Untreated inflammation is bad for the brain. Over time, repeated bouts of inflammation predispose to the gradual loss of nerve cells from the brain and spinal cord. This gradual degenerative process is what we can quantify with brain atrophy and measurements of neurofilament. Loss of nerve projections (axons) begins very early in the inflammatory process, occurs both within and distant from lesions, and is probably the main driver of disability.
Most effective DMTs work by targeting cells of the innate and adaptive immune systems, thereby limiting the amount of inflammation in the spinal cord. While the highly effective DMTs are very good at preventing relapses, they are much less effective at halting the degenerative component of the disease. This implies to me that while inflammation is an important trigger of nerve cell death in MS, the relationship is not straightforward.
We need better strategies for preventing nerve cell death. Several drugs have been toted as possible neuroprotectants – a useful guide here – but none of these has enough evidence to support its use in the clinic yet.
Cytokines are molecular messengers produced by cells of the immune system. Cytokines allow various players in the immune system to communicate and co-ordinate their response to a stimulus. As well as influencing other cells of the immune system, cytokines can shape the behaviour of non-immune cells as well.
Previous work had shown that giving interleukin-4 (IL-4, a cytokine) to mice made their MS better. While the simplest explanation for this was that IL-4 altered the types of immune cells entering the CNS, another possibility was that IL-4 exerted a direct neuroprotective effect on nerve cells. IL-4 is an interesting cytokine with multiple roles. It is produced by a subtype of helper T cell – Th2 cells – and helps to divert naive T cells down the Th2 road, activate eosinophils, and push B cells towards producing a special kind of antibody called IgE. All of these responses are thought to be beneficial, in evolutionary terms, for fighting parasites. This is also the dominant immune response seen in allergic inflammatory disorders like asthma.
This elegant new study aimed to work out how IL-4 could prevent nerve cell death in mouse MS. First, they showed that in 3 different mouse MS models, giving IL-4 inside the central nervous system (CNS) dramatically improved the ‘chronic’ phase of the disease, which is meant to mimic the advanced phase of MS in humans. They then asked whether this protective effect was due to a direct action in nerve cells, or via effects on the immune system. To do this, they used a clever technique called a conditional knockout: they made mice which lacked the receptor for IL-4 on nerve cells, but had intact IL-4 receptors on all other cells. This meant that, in these mice, IL-4 could act on all cell types except for neurons. This experiment demonstrated that the protective effect of IL-4 was due to a direct action on nerve cells. They then showed that the clinical benefits of IL-4 were associated with a beneficial effect on axonal pathology – they found that the density of axons and the number of axonal swellings (precursors to axonal loss) were normalised by IL-4 treatment. The authors then demonstrated that IL-4 actually enhanced the outgrowth of axons, and that this effect was again due to direct signalling in nerve cells themselves. Finally, they showed that giving IL-4 through the nose was also effective at protecting the mice from the advanced phase of the disease.
These results are phenomenal. In a mouse model of MS, the cytokine IL-4 halted the degenerative component of the disease via a direct effect on nerve cells.
The implications for human MS are immediate. If giving a nasal version of IL-4 halts the neurodegenerative component of the disease in mice, should we be thinking about a phase I trial in human MS?
First, just because this has worked in mice is no guarantee it will work in humans. We are still very bad at modelling the early parts of the MS disease process in mice – largely because we don’t understand what goes on in human MS – and so the picture may be much muddier in humans. Although the types of immune cells and the degree of inflammation in the CNS weren’t substantially affected by the treatment, it would be important to know what IL-4 does to the immune cells present in the human CNS. Even if the protective effects are due to a direct action on neurons, IL-4 will doubtless have interesting – and possibly also therapeutic – effects on the immune cells in the CNS.
Second, I wonder if it matters when IL-4 is administered. In this study IL-4 could be given at a fixed time after the induction of the disease. I suspect that there is an early window of intervention, shortly after a relapse, when axons are particularly vulnerable to inflammatory injury. This study shows nicely that there is detectable axonal damage early in the disease and that axons can be protected at this stage. In my view, to be helpful for people, IL-4 would probably have to be given at the same time, or shortly after relapses.
Third, thinking about off-target effects is especiallly important when using cytokines as therapy. IL-4 makes allergic inflammation worse. As well as excluding people who have asthma and similar disorders from a trial, it would be important to watch out for the occurrence of new cases of asthma, eczema, allergic rhinitis etc.
Caveats aside, I think this is a fantastic, complete, and important piece of work which brings a new potential neuroprotective drug into the arena. Bring on IL-4.
Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation. Amelioration of disability was abrogated upon neuronal deletion of IL-4R. We discovered direct neuronal signaling via the IRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair. Nasal IL-4 application, suitable for clinical translation, was equally effective in improving clinical outcome. Targeting neuronal IL-4 signaling may offer new therapeutic strategies to halt disability progression in MS and possibly also neurodegenerative conditions.