IFNs_at_age_50_past_current_and_future_impact_on_biomedicine

Tion of cytotoxic effector function among cells of

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tion of cytotoxic effector function among cells of innate and adaptive immunity including NK cells, dendritic cells, macrophages and T cells. Indeed, the property of stimulating macrophages contributed substantially to the recognition of IFN- γ as a biologically important lymphokine and as a ‘different’ IFN 150 . Human therapeutic applications Based on preclinical studies of broad spectrum inhibi- tion of virus replication, IFNs were initially investigated as antivirals with activity against RNA and DNA viruses. Clinical effectiveness for both has now been established. But development of relatively specific, low molecular mass antivirals has largely supplanted broad application except for HBV and HCV chronic infections. The first US Food and Drug Administration (FDA) approval for IFN- α 2, however, was not for virus infection but for cancer, which was driven by interest created by publicity result- ing from its effectiveness in American Cancer Society trials. Subsequently, placebo-controlled randomized trials established the effectiveness of IFN- β for relaps- ing, remitting MS — an apparent paradox in terms of the mechanistic understanding of IFN actions, as IFNs, as discussed above, are generally immune augmenting rather than immunosuppressive. Presently, a number of drugs are being or have been designed to target different components of the IFN system for different therapeutic indications (FIG. 5) . Viruses. The recognition that HBV often caused a chronic infection leading to cirrhosis and hepatocellular carcinoma suggested that infected patients might benefit from IFNs 151 . Initial clinical trials of impure IFN- α 152 suggested benefit but studies with impure IFN- β were less promising 153 . These low-dose studies were followed, however, by higher doses of recombinant IFNs, when they became available, which then confirmed beneficial effects 154 . HBV chronic infection evolves with hepatitis e antigen (HBeAg)-positive quiescent viruses escaping inhibition during conversion of an immunotolerant to an immunoactive phase, with enhanced immune elimination of infected hepatocytes 155,156 . In many, this immune response causes suppression of viral replication and HBeAg loss. A quiescent phase or ‘healthy carriage’ may ensue but disease reactivation is common (HBeAg- negative disease 157 ). In HBeAg-positive early HBV infec- tion, IFNs have not been particularly effective. However, in the immunoactive chronic phase, HBV is sensitive to IFN- α 2 and the ongoing immune response is aug- mented, leading to quiescent HBeAg-negative disease in up to 40% of patients. IFN- α 2 (Roferon-A, Hoffmann- LaRoche; Intron-A, Schering–Plough), now usually in the form of a long-acting pegylated version, has been widely used to treat HBeAg-positive HBV infections 158 .
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  • Spring '10
  • SAMUELS
  • Nature Publishing Group, IFNs

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Christopher Reinemann
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