Increased disability and MRI lesions after discontinuation of IFN-beta-1a in secondary progressive MS

Interferon beta (IFN-beta) has been shown in several clinical trials to have efficacy in MS. Its mechanism of action, however, remains unclear. In this review, several biological activities of IFN-beta are highlighted, including its inhibitory effects on proliferation of leukocytes and antigen presentation. Furthermore, IFN-beta may modulate the profile of cytokine production toward that of the anti-inflammatory phenotype, and this appears to occur in the systemic circulation and within the CNS. Finally, IFN-beta can reduce T-cell migration by inhibiting the activity of T-cell matrix metalloproteinases. These activities are likely to act in concert to account for the mechanism of IFN-beta in MS.

Inflammation can contribute to brain injury, such as that resulting from ischemia or trauma. The authors have previously shown that the cytokine interferon-beta (IFN-beta) affords protection against ischemic brain injury, which was associated with a diminished infiltration of neutrophils and a reduction in blood-brain barrier (BBB) disruption. The goal of the current study was to directly assess the effects of IFN-beta on neutrophil infiltration, with the use of an in vivo assay of neutrophil infiltration with relevance to ischemic brain injury. Intrastriatal injection of recombinant rat cytokine-induced neutrophil chemoattractant-1, a member of the interleukin-8 family (1 microg in 1 microl), triggered massive infiltration of neutrophils and extensive BBB disruption 6 hours later, as measured using immunofluorescence microscopy and magnetic resonance imaging in the rat, respectively. Depleting the animals of neutrophils before interleukin-8 injection prevented BBB disruption. Treatment with IFN-beta (5 x 106 U/kg) almost completely prevented neutrophil infiltration and attenuated BBB damage. Gelatinase zymography showed matrix metalloproteinase-9 expression in the ipsilateral striatum after interleukin-8 injection. Both neutrophil depletion and IFN-beta treatment downregulated matrix metalloproteinase-9. IFN-beta has already been approved for human use as a treatment for the chronic inflammatory disorder multiple sclerosis. The potential value of IFN-beta as a treatment that can attenuate acute brain inflammation is considered.