that lacked full activity of any one of three specific cytokines (TNF-α, IL-6, or CCL7) with two groups of mice (B6 and B6-129 mice) that had normal cytokine production (n=3 to 5 in each group) serving as controls. The researchers found that there was no significant difference in survival among any of the test groups when compared with controls. Because no specific cytokine was found to be associated with a difference in survival, the researchers then investigated how suppression of the cytokine response, in general, affected survival. To that end, the researchers subjected test mice to different treatment schemes of steroids, which are known to suppress cytokine production. There were 4 categories of mice in this study: 1) mice that received no steroids whatsoever during the experiment (n=5); 2) mice that received steroids daily for 3 days before inoculation (n=5); 3) mice that received steroids daily beginning 3 days before inoculation and continued to receive them through the course of the study (n=5); and 4) mice that received steroids beginning 3 days after inoculation (n=5). The researchers found that weight loss among mice (an indicator of morbidity) that received steroids “was not significantly different from the untreated mice” and “mortality rates were similar in all groups of mice, regardless of treatment.” The researchers conclude that “inhibition of the cytokine response to infection with highly pathogenic H5N1 influenza virus is not sufficient to protect mammalian hosts from death.” Rather, they recommend that “therapies that target the virus rather than cytokines may be preferable.”1 Reference
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