Evidence for cytokine dysregulation in multiple sclerosis: peripheral blood mononuclear cell production of pro-inflammatory and anti-inflammatory cytokines during relapse and remission.

We investigated circulating anti-inflammatory and pro-inflammatory cytokines, and their ex vivo PBMC production in the absence or presence of the neuroantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) and T cell mitogen (PHA) in MS patients in relapse and remission, patients with other neurological disorders (OND) and normal healthy controls. MS patients in relapse exhibited significantly increased PBMC production of TNF-alpha spontaneously compared with MS remission and healthy controls and with MBP compared with MS remission. Patients in relapse had significantly increased spontaneous, PHA- and MBP-induced PBMC IL-1beta production compared with remission MS, and was increased compared (PHA only) with OND and healthy controls. In relapse there was also significantly increased PBMC IFN-gamma production (PHA only) compared with remission and a significantly lower production of biologically active TGF-beta1 (PHA only) compared with remission MS and OND. In contrast, MS patients in remission produced significantly less spontaneous and MBP-induced TNF-alpha, spontaneous, PHA- and MBP-induced IL-1beta and PHA-induced IFN-gamma together with increased production of biologically active TGF-beta1. MOG non-specifically increased PBMC TNF-alpha and IL-1beta production in all groups. Pro-inflammatory cytokines in corresponding plasma samples were undetectable whilst the concentration of biologically active TGF-beta1 was the reverse of ex vivo PBMC findings. The increase in biologically active TGF-beta1 production ex vivo in OND patients, despite active disease, compared with the low level in the MS relapse may indicate a regulatory defect in MS. We conclude that the balance between biologically active TGF-beta1 and the pro-inflammatory TNF-alpha, IL-1beta and IFN-gamma is dysregulated during MS relapse-remission and that normal counter-regulatory mechanisms during the relapse phase are defective.

Dose and Frequency of Administration of Interferon-beta Affect its Efficacy in Multiple Sclerosis.

Data reviewed in this article demonstrate that both interferon-beta-1a (IFNbeta-1a) and interferon-beta-1b (IFNbeta-1b) show a dose-response relationship in multiple sclerosis at current clinical doses. Moreover, the efficacy of these therapies is probably dependent on their frequent administration to maintain optimal levels of biological effect. These results differ from the conclusions of a recent review of data comparing two doses of IFNbeta-1a, given intramuscularly once weekly, that showed no difference in efficacy between the two doses. This and other results were interpreted to indicate that the current dose of this product (30microg intramuscularly once weekly) is optimal. However, the data reviewed here indicate that the efficacy of IFNbeta differs depending on the features of the dose regimen, including total dose, route and frequency of administration. Direct comparative data indicate that 44microg given subcutaneously three times weekly is more effective on clinical and magnetic resonance imaging measures, at least up to 48 weeks of therapy, compared with 30microg intramuscularly once weekly; risk-benefit favours 44mug three times weekly over 30mug once weekly.