EAE Dogma..is it down the pan again? Tregulatory cells dogma biting the MS dust

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Yesterday ProfG was abit controversial and today I am going to be. Let’s see what the EAEers have to say about this one. I have been around long enough to see dogmas come and go. When a dogma is formed it seems that every treatment that works , works by the mechanism of day. When you get an old timer like me you see that some people forget their own work because the same experiments works by CD8 suppressors, anergic cells, CD4 Th2 cells and then came CD4 T regulatory cells. They have a marker called Fox3P. It makes you think you should not believe them and you need to do it yourself as you can’t trust their judgement after all, how does a CD8 T cell become a CD4 T cell become a regulatory B cell.?

The EAE Dogma machine say that T regulatory cells are the reasons why so many treatments work in MS, because they control MS. So the obvious experiment for the neuros to do is augment their function or Transfer them in. NDG did the first experiment by giving interleukin-2 and maybe cured PML, so it could be done in MS did their MS disappear forever. Then came daclizumab and blocked the interleukin-two receptor and blocked T reg function and guess what happened..,Yep it inhibited not enhanced MS, Guess what? This isn’t acknowledged by the establishment. Luckily for them daclizumab use was withdrawn and did not need to be discussed.

Now I get why the body would want to keep the immune system in check and not waste energy making pointless immune responses, once the immune response has been generated, e.g. to fight infectiom why would you want to get rid of it. The T cell receptors for an infection are surely essentially the same of an autoimmune T cell receptor as it is the fine receptor specificity that make it autoimmune or not. Would the immune system sense this. There are suprisingly very very few mouse studies where T regulatory function is augmented or Transfered after the first attack to prevent relapse.

This experiment is done here just like the mouse experiments where the T regulatory cells and they are injected intravenously. In themouse this inhibits EAE but MS it does nothing. The intrathecal experiment is too small to be informative, but as we know T regulatory cells make cytokines that are repair factors.So it will be interesting to see how this is explained not enough T regulatory cells transferred the wrong type of cells. But is MS, EAE? or are EASers dreamers who follow dogma abit too much? or is it another example of poor replication of the animal data.

Administration of CD4(+)CD25(high)CD127(-)FoxP3(+) Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study.Chwojnicki K, Iwaszkiewicz-Grześ D, Jankowska A, Zieliński M, Łowiec P, Gliwiński M, Grzywińska M, Kowalczyk K, Konarzewska A, Glasner P, Sakowska J, Kulczycka J, Jaźwińska-Curyłło A, Kubach M, Karaszewski B, Nyka W, Szurowska E, Trzonkowski P.BioDrugs. 2021 Jan 5. doi: 10.1007/s40259-020-00462-7

Background: Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (Tconv) cells break the blood-brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4+CD25highCD127FoxP3+ T regulatory (Treg) cells may inhibit this destruction through suppressive activity exerted on Tconv cells.

Methods: We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous Treg cells for relapsing-remitting MS. The patients received either expanded ex vivo Treg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 106 Treg cells/kg of body weight) or freshly isolated Treg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 106 Treg cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up.

Results: No severe adverse events were observed. Self-assessed quality of life (EuroQol-5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of Treg cells or Tconv cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, Treg cells in all patients consisted of two different phenotypes: peripheral Treg cells Helios(-) (≈ 20%) and thymic Treg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group.

Conclusions: No serious adverse events were reported in the 14 patients with MS treated with Treg cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety.

Trial registration: EudraCT: 2014-004320-22; registered 18 November 2014.

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MouseDoctor

3 comments

  • I read manny manny moons ago that when you inject Treg in the blood most of them died

    It would be interesting to see if they hang aroud after infusion

    Have to look for that study

    • I totally agree based on my own experience. This is the main challenge with these transfer experiments – the survival of the transferred cells. I have tried to transfer iv Foxp3+ T cells that express GFP several times and I could never detect them afterwards in any organ. In a human setting, how can you verify that the injected Tregs have survived? Before answering that, the “Treg dogma” cannot be rejected.

      • Thanks for the info…..I heard of some people doing a cMV trial they grew up a 100 million cells for each person and they were all dead the next day…They had CD95 FAS on them and all comitted FAs-mediated suicide.

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