I used to jest about glatiramer acetate (GA) and its mechanism of the month. It seems to get one every few months and that perhaps was because of the label where is was said to target the mechanism thought to be responsible for MS. So as a new mechanism came along, sure enough GA was shown to act on that mechanism.
This is all well and dandy but I always said that it must work on the mechanism not so well, because if it was so good at stopping a mechanism that is essential for MS, then it would be a High efficacy drug and work on everyone.
Is GA a high-efficacy drug? Not for many people according to the trial results.
Now we had the B cell gurus telling us/infering that ocrelizumab works because it inhibits T cells and CD8 T cells at that. Do all high efficacy drugs affect CD8 T cells?….alemtuzumab is pretty good, cladribine is so-so, but now we have teriflunomide inhibiting CD8 T cells according to the recent report
Tilly G, Cadoux M, Garcia A, Morille J, Wiertlewski S, Pecqueur C, Brouard S, Laplaud D, Degauque N. Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells. Front Immunol. 2021 Oct 5;12:730342. doi: 10.3389/fimmu.2021.730342
Background and objectives: Inhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide.
Methods: High-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles.
Results: We found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism.
Discussion: Overall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS.
So Teri does not affect B cells so either my hypothesis is wrong or teri is not a very potent DMT. I can’t have it both ways.
Now I have to say they did not even look at memory B cells and this just goes to show that most people think our ideas are a crock of SH1. But you put in all that effort to look into Th1, TH17 ThX, ThY and dont look at B cell subsets.
However I also look at the CD8 data and it doesnt really smack me in the eye that something major is going on, But there may be did effects for individuals. So if CD8 cells are important in MS then maybe it says teriflunomide could be better. We sort of know this don’t we because companies still do trials of their next great hope against teriflunomide with the view that they will get better success.
If the answer is CD8 how do ou prove or disprove it. It makes me think a CD8 specific blocker will be developed. Is this what we want
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