Th17 cells in multiple sclerosis express higher levels of JAK2, which increases their surface expression of IFN-γR2.

IFN-ß inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-γ decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases.

T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta.

OBJECTIVE: T-helper 1 (Th1) and Th17 lymphocytes are involved in experimental autoimmune encephalomyelitis, the model of multiple sclerosis (MS). We characterized the Th1/Th17 cell populations in peripheral blood (PB), their interferon (IFN) receptor expression sensitivity to IFN-beta in MS patients. METHODS: In 30 untreated patients with active MS (AMS) and 32 with inactive MS (IMS), and in 22 healthy subjects, we measured intracellular cytokine expression, interleukin-17-producing myelin basic protein-stimulated PB lymphocytes, surface IFN type I receptor chain1 (IFN-alphaR1) expression, IFN-beta-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation, and apoptosis of anti-CD3 monoclonal antibody-stimulated PB lymphocytes. RESULTS: Th17 cell percentage increased around sevenfold in AMS compared with IMS or healthy subjects, but there was no change in Th1 cells. Th17 cells in AMS were myelin basic protein specific. The longitudinal follow-up of 18 MS patients shifting between AMS and IMS showed that the percentage of Th17 but not Th1 cells always increased in AMS. IFN-alphaR1 expression, IFN-beta-induced STAT1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. IFN-alphaR1 expression and IFN-beta-dependent STAT1 activation progressively increased in vitro with a highly significant positive correlation only in developing Th17 but not in Th0 or Th1 cells. INTERPRETATION: Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-alphaR1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-beta therapy.

The therapy of multiple sclerosis with immune-modulating or immunosuppressive drug. A critical evaluation based upon evidence based parameters and published systematic reviews.

Today many different drugs are available for treatment of multiple sclerosis (MS). Interferons, glatiramer acetate, mitoxantrone, and natalizumab have been approved by the regulatory authorities of many countries for the treatment of MS. Evidence based medicine (EBM) principles allow physicians to better address the correct treatment for patients. This article aimed to review all the clinical trials on immune-modulating and immunosuppressive drugs on the basis of the EBM principles. Based on the evidence to date interferon beta represents the best therapeutic option, particularly if given at high doses and with multiple injections per week. Due to its lower efficacy, glatiramer acetate should be used as a second choice in case of intolerable side effects or toxicity of interferon beta. Great efficacy has been demonstrated for mitoxantrone and natalizumab. These drugs should be, however, used with particular attention for their potential toxic effects.

Adherence to interferon-beta treatment and results of therapy switching.

Adherence to long-term therapy has always been a problem in all fields of medicine. In multiple sclerosis (MS), treatment consists of parenteral administration of immune-modulating drugs once or several times weekly for an as yet undetermined length of time. Different studies on the MS patients' compliance showed that the most frequent cause of stopping treatment is the perceived lack of efficacy and that most treatment withdrawals occur during the first year of treatment. A trial aimed to identify the minimum effective IFNbeta dose showed that some patients had disease activity after switching to a lower IFNbeta dose. OPTIMS (OPTimization of Interferon dose for MS study) was a multicenter study, involving 24 Italian MS centers, 216 patients, aimed to identify a treatment response indicator allowing the early identification of poorly responding patients. A single active scan during the first 6 months of IFN treatment had a significant positive predictability of 59% (95% confidence interval, 41-76; p=0.05) on the presence of clinical signs of disease activity during the further 2-year follow-up.

Pro-inflammatory cytokine and chemokine mRNA blood level in multiple sclerosis is related to treatment response and interferon-beta dose.

Of 37 multiple sclerosis patients, 19 suboptimal responders were randomized to 375 (n=12) or 250µg (n=7) interferon (IFN)-ß-1b. mRNA levels of 23 cytokines, chemokines, and chemokine receptors were quantified by TaqMan low-density array (TLDA) real-time polymerase chain reaction. Better treatment responses or increased IFN-ß doses were associated with elevated IL-10 and TGF-ß and decreased CXCL10, IL-18, IFN-γ, and TNF-α transcript levels. Adjusting for dose, poor treatment responses resulted in a 4-fold increase in CXCL10 and IFN-γ expression (Mantel-Haenszel RR=3.74, p<0.0001). CXCL10 and IFN-γ mRNA levels were reliable indicators of treatment response. TLDA can be used to tailor IFN-ß-1b therapy.

Interferon-beta1a for the treatment of multiple sclerosis.

At present, two types of recombinant human interferon (IFN)-beta are in clinical use. IFN-beta1a is produced in genetically engineered Chinese hamster ovary cells, and its amino acid sequence and glycosylation pattern are identical to those of endogenous human IFN-beta. The beneficial effect of IFN-beta in multiple sclerosis (MS) probably results from different mechanisms of action, such as a direct effect on plasma cells modulating IgG synthesis, an increase of interleukin (IL)-10 levels, the inhibition of IL-1beta and tumour necrosis factor alpha, the stimulation of IL-1 receptor antagonist production, the inhibition of proliferation of leukocytes, a decreased antigen presentation in microglia, a reduction of T cell migration into the brain by inhibition of the activity of T cell matrix metalloproteinases, and a downregulation of adhesion molecules. IFN-beta1a has been shown by several multicenter controlled trials to be effective in relapsing-remitting MS. It reduces relapse rate by 30-50%, magnetic resonance imaging signs of disease activity in 30-80% and disability progression by 30%. It is also effective in preventing conversion to clinically definite MS when given at the time of a first demyelinating event (i.e., at the very beginning of the clinical disease). No clear evidence of the persistence of the efficacy over the long-term has stood out from a systematic analysis of published trials. A Cochrane review concluded that, in fact, the clinical effect beyond the first year of treatment is not clear. Finally, no efficacy has been shown in secondary progressive or primary progressive MS. However, IFN-beta1a is very well tolerated and the most frequent side effects are mild (local skin reaction and flu-like symptoms) and decline in frequency or disappear after the first 3-6 months of treatment. Although the optimal frequency between once weekly or multiple weekly administrations is still controversial, all protocols require multiple monthly injections. Some patients might find it hard to cope with such a treatment regimen over the long term. Ongoing trials with new powerful immunomodulatory drugs, such as monoclonal antibodies, that require only monthly or bimonthly parenteral administrations will probably offer a better tolerated treatment option in the near future.