Multiple sclerosis is linked to rogue immune cells that attack mature neurons. Remarkably, immature neurons secrete a protein called LIF, which not only inhibits this attack, but also promotes repair of the damaged nerves.
Multiple sclerosis (MS) is a disabling autoimmune neurological disease that commonly affects young adults; in Britain alone there are more than 100,000 people with the disease. MS involves damage to the myelin sheath that normally insulates the electrical activity of nerve fibres. This in turn leads to a wide range of symptoms as specific nerves become inflamed and lose function. There is no cure. However, work on animal models has been encouraging, as it has shown that the transplantation of nerve progenitor cells not only inhibits the autoimmune attack that drives the disease, but also promotes the repair of damaged neurons1. In fact, in North America, human stem-cell transplantation is commercially available to patients with MS.
But is cell transplantation really necessary? Not according to Cao et al.2, who report an exciting discovery in Immunity. They find that, at least in animal models of MS, a stem-cell-related cell-signalling protein called leukaemia inhibitory factor (LIF)3 can partially cure the disease. This finding opens the way for the development of a cell-free therapy for MS that is simple, safe and widely accessible.
Cao and colleagues studied mice that had experimental autoimmune encephalomyelitis (EAE) — a model of MS. They found that damage to the central nervous system was reduced not only by the intravenous delivery of neural progenitor cells, but also by simply injecting the medium in which these cells were cultured. This suggested that a cell-derived soluble factor provides the protective effect, and the authors' screening studies revealed that the crucial factor is LIF. Indeed, commercially available LIF alone successfully replaced the cell therapy2.
Cao et al. next turned their efforts to investigating exactly how LIF exerts its beneficial effect. They found that it acts through suppression of a specific type of immune cell called a TH17 cell4. This class of T cell functions to defend the gut and mucosal tissues from invading pathogens. Sometimes, however, rogue TH17 cells arise within otherwise healthy host tissues, leading to autoimmune inflammation — as occurs in the central nervous system of patients with MS.
Notably, a mediator of inflammation called IL-6 is essential for TH17-cell development; and herein lies a twist in the tale. Structurally, IL-6 and LIF are very closely related. So how is it that IL-6 exacerbates MS, whereas LIF protects against the disease? The answer lies in the balance between LIF and IL-6 in affecting T-cell differentiation5 — the 'LIF–IL-6 axis'. This pivotal axis is a cell-fate decision fork leading to either an IL-6-driven TH17-cell lineage or a LIF-driven Treg-cell lineage. Notably, the Treg-cell lineage is protective, promoting self-tolerance.
To respond to LIF or IL-6, cells must express the corresponding receptors at their surface. Of the two subunits of the LIF receptor (gp190 and gp130), gp190 endows specificity for LIF binding. In the IL-6 receptor, however, both subunits are gp130, and so LIF cannot activate it. Cao et al. show that undifferentiated peripheral T cells obtained from either EAE mice or patients with MS undergo transient expression of gp190 when activated. When LIF was added, the cells retained gp190 and so — through activation of an inhibitory signalling cascade, the ERK pathway — failed to mature into the inflammatory, myelin-attacking TH17 cells. Thus, in EAE and MS, a yin–yang type of LIF versus IL-6 regulation seems to operate, which is determined by the expression of gp190 (Fig. 1).
The fate of the immature, LIF-blocked TH17 cells remains ambiguous. The authors find no evidence that LIF causes these cells to mature down another lineage2. However, previous work5 suggests that the cells would develop into Treg cells in response to LIF. This uncertainty ought to be resolved because, if Treg cells indeed arise, the myelin-protective immunity offered by these cells would perpetuate the beneficial effect of LIF therapy.
By identifying LIF as a potential treatment for MS, the present paper holds promise of early translation to the clinic. However, soluble LIF cannot be used for treatment purposes because it is rapidly degraded by protease enzymes in the blood. To overcome this problem, my team and our collaborators have developed LIF in the form of biodegradable nanoparticles5,6. This formulation was successful not only in providing a slow-release vehicle for LIF, but also in operating as a 'magic bullet' to target LIF directly to specific cell types — for example, to T cells for the induction of Treg cells, or to nerve cells for their repair. Another reported7 therapeutic approach involves delivering LIF by means of a viral vector.
But can LIF be beneficial in patients with MS who already harbour fully differentiated inflammatory TH17 cells? A recent clinical trial8 is highly relevant to answering this question. The trial involved depletion of circulating T cells — including TH17 cells — using the therapeutic antibody alemtuzumab. T-cell populations were then allowed to recover, from undifferentiated precursors resistant to alemtuzumab. The newly emerging populations included Treg-type cells that secreted neuro-protective factors in response to products of damaged myelin; this cell population was absent from pretreatment blood samples taken from the patients. The beneficial effects of the treatment are profound, continuing over several years. These effects are consistent with the idea that newly arising, myelin-reactive Treg-type cells form a self-sustaining population of mature cells that can oppose the maturation of myelin-reactive TH17 cells.
Clearly, great strides towards improved treatment of MS are being made. New means of exploiting the natural protective properties of LIF in both the immune and the nervous systems are now available to take Cao and colleagues' results into preclinical studies. Future studies in which T-cell depletion is combined with LIF therapy are eagerly awaited.