Opinion
Therapeutic potential of LIF in multiple sclerosis

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Therapies for multiple sclerosis (MS) reduce the relapse rate but are unable to stop neurological decline. Here, we evaluate the potential of leukemia inhibitory factor (LIF) as a novel therapeutic in diseases with a neurodegenerative and inflammatory component, such as MS. LIF, which can be a proinflammatory cytokine, can also modulate the immune response in a beneficial way. Recent evidence demonstrates a crucial role of LIF in neuroprotection and axonal regeneration as well as the prevention of demyelination. Finally, LIF is an important survival factor for stem cells and neuronal precursors. Therefore, we propose that LIF is a potential therapeutic candidate for MS.

Section snippets

Neuroprotective therapies are needed for multiple sclerosis (MS)

MS is the most common cause of nontraumatic neurological disability in North America and Europe. Most patients initially develop a relapsing–remitting form of the disease (RRMS), characterized by episodes of neurological disability followed by episodes of improvement. After 8 to 20 years, the majority of patients with RRMS develop secondary progressive MS. In this stage, patients usually suffer few if any attacks but accumulate neurological disability. Approximately 15% of patients are

LIF as part of the endogenous biological response to protect the CNS

LIF is undetectable in the healthy nervous system, but its expression increases after different types of neuronal distress, including nerve injury, ischemia, spinal cord injury, in MS lesions, in the hippocampus of patients with Alzheimer's or Parkinson's disease and after seizure 2, 4, 5, 6, 7, 8, 9. It has therefore been hypothesized that the activation of LIF signaling is part of an endogenous neurobiological response that limits nerve injury. Indeed, LIF can protect neurons and

Immunomodulatory properties of LIF

Although the protective effects of LIF on neurons and oligodendrocytes make it a good therapeutic option for MS, its immunomodulatory properties are also relevant, especially when considering LIF administration in a chronic autoimmune disease such as MS. LIF has proinflammatory effects in rheumatoid arthritis, during cutaneous inflammation and after overexpression in the mouse spinal cord 30, 31, 32. In arthritis models, LIF activates osteoclast activity, thereby inducing bone resorption and

Regeneration and repair

It was once believed that damaged neurons could not be replaced, making neurodegeneration in MS a detrimental and irreversible event. We now know that multipotent neural stem cells (NSCs) persist in the adult brain, but their contributions to repair after brain injury are limited. Stimulation of the regenerative potential of endogenous progenitors with appropriate signals could be of therapeutic value. Interestingly, LIF prevents the differentiation of embryonic stem (ES) cells by promoting

Therapeutic implications and concluding remarks

In vitro and in vivo animal studies have provided exciting new insights into the protective effects of LIF during neuroinflammation, but two important concerns, safety and efficacy, remain hurdles for the application of LIF in the clinic. A phase I safety study with recombinant human LIF (rhLIF), AM424 (AMRAD Operations, Australia), has been completed in patients with advanced cancer [65]. LIF, ranging from 0.25 to 16 μg/kg body weight, was administered subcutaneously on a daily basis after

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