Conclusions

The availability of orally active inhibitors of ICE will no doubt advance anticy-tokine-based therapies for a variety of inflammatory and autoimmune diseases. Initially, ICE inhibition was thought to be highly specific, because it blocked the secretion of IL-1p. Inhibition of IL-1P also appeared to be safe in terms of host defense perturbations. With the discovery that processing of proIL-18 is also accomplished by ICE, there was no longer the advantage of specificity. In terms of host defense effects of ICE inhibitors, the role of IFN-y (as a product of IL-18 activity) must be considered, since a reduction in IFN-y is thought to be undesirable in terms of defense against tuberculosis and some other infectious diseases. On the other hand, inhibition of the Th1 response by ICE inhibitors (due to reduced IFN-y production) is a worthwhile strategy in many diseases. For example, graft versus host disease, organ rejection, type I diabetes, and other autoimmune diseases of the Th1 type. In many ways, a reduction in IFN-y due to inhibition of ICE may be beneficial in multiple sclerosis where both inhibition of IL-1 (119) and IFN-y result in reduced disease. Indeed, overexpression of IFN-y in the central nervous system of mice results in a spontaneous development of a disease very similar to that of multiple sclerosis (120). The clinical challenge of studies with ICE inhibitors is not whether they will reduce inflammation due to IL-1p. Those disease have al ready been identified in humans. The challenge will be from the safety side, since ICE inhibitors reduce IFN-y in several models of disease. Nevertheless, when compared to the well-established toxicities, side effects, and host defense abnormalities of chronic corticosteroid use, inhibitors of ICE offer a unique opportunity to reduce disease, because they encompass both anti-inflammatory and immunosuppressive properties without the metabolic consequences and global immunosuppression of corticosteroids.

0 0

Post a comment