Could cytokines levels or adhesion molecules expression be predictor of IFN-beta treatment response in multiple sclerosis patients?

OBJECTIVE: Some patients with relapsing-remitting multiple sclerosis (RRMS) do not respond to treatment with interferon-beta and continue to have relapses and new enhancing lesions on MRI. The markers which would predict the treatment response are still not known. The objectives of the study were to compare cytokines levels (IFN-gamma, IL-4, IL-6, IL-10) and expression of adhesion molecules before and during treatment in responders and nonresponders to IFN-beta treatment. METHODS: Twenty-nine patients with RRMS were enrolled in the study. Cytokine levels were evaluated by ELISA in supernatants of IONO/PMA activated PBMC cultures (IFN-gamma, IL-4, IL-6, IL-10), and by flow cytometry (intracellular IFN-gamma, IL-4 and IL-2R expression) before and during treatment. Expression of adhesion molecules (VLA-4, ICAM-1) was evaluated by flow cytometry (CD49+ and CD54+) before and during treatment. RESULTS: Only 9 of 29 patients were responders to treatment according to definition (no relapse in the first 2 years of treatment). We found significant differences in the expression of IL-2R after 1 month of treatment, intracellular IFN-gamma after 6 months of treatment and IL-10 level in nonactivated PBMC cultures after 1 week of treatment. CONCLUSION: We concluded that the differences we had found between responders and nonresponders are most probably incidental and not predictive of treatment response. Our study shows that cytokines levels and expression of adhesion molecules cannot be used as markers for treatment response.

Anaplastic oligodendroglioma and gliomatosis type 2 in interferon-beta treated multiple sclerosis patients. Report of two cases.

The concurrence of multiple sclerosis (MS) and brain tumors has been reported, but it is not known whether MS patients are at greater risk of harbouring the latter. The most common cerebral neoplasms reported in MS patients were oligodendroglioma, astrocytoma, glioblastoma and gliomatosis. MS can also present as a mass lesion that mimics a brain tumor. To establish the correct diagnosis radiological follow-up and/or histological confirmation is needed. Two cases of coincidental MS and brain tumors are reviewed. One is a 26-year-old woman with relapsing-remitting MS and an anaplastic oligodendroglioma, the other a 49-year-old woman patient with relapsing-remitting MS and gliomatosis type 2. Both patients were treated with interferon-beta1b and both died from the tumor. The concurrence of MS and brain tumors could be purely coincidental, or the result of neoplastic transformation of reactive glial cells in the areas of demyelination. The combination of a brain tumor and MS, and interferon-beta treatment could also be pure coincidence or an unknown side effect of treatment. Although interferon-beta has been said to function as a tumor-suppressor protein, the influence of long-term treatment of MS patients on cancer development is not known.

IFN-beta1a and IFN-beta1b have different patterns of influence on cytokines.

Multiple sclerosis is characterized by elevated levels of proinflammatory cytokines produced by Th1 cells and decreased levels of anti-inflammatory cytokines produced by Th2 cells. IFN-beta treatment shifts the immune response from the Th1 to Th2 pattern, thus enhancing the production of anti-inflammatory Th2 cytokines such as IL-4, IL-10, and decreasing the production of proinflammatory Th1 cytokines such as IFN-gamma. To determine which IFN-beta has the stronger immunomodulatory effect we compared the levels of IL-4, IL-10, and IFN-gamma of 12 relapsing-remiting MS patients treated with IFN-beta1b (Betaferon) with those of 10 patients treated with IFN-beta1a (Avonex). There were no statistically significant differences in duration of disease, number of relapses before and during treatment, and in EDSS after 2 years of treatment. After 1 year of treatment the concentration of IFN-gamma was significantly lower in the Betaferon group, and concentrations of IL-4 and IL-10 were significantly higher in the Avonex group. It appears that IFN-beta1b has a downregulatory effect on both Th1 and Th2 cytokines, while IFN-beta1a causes a shift of the cytokine profile toward the Th2 phenotype. These two IFN have different influences on the pattern of cytokines in MS: IFN-beta1a enhances the production of anti-inflammatory cytokines IL-4 and IL-10 and IFN-beta1b decreases the production of the proinflammatory cytokine IFN-gamma.