IFN-β is one of the most widely used treatments for MS. However, a major limitation with IFN-β is that a 30 to 50% of MS patients do not respond to IFN-β therapy. Therefore, it is desirable to identify responders and non-responders prior to the initiation of treatment. In a series of experiments in mice, we identified that mice with TH1-EAE benefit from IFN-β treatment with reduction in levels of disability, while mice with TH17-EAE do not respond and disease worsens.
1-EAE, induction of anti-inflammatory cytokine, IL-10, was increased with beneficial IFN-β treatment. Since IFN-β treatment inhibited TH
1-EAE, we speculated that effective IFN-β treatment depended on high IFN-γ levels during EAE. In fact, IFN-β was effective in treating active EAE C57BL/6 mice, but worsened EAE in IFNγR−/;−
mice. Furthermore, when EAE was induced via passive transfer of C57BL/6 TH
1 cells into IFNγR−/;−
recipients, IFN-γ influences a broad range of cells in its complex interactions with IFN-β. Cell culture experiments, concordant with in vivo
studies in EAE, revealed that the induction of IL-10 by IFN-β in T-cells required APCs and also required cooperative IFN-γ signaling, indicating that the APC’s were the target of this activity of IFN-β. Popular speculation on the mechanism of IFN-β treatment is that it attenuates disease by inhibiting the differentiation of TH
. We find that IFN-β inhibits IL-17 production in vitro
and in EAE, yet IFN-β is ineffective in treating TH
17-induced EAE and increases symptoms in these mice.
In RRMS a subset of non-responders had high serum levels of the TH
17 cytokine, IL-17F before IFN-β therapy was initiated. IL-17F is produced by TH
17 cells in EAE27
suggesting that this group of MS patients is skewed towards a TH
17 version of disease. Furthermore, these patients also had high levels of endogenous IFN-β compared to responders. This correlation between high IL-17F and IFN-β concentration in the serum suggests a tight biological association between these two cytokines. Two hypotheses, which may not be mutually exclusive, could explain this phenomenon.
One hypothesis is that these non-responders have aggressive TH
17 disease. To counteract inflammation, their immune systems up-regulates IFN-β. Since endogenous IFN-β levels are already high, IFN-β treatment is ineffective. A second hypothesis is that IFN-β is pro-inflammatory during TH
17 disease. Not only would IFN-β treatment be ineffective, it could worsen symptoms. This is supported by observations in EAE, where symptoms worsened with IFN-β treatment in TH
17-EAE, a finding concordant with the data in RRMS, where patients with high IL-17F and IFN-β have exacerbated disease. Observations in neuromyelitis optica (NMO), another demyelinating disease, provide evidence for this hypothesis. NMO lesions are granulocytic28,29
17 responses attract granulocytes to sites of inflammation30–32
. Furthermore, NMO patients have high levels of IL-17 in the CSF33
. Finally, IFN-β treatment of NMO induces relapses2,34,35
. Therefore, the disease processes of NMO and the IL-17Fhi
non-responders could be very similar.
The data presented in this study demonstrates a phenomenon often seen with cytokines. IFN-β has polar effects in different contexts, leading to benefit in TH
1 conditions, but harm in TH
17 conditions. This duality of functions for cytokines is often referred to as a Janus-like, quality after the two headed God from Roman mythology, with opposite activities attributed to the very same molecule37
. This very feature of IFN-β provides an opportunity to explore some logical biomarkers that might have predictive value in assessing the response to a popular therapy for MS.