Progression Starts Early

Hampton DW, Serio A, Pryce G, Al-Izki S, Franklin RJ, Giovannoni G, Baker D, Chandran S.

Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol Commun. 2013 Dec;1(1):84. [Epub ahead of print]

Backgound: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.
RESULTS:By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.
CONCLUSIONS:These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis

We have been talking about the best treatment for stopping relapsing disease in animals over the past couple of weeks. This is a transient depletion followed by delivery of the disease causing molecules via an immune tolerogenic route. In this study relapsing neurodegenerative disease was set in motion and then at different time points further relapses were stopped. We then looked to see what had happened in the CNS a few months later. It was clear that despite elimination of relapsing disease some nerve tracts showed progressive neurodegeneration, rather disturbing this occurred even after after a single attack. With each attack different nerve tracts started to degenerate. Therefore even in this simple model of MS it can be seen that relapses cause nerve damage and therefore stopping them, as quickly as possible, is important. Likewise in this case the autoimmune response can trigger a neurodegenerative condition and this progressive neurodegeneration can occur even from disease onset. From a clinical prospective stopping the disease in its tracks early was not associated with marked clinical progression but this could be seen once a number of relapses had occurred. This study further suggests that we should aim to treat early and effectively and to us it suggests that targeting T cells, at least in the periphery will not be the answer to treating progressive MS. This is not something that T cell immunologists/EAEologists are willing to accept or read. Can the odd autoreactive T cell be found in the peripheral blood and/or CNS, yes sure they can be. The immune tolerance needs autoreactive T cells to be present fr it to work. So this allows the doubters to cling to their increasingly flimsy view of T cells causing progressive MS. Yet Neuros continue to try and stop progressive MS by targeting T cell responses. So far targeting these cells in the periphery has uniformly failed to stop progressive MS. 

At what point do you stop and say that some bits of autoimmune dogma are probably not correct

This work from TeamG.

Labels: ,