Tuesday, 5 April 2016

And the T cells are back...

Mol Neurobiol. 2016 Mar 29. [Epub ahead of print]

Cytokine Profile in Patients with Progressive Multiple Sclerosis and Its Association with Disease Progression and Disability.

Kallaur AP, Oliveira SR, Simão AN, Alfieri DF, Flauzino T, Lopes J, de Carvalho Jennings Pereira WL, de Meleck Proença C, Borelli SD, Kaimen-Maciel DR, Maes M, Reiche EM.

Abstract

Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability.

We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay.

IL-1β, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1β and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patients with progressive MS with disease progression presented higher TNF-α, IFN-γ, and IL-10 levels than those without disease progression. Patients with progressive MS with disease progression showed a higher frequency of positive gadolinium-enhanced lesions in MRI; higher TNF-α, IFN-γ, and IL-17 levels; and decreased IL-12 levels compared with RRMS patients with progression. There was a significant inverse correlation between IL-10 levels and EDSS score in patients with progressive MS. The results underscore the complex cytokine network imbalance exhibited by progressive MS patients and show the important involvement of TNF-α, IFN-γ, and IL-17 in the pathophysiology and progression of the disease. Moreover, serum IL-10 levels were inversely associated with disability in patients with progressive MS.

Figure: T cell immunity

So the T cells never left? And if you have been following our blog for some time, you'd agree that the T cell/B cell box set is prime time watching without the cliffhanger ending.

But, what do we have extra from this group?
  • There is an imbalance in the cytokine pathway in progressive disease, this includes Th1 (IFN-γ), Th2 (IL-4, IL-10), Th17 (IL-17) and Treg (IL-10) cytokines.
  • Over the short-term (five years) progressive patients had increased TNF-α, IFN-γ, and IL-10 levels compared with those without disease progression. 
  • Serum IL-10 levels were inversely correlated with the disability of progressive MS patients and therefore an endogenous anti-inflammatory response is essential.

I'll be adding this to the other tidbits of knowledge gleaned over the years: 1) MS is an autoimmune disorder; 2) T cell activity, whether it be good (IL-10, TGF-β) or bad (IL-1, IL-2, TNF-α, IFN-γ) plays an important role in MS; 3) There is no predefined end point, ergo immunosupression/immune modulation should work at all stages of disease (and should be heeded even in progressive trials).

9 comments:

  1. Hum ...
    Why do not we see a clinical trial looking at the simultaneous action of B and T cells? Or only T cells or only B ...

    ReplyDelete
    Replies
    1. Good question, firstly clinical trials perform analysis on all biological parameters, but only those relevant to the perceived mode of action of the trial drug in question see the light of day. Secondly, the duration of most clinical trials isn't long enough to make hard conclusions about what is happening in the disease. If you look at the old long term natural history studies following patients from their first presentation through to current day, they are MRI studies. We know very little about what happens in the evolution of the disease biologically on a large scale in adult MSers.

      Delete
    2. Alemtuzumab, cladribine both hit T and B

      Delete
  2. Fingolimod increased the regulatory B cells rates in relation the whole B cells family (into the blood, and the CNS). Reg B cells products IL-10, which inversely correlates the EDSS.
    And there was an ACTRIMS forum study which suggests that Gilenya can be effective in secondary progressive ms.
    https://actrims.confex.com/actrims/2016/meetingapp.cgi/Paper/1484
    What is your opinion?

    ReplyDelete
    Replies
    1. Fingolimod failed in large trial in PPMS.I do not believe there is something fundementally different between PPMS and SPMS (bar obvious relapses).It is not being tested in SPMS but would think the same fate would hapen in SPMS. This is a small trial but interesting Siponimod is being tested in SPSM as we write if this is positive it will please Novartis as the fingolimod patent soon expires.

      IL-10 also comes from macrophages

      Delete
  3. Why do you think that current DMDs with B and T cell inhibition, like Alemtuzumab, have failed thus far in progressive MS patients?

    ReplyDelete
    Replies
    1. Please read education posts education bar above. teaching posts

      Pathways to progression why don't relapsing remitting drugs work in progressive MS
      http://multiple-sclerosis-research.blogspot.com/2015/04/education-pathways-to-progressive-ms.html

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.