TNF driving progression

Rossi S, Motta C, Studer V, Barbieri F, Buttari F, Bergami A, Sancesario G, Bernardini S, De Angelis G, Martino G, Furlan R, Centonze D. Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration.Mult Scler. 2013 Jul 25. [Epub ahead of print]


BACKGROUND:Chronic inflammation leads to gray matter damage in progressive multiple sclerosis (MS), but the mechanism linking inflammation and neurodegeneration is unclear.
OBJECTIVE: The objective of this paper is to investigate the synaptic mechanism of inflammatory neurodegeneration in progressive forms of MS.
METHODS: Cytokine and neurofilament-light were determined in cerebrospinal fluid (CSF) of MS patients. In vitro electrophysiology and cell swelling experiments were performed to measure the effects of inflammatory cytokines in the CSF of MS patients on synaptic transmission and neuronal integrity.
RESULTS: Tumor necrosis factor-α (TNF) was higher in CSF of progressive MS subjects, and caused excitotoxic neuronal death in vitro. In murine brain slices incubated in the presence of CSF from progressive MS, in fact, we observed increased spontaneous excitatory postsynaptic currents (sEPSCs) and glutamate-mediated neuronal swelling through a mechanism dependent on enhanced TNF signaling. We also suggested a pathogenic role of B cells in TNF CSF increase, exacerbation of glutamatergic transmission and neuronal damage, since CNS depletion of B cells with intrathecal rituximab caused a dramatic reduction of TNF levels, of TNF-induced sEPSC alterations, and of neurofilament CSF concentrations in a patient with progressive MS.
CONCLUSION: Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.

Damn my patent on TNF inhibition in the CNS has long since expired, but targeting TNF has become a no-no because inhibition of TNF has been attributed to disease worsening. 

This study highlights that you need to treat a disease and not just a mechanism. 

The immunologist world view is that everything revolves around inflammation and T, cells and B cells and block this and you solve everything. 

This study confirms what I have long suspected that TNF is involved in neural signalling. When you have a cytokine storm after alemtuzumab administration, your old lesions become reactivated. This suggests to me that demyelinated pathways may be even more vulnerable to this. So when anti-TNF makes MS worse it may not be just because of immune effects but something to do with neural function. 

That anti-TNF does not worsen EAE is used as a stick to beat the animal modellers, but element may have been lacking in the animal studies as the reagents were never administered to animals with demyelination, so people are comparing chalk with cheese. I wonder what would happen if you gave an animal with demyelination anti-TNF.

Would this slow progression as it is implicated that high TNF levels are damaging. Will Ibudilast inhibit this mechanism?

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