A new model for Primary Progressive MS

Waisman A, Regen T. A new model for primary-progressive multiple sclerosis? Acta Neuropathol. 2013 Sep  [Epub ahead of print]

Hurray I say a new model for progressive MS will help us examine treatments. This is claimed for a mouse model that develops disease very slowly and get sick from 3-4 months and most have moderate disease by 1 year. However this is an editorial about another paper  

Lowther EL et al. Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response. Acta Neuropathol 2013 Sept [Epub]

Multiple sclerosis is considered a disease of complex autoimmune etiology, yet there remains a lack of consensus as to specific immune effector mechanisms. Recent analyses of experimental autoimmune encephalomyelitis, the common mouse model of multiple sclerosis, have investigated the relative contribution of Th1 and Th17 CD4 T cell subsets to initial autoimmune central nervous system (CNS) damage. However, inherent in these studies are biases influenced by the adjuvant and toxin needed to break self-tolerance. We investigated spontaneous CNS disease in a clinically relevant, humanized, T cell receptor transgenic mouse model. Mice develop spontaneous, ascending paralysis, allowing unbiased characterization of T cell immunity in an HLA-DR15-restricted T cell repertoire. Analysis of naturally progressing disease shows that IFNγ+ cells dominate disease initiation with IL-17+ cells apparent in affected tissue only once disease is established. Tregs accumulate in the CNS but are ultimately ineffective at halting disease progression. However, ablation of Tregs causes profound acceleration of disease, with uncontrolled infiltration of lymphocytes into the CNS. This synchronous, severe disease allows characterization of the responses that are deregulated in exacerbated disease: the correlation is with increased CNS CD4 and CD8 IFNγ responses. Recovery of the ablated Treg population halts ongoing disease progression and Tregs extracted from the central nervous system at peak disease are functionally competent to regulate myelin specific T cell responses. Thus, in a clinically relevant mouse model of MS, initial disease is IFNγ driven and the enhanced central nervous system responses unleashed through Treg ablation comprise IFNγ cytokine production by CD4 and CD8 cells, but not IL-17 responses.

Em my bubble may have been burst, because I was thinking of something that may not of had T cells at is core, given the failure so far of T cell therapies to halt progressive MS.

However, it says that it is the Th1 cells not the Th17 cells that are doing the business. Now it may be argued by some that the Th17 type are a staging development before cells become Th1. Whilst many immunologists believe it is the Th17 cells that are the problem, this late arrival of Th17 after Th1 cells can be seen in quite a few other EAE models and as said many times that inhibition of Interleukin 17 does limited stuff in early EAE. 

Next also show that Tregs stop you from getting autoimmunity, so blocking Treg formation may not be a good thing. Interestingly when they come back disease slows, but is this because of burn out of the disease from the one-hit EAE that occurs in C57BL/6 background mice. Could this be progression that starts with T cells and becomes T cell independent

What would be their response to immunotherapy? 

Maybe a project to look at the histology, after all I have seen these mice

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