Changes in plasma cytokines induced by interferon-beta1a treatment in patients with multiple sclerosis.

It has been postulated that the efficacy of interferon-beta1a in multiple sclerosis may be due to the induction of type 2 cytokines. In this report we demonstrate that after 3 months of therapy, there is no sustained alteration in the plasma levels of type 1 (IL-12, IL-1beta and TNF-alpha) or type 2 (IL-6, IL-10) cytokines, but rather repeated induction of both with each injection. Little alteration is seen in the profile of cytokines induced with time, despite a decline in side effects. This suggests that IFN-beta1a causes repeated transient modulation of cytokine expression, but no sustained deviation in the type 1/type 2 balance.

Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation.

Putative markers of inflammation such as serum beta2-microglobulin and neopterin have been shown to be transiently upregulated following interferon-beta (IFN-beta) administration to multiple sclerosis (MS) patients. However, to date the role of the important inflammatory mediators serum amyloid A protein (SAA) and C-reactive protein (CRP) have not been described. Here we show that SAA but not CRP is elevated in relapsing-remitting MS patients compared to normal healthy individuals, and furthermore that both are transiently upregulated following intramuscular injection with IFN-beta1a (Avonex). This pattern of expression was found to parallel that of beta2-microglobulin and neopterin following injection and was mirrored by a selective activation of peripheral monocytes with respect to upregulation of receptors known to be involved in the inflammatory response (HLA-DR, CD16 and CD86). Injection of saline solution intramuscularly to six healthy control individuals did not produce a similar upregulation of any of the inflammatory markers investigated. Following IFN-beta1a injection, all inflammatory responses were attenuated at week 12 of therapy in comparison to those following the initial injection in a group of follow-up patients. In addition, IFN-beta1a injected on a weekly basis did not produce a sustained modulation of any of the markers investigated in patients treated for 32 weeks.

Monocyte-derived dendritic cells: a potential target for therapy in multiple sclerosis (MS).

Monocytes can differentiate into dendritic cells (DC), cells with a pivotal role in both protective immunity and tolerance. Defects in the maturation or function of DC may be important in the development of autoimmune disease. We sought to establish if there were differences in the cytokine (granulocyte-macrophage colony-stimulating factor and IL-4)-driven maturation of monocytes to DC in patients with MS and whether drugs used to treat MS affected this process in vitro. We have demonstrated that there is no defect in the ability of magnetic activated cell sorting (MACS)-purified monocytes from patients with MS to differentiate to DC, but equally they show no tendency to acquire a DC phenotype without exogenous cytokines. Interferon-beta1a prevents the acquisition of a full DC phenotype as determined by light and electron microscopy and by flow cytometry. Methylprednisolone not only prevents the development of monocyte-derived DC but totally redirects monocyte differentiation towards a macrophage phenotype. Evidence is evolving for a role for DC in central nervous system immunity, either within the brain or in cervical lymph nodes. The demonstrated effect of both drugs on monocyte differentiation may represent an important site for immune therapy in MS.