Groundbreaking news concerning multiple sclerosis (MS) appeared in the mainstream media earlier this year when CNN and others reported that Chander Raman and colleagues had identified two unique forms of MS, underscoring the unforeseen complexity of this disease. Their landmark publication focused on the role of T helper-1 (Th1) versus T helper 17 (Th17) cells in mediating MS progression.
Both of these Th cell types have been implicated in promotion of MS in the past, and the current study examined their individual roles in the response to IFN-β therapy. Using an established murine model of MS, the authors showed that successful responses to exogenous IFN-γ administration depended upon the presence of Th1-induced interferon gamma (IFN-γ). When MS was mediated by Th17-derived interleukin 17 (IL-17), and serum IFN-γ levels were low, IFN-β therapy was not protective.
Notably, this study went on to show that, prior to treatment, a subset of human MS patients exhibited high serum levels of IL-17 and IFN-β, which were shown to correlate with a subsequent poor response to IFN-β therapy. Therefore, serum IFN-β and IL-17 levels may be predictive biomarkers of the unique Th17-mediated form of MS.
In fact, the authors suggest that IFN-β has contrasting effects in different contexts: beneficial under Th1 conditions and detrimental under Th17 conditions. Most importantly, this may explain why some individuals do not respond appropriately to IFN-β therapy.
Nonresponders may produce endogenous IFN-β to counteract Th17-mediated inflammation rendering them less responsive to exogenous IFN-β. Alternatively, IFN-β may, in fact, act as a pro-inflammatory cytokine during Th17-mediated disease, which may explain the fact that IFN-β treatment can actually exacerbate MS in some cases.
If confirmed in additional human studies, these findings could significantly increase mechanistic understanding of MS disease development. Furthermore, this may eventually lead to improved approaches for treating MS patients. In particular, it is plausible that if the serum levels of IFN-β and IL-17 continue to show correlation with MS disease classification and response to IFN-β therapy, a simple blood test could be used to better direct treatment options in the future.
Although it will likely be some time before this data can be used to tailor therapeutic regimens for patients presenting with different MS subtypes, there are more immediate implications for monitoring IFN-β responsiveness in patients with an elevated IL-17/IFN-β versus IFN-γ profile. Specifically, this new phenotypic category of MS may be associated with previously identified genetic markers, or in cases where there is a development of neutralizing antibodies to the IFN-β therapeutic protein.
Bridging studies using retrospective samples collected over time from IFN-β responders and nonresponders would be useful to determine if these latest findings are associated with specific gene polymorphisms and/or the development of neutralizing antibodies against IFN-β. Not only would these studies be of interest to scientists analyzing the mechanisms of MS development and disease progression, they may eventually provide guidance to physicians for clinical protocols as well.
A great deal of research has been conducted in an attempt to determine the role of anti-IFN-β antibody development by MS patients, and the subsequent effects on their responsiveness to IFN-β therapy. The two types of anti-IFN-β antibodies produced are defined in functional terms.
Binding antibodies (BAbs) include any antibodies that can bind to IFN-β. Neutralizing anti-IFN-β antibodies (NAbs) are a subset of BAbs and have the ability to inhibit the biological activity of IFN-β protein, thereby potentially decreasing a patient’s responsiveness to IFN-β therapy.
In fact, several studies have shown the presence of NAbs in the serum of some MS patients who have failed to respond to IFN-β therapy. So, in addition to a skewed IL-17/IFN-β serum cytokine ratio, the presence of NAbs, therefore, suggests another mechanism by which patients may fail to respond to IFN-β therapy.
Research into the development and functional consequences of NAbs has produced a wide range of mixed results. PBL InterferonSource has developed an assay that helps analyze NAbs in MS patients. Even within the population of patients who respond positively to IFN-β therapy, NAb production represents a major concern since it may diminish therapeutic efficacy and, thus, warrants close monitoring.