The basic concept of inhibition of ICE to reduce the processing and secretion of IL-ip in disease states received a great deal of support following the publication of clinical trials of IL-1 receptor antagonist (IL-IRa) in patients with rheumatoid arthritis and graft versus host disease. Also, the importance of endogenous IL-IRa in patients with rheumatoid arthritis is supported by a study using the administration of soluble IL-1R type I to these patients. Since the soluble form of IL-1R type I binds IL-IRa with a greater and near irreversible affinity than that of IL-1 a or IL-ip, the use of the soluble IL-1R type in humans worsened disease in these patients (21). Although IL-iRa was used in three trials to reduce 28-day mortality in sepsis, the overall success of any anticytokine-based therapy in this patient population precludes any conclusion whether the anticytokine is effective (22-24). In each of these three trials, there was clear evidence of improved outcome in subgroups treated with IL-1Ra compared to placebo-treated patients. However, in each trial, the entire group did not reach a statistically significant reduction in mortality. On the other hand, the use of IL-1Ra is patients with rheumatoid arthritis and graft versus host disease provides convincing evidence that blocking IL-1 reduces disease and, moreover, blocking IL-1 is safe. Of course, inhibition of IL-1P is not the sole effect of ICE inhibition, and the lack of specificity of this strategy in humans may yield different results when it is used in the same diseases.
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