Interferon-beta: mechanism of action and dosing issues.
In patients with multiple sclerosis (MS), activation of immune cells and breakdown of the blood-brain barrier (BBB) lead to demyelination and axon injury. Although repairing damage to neurons is not possible, immunomodulating therapies can reduce the inflammatory processes that lead to demyelination. Interferon-beta (IFN-beta) is a polypeptide, normally produced by fibroblasts, that has antiviral and antiproliferative effects. Binding of IFN-beta to its receptor induces a complex transcriptional response. In immune cells (the most likely target of IFN-beta's therapeutic effect in MS), IFN-beta reduces antigen presentation and T-cell proliferation, alters cytokine and matrix metalloproteinase (MMP) expression, and restores suppressor function. Therapeutic forms of IFN-beta can be produced in bacterial expression systems (IFN-beta1b) or in mammalian cells (IFN-beta1a). These forms have some differences in their amino acid sequence and posttranslational modifications, but the transcriptional response to IFN- beta1b and IFN-beta1a appears to be similar, if not indistinguishable. However, the biological response and the clinical effect do vary with changes in the dosing frequency of IFN-beta. In clinical trials, IFN-beta1a IM administered weekly elicits a transient biological response compared to IFN-beta1b administered SC every other day or IFN-beta1a (administered SC three times per week). Comparative clinical trials suggest that the differences in the biological response are clinically meaningful: more frequent IFN-beta administration produces superior clinical responses.
Markowitz
Clyde E
CE
Multiple Sclerosis Center, University of Pennsylvania, Three West Gates Building, Philadelphia, PA 19104, USA. cmarkowi@mail.med.upenn.edu
D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D016899:Interferon-beta / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism
D016207:Cytokines; D007155:Immunologic Factors; D016899:Interferon-beta; D020782:Matrix Metalloproteinases