THE LANCET Neurology Vol 1 July 2002
Two cytokines—ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF)—may play a part in multiple sclerosis (MS) pathology, according to two new papers. To date, the focus of MS research has been on the immunological mechanisms that cause demyelination. However, these new data show that the mechanisms that regulate the integrity of the myelin sheath, as well as glial precursor cell proliferation and oligodendrocyte survival, might also influence disease outcome.
In the first study, Ralf Gold and colleagues (University of Wuerzburg, Austria) showed that CNTF protects oligodendrocytes against apoptosis in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS (Nat Med 2002; 8: 620–24). “We have shown that in CNTF knockout mice EAE takes a more severe disease course corresponding to defective oligodendrocyte precursor cell proliferation, enhanced oligodendrocyte apoptosis, and increased myelin vacuolation associated with axonal damage”, explains Gold. “These specific pathological features could be prevented by treatment with an antiserum against TNF-, suggesting that this cytokine acts as a counterplayer of CNTF.” The same researchers have shown that patients with MS who have a homozygous null mutation within the CNTF gene develop symptoms on average 10 years earlier, and have more severe motor signs, than most patients with MS (Arch Neurol 2002; 59: 407–09).
In the second study, Trevor Kilpatrick and co-workers (University of Melbourne, Australia) showed that administration of LIF, which is from the same family of cytokines as CNTF, preverses the loss of oligodendrocytes in EAE, and reduces its clinical severity (Nat Med 2002; 8: 613–19). “The significance lies in the fact that LIF acts by preventing oligodendroglial cell death, the neural cells that are targeted in MS, rather than by anti-inflammatory mechanisms”, he says.
“We currently do not have appropriate therapy to treat the neurodegenerative component of MS”, says Kilpatrick, who thinks that LIF may be an attractive combinatorial therapy to be used with standard immunomodulators; each could inhibit discrete components of disease pathogenesis. However, “clinical testing of LIF would provide new challenges as standard surrogate markers on MRI such as T2 lesion load and the number of Gadolinium-T1 enhancing lesions will be useless end-points in phase II studies”, he says. “These markers are indicators of the inflammatory component of the disease and LIF is not an anti-inflammatory. Other paradigms that measure the neurodegenerative component of the disease such as the number of ‘black holes’ on T1-weighted imaging might be more applicable.”