As we are in pantomine season when the baddy (ghost) is behind you about to pounch, and when you ask I wonder where the baddy is? The audience shouts out “he’s behind you” and you don’t turn your head, you slowly turn your body as the baddy turns to stay behind your back, so when you turn round, there is nothing there. So you say “Oh no he isn’t” and the audience says “Oh yes he is”. You say “Oh no he isn’t” and they shout louder “Oh yes he is”….It’s comical (OK… you have to be there).
So in sceince every thing that inhibits an inflammatory disease is now due to the action of regulatory cells and this is the “insight” we get here and as the T regulatory cell that doesn’t quite work out, its the regulatory B cells a also. You don’t look anywhere else than that to get an explanation. So if you say it isn’t that the science community shout back loud and clear “Oh yes it is!”. Cells are called regulatory because the cells make IL-10, a T cell inhibitor, but a well known B cell growth factor. But that’s ignored and they are regulatory cells and the science mafia say “bang that into your head”.
However, to be devil’s advocate I say the reason the drug works may not simply because they augments regulatory T cells, my colleagues shout “Oh yes it is”. But the my answer is “It’s behind you as you are not looking in the right place”
However, this is too easy an explanation to say it is all down to regulatory cells. It is the same-old, same-old and every thing works the same way. Therefore, you have to ask why does that one work well and why doesn’t that one work? You are telling me they both work by augmenting T regulatory cells.
So the real reason is…”It’s behind you” you are not looking in the right place. Now I am happy to accept that balance is important, but most evidence suggests that inhibition of T and B cells is not what you really need to combat progressive MS. So I don’t buy the simplistic answer that augmenting regulation of T & B cells is the answer. But, if this really is how siponimod really works, then it says to me we need more than this if we are going to get to the bottom of progressive MS.
What do you think?
Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis. Wu Q, Mills EA, Wang Q, Dowling CA, Fisher C, Kirch B, Lundy SK, Fox DA, Mao-Draayer Y. JCI Insight. 2020 Jan 14. pii: 134251. doi: 10.1172/jci.insight.134251. [Epub ahead of print].
BACKGROUND: Siponimod (BAF312) is a selective sphingosine 1-phosphate receptor 1 and 5 (S1PR1, S1PR5) modulator recently approved for active secondary progressive multiple sclerosis (SPMS). The immunomodulatory effects of siponimod in SPMS have not been previously described.
METHODS:We conducted a multi-centered randomized, double-blind, placebo-controlled AMS04 mechanistic study with 36 SPMS participants enrolled in the EXPAND trial. Gene expression profiles were analyzed using RNA derived from whole blood with Affymetrix Human Gene ST 2.1 microarray technology. We performed flow cytometry based assays to analyze the immune cell composition and microarray gene expression analysis on peripheral blood from siponimod-treated participants with SPMS relative to baseline and placebo during the first year randomization phase.
RESULTS:Microarray analysis showed that immune-associated genes involved in T and B cell activation and receptor signaling were largely decreased by siponimod, which is consistent with the reduction of CD4+ T cells, CD8+ T cells, and B cells. Analysis done by flow cytometry showed that within the remaining lymphocyte subsets, there was a reduction in the frequencies of CD4 and CD8 naïve T cells and central memory cells, while T effector memory cells, anti-inflammatory Th2, and T regulatory (Treg) cells were enriched. Transitional Bregs (CD24hiCD38hi) and B1 cell subsets (CD43+CD27+) were enriched, shifting the balance in favor of regulatory B cells over memory B cells. The pro-regulatory shift driven by siponimod treatment included a higher proliferative potential of Tregs compared with non-Tregs, and upregulated expression of PD-1 on Tregs. Additionally, a positive correlation was found between regulatory T cells and regulatory B cells in siponimod treated participants.
CONCLUSION: The shift toward an anti-inflammatory and suppressive homeostatic immune system may contribute to the clinical efficacy of siponimod in SPMS.
Speaking to MD2 today about what type of science do we do?
MD2 suggested we follow the “Danish School of Science”
This is typified by Hans Christian Anderson…No not fairy tale stuff…but we would rather say the “Emporer has no clothes :-)”