Thursday, 5 May 2016

T cells for secondary progressive MS

Takashi Yamamura, Ben J.E. Raveney, Shinji Oki
Study of eomesodermin-expressing CD4+ T cells sheds new light on the pathogenesis of secondary progressive multiple sclerosis

In the pathology of multiple sclerosis (MS), T helper type 1 (Th1) cells secreting interferon-γ and Th17 cells producing interleukin-17 are linked with acute inflammation in the relapsing–remitting form of MS. Supportive of this, transferring Th17 cells and Th1 cells reactive to central nervous system myelin can induce the animal model for MS – experimental autoimmune encephalomyelitis (EAE). We have recently shown that CD4+ T helper (Th) cells distinct from Th1 or Th17 cells, whose functions depend on the transcription factor eomesodermin (Eomes), are pathogenic for chronic neuroinflammation associated with the late stage of EAE. For analysis, we actually used mice whose T cells lack expression of NR4A2, a critical transcription factor for Th17 cells,which is upregulated in the peripheral blood T cells from relapsing–remitting MS. In a series of experiments, we showed that a standard form of EAE induced in C57BL/6 mice with MOG 35–55 peptide is dissected by the early stage mediated by Th17 cells expressing NR4A2 and the late stage mediated by the Eomes+ Th cells. Interestingly, the Eomes+ Th cells were found to increase in the peripheral blood and cerebrospinal fluid of patients with the secondary progressive form of MS (SPMS), but not of relapsing–remitting MS, indicating that the results in chronic EAE have translational implications for understanding human SPMS.

Raveney BJ, Oki S, Hohjoh H, Nakamura M, Sato W, Murata M, Yamamura T.Eomesodermin-expressing T-helper cells are essential for chronic neuroinflammation.Nat Commun. 2015;6:8437.

A conventional experimental autoimmune encephalomyelitis (EAE) model induced in C57BL/6 mice with MOG35–55 (control) shows persistent paralysis lasting more than several months. 

(Funny that when you have lost all the nerves in the spinal cord that you find that you can't walk:-) and it is interesting that it is OK to leave mice paralysed for several months...only in the Far East? 
So much for the 3Rs and ethical review of animal experiments!)

In a recent study , it was reported that late-onset EAE was induced in mice whose T cells lack expression of NR4A2, a transcription factor for T helper type 17 cells (NR4A2 KO). The results allowed us to conclude that EAE can be separated into the acute and late stage, characterized by acute inflammation caused by NR4A2 + T cells and the late stage, which is independent of NR4A2 expression, but dependent on eomesodermin-positive cytotoxic T helper cells.

So this study makes the idea that Eome expressing T cells drive secondary progression

Eomes is known to associate with natural killer cells and CD8+ cytotoxic T cells. Reminiscent of this, the Eomes+ Th cells were found to have cytolytic potentials that are mediated by granzyme B. We have also data suggesting that granzyme B plays a critical role in the neurodegeneration associated with chronic EAE. A variety of immunological and pharmacological interventions, including granzyme B siRNA, proved to be efficacious for treating the chronic EAE induced in NR4A2 conditional knockout mice.

Currently, there is no approved drug for SPMS. The pathogenesis of SPMS remains obscure, though the presence of germinal center in the central nervous system from SPMS autopsy cases suggests the role of autoantibody and immune-mediated pathology. Our study shows that the Eomes+ Th cells and their functional molecules are a potential target for therapy in SPMS. It is also possible that the Eomes+ Th cells might be involved in the chronic neuroinflammation associated with other inflammatory or neurodegenerative disorders. To answer the questions, further characterization of the Eomes+ Th cells and study of developmental pathways for the unique CD4+ T cells are underway 

You have been claiming there are no new ideas on blog so here is one that secondary progression is caused by T cells expressing Eomes and these are more common in MS.
However, is the blood is going to contain loads and loads of the disease causing cells? Or is it likely that they are only a very tiny fraction of the blood cells. 

So if you are seeing loads of eomes is it going to be disease-related? or maybe age-related? as people with secondary progressive MS are going to be older and eight years older in this case?

Recently we had Steinman L, Zamvil SS. (Beginning of the end of two-stage theory purporting that inflammation then degeneration explains pathogenesis of progressive multiple sclerosis. claiming its all B cells and immunology and now here is another one...

Secondary progression is caused by T cells. They
express Eomesodermin also known as T-box brain protein 2 (Tbr2) and knockout of this affects nerve development and have small brains. These eome expressing cells make granzyme which is a toxin protein made by T cells.

So MS is all autoimmunity

Only one spanner in the works is why has T cell immunotherapy such as with alemtuzumab and HSCT not halted secondary progression?  

Why was this issue not addressed in the paper..Simple question to ask?

Is it  just rubbishy EAE with very late onset? 

Will it ever be repeated?


  1. In this point of view, fingolimod or natalizumab may be better option...

  2. Natalizumab failed in SPMS according to Biogen yet T-cells are still considered therapy for SPMS. Maybe the drug needs access into the CNS in order to work. The intrathecal study of B-cell therapy failed in the NIH study. Are we trying to fit a square peg into a round hole?

  3. Am very confused, this is like feeding my 3 year old; one night pepperoni pizza is all good yet on another night she has to have the 'yucky bits' removed.

  4. It shows you that for any one situation there can be different views about the mechanisms of anything.

    Maybe T cells can cause secondary progression and if true then we have a treatment or rather a few treatments ready made.

    But if this is the case we need to repeat it and then explain response to therapy in MS

  5. Then the "ideal therapy" would be one that bleached B cells, which is involved seems to onset of the disease, and T cells and Eomes, which are implicated in the perpetuation, and progression of the disease?

    So Natalizumab, fingolimod and alemtuzumab in SPMS not produce significant results positively because it does not target Eomes?

    Daclizumab could act Eomes then ja'que far as I remember it acts in natural killer cells?

    Ocrelizumabe would act then in Eomes?

    There are many questions ...


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