MS Society-funded research uncovers new mechanism by which front-line MS therapeutic interferon-beta suppresses harmful inflammation
T-lymphocytes (T-cells) are a class of immune cell that fight infection. They are also one of the primary contributors to the development of MS. During an MS attack, myelin-reactive T-cells invade the central nervous system (CNS) where they orchestrate and direct an autoimmune response against myelin, resulting in demyelination. An important step in this process is mediated by antigen-presenting cells (APCs), which capture antigens (substances that the immune system perceives to be dangerous) and send out specific signals that T-cells use to mount their autoimmune response against a target.
One of the front-line therapies for relapsing-remitting MS is interferon-b (IFN-b). It works by suppressing inflammation brought on by T-cells, but just how it does so is not well understood. Evidence suggests that IFN-b targets T-cells indirectly by altering signals originating from APCs that are required for T-cell activation. Whether IFN-b can directly target T-cells in the absence of APCs is less clear.
A team of researchers, led by principal investigator Dr. Manu Rangachari (who holds an EMD Serono, Canada endMS Research and Training Network Transitional Career Development Award from the MS Society and MS Scientific Research Foundation), tested whether IFN-b could alter T-cell behaviour in the absence of APCs. They focused on a T-cell subtype, called Th1, known to play a critical role in myelin-targeted autoimmunity. Their findings were published in the online journal PLoS ONE.
The first set of experiments was conducted in cell culture. Th1 cells, grown in cell cultures that were devoid of APCs, were exposed to IFN-b. The effect of IFN-b treatment on both cell proliferation (increase in cell number) and inflammatory potential of Th1 cells was then measured.
The research team next investigated whether IFN-b, in the absence of APCs, could influence the ability of Th1 cells to induce an MS-like disease in mice. To this end, Th1 cells, pre-programmed to be myelin reactive, were grown in cell culture lacking APCs in either the presence or absence of IFN-b. These myelin-reactive Th1 cells were then injected into mice, leading to the development of an MS-like disease. Disease severity was compared between mice injected with either IFN-b treated or non-treated Th1 cells. Two factors determined disease severity: tail and limb disability, and the number of T-cells that infiltrated the CNS.
IFN-b treatment reduced the proliferation and inflammatory potential of cultured Th1 cells. Since APCs were not present in the cultures, the researchers concluded that IFN-b could affect Th1 cells directly without any involvement from APCs.
When pre-treated with IFN-b, myelin-reactive Th1 cells, grown in the absence of APCs, induced a milder MS-like disease in mice. The mice had lower disability scores and fewer CNS-infiltrating T-cells.
In this study, the researchers demonstrated IFN-b’s ability to reduce harmful inflammation by suppressing Th1 immune cell function independently of APCs. This mechanism is in addition to, but distinct from, IFN-b’s previously described role of indirectly suppressing Th1 function by altering signals originating from APCs.
Many individuals with relapsing-remitting MS do not respond to IFN-b treatment. It is, therefore, important that we identify the cellular mechanisms that determine when IFN-b is effective, and when it isn’t. The researchers suggest that this information could help to identify groups of individuals who would best respond to IFN-b treatment, as well as to identify potential biomarkers to predict therapy responsiveness. The researchers further suggest that, in the long-term, a better understanding of IFN-b’s role in the suppression of Th1 immune cell function could lead to creation of novel or multi-drug therapies. This would, in turn, bring effective treatment to a greater number of individuals living with MS.
Boivin N et al. (2015). Interferon-b suppresses murine Th1 cell function in the absence of antigen-presenting cells. PLoS ONE. 10(4): e0124802.
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