Making T reg cells. Explaining the daclizumab conundrum

How does daclicumab work?

Are immunologists fudging the mechanisms to keep dogma alive?

T regulatory cells that express CD25 and Fox3P are the main way that immunologists think that autoimmunity is blocked.

However, a dirty little fact causes problems:-( as blockade of CD25 to inhibit cell function with daclizumab does not make MS worse, it makes it better. 

But it should make things worse if T regs were blocking established autoimmunity as anti-CD25 blocks T reg function.

An easy way to explain this is that it is blocking activated T cells that express CD25 or more recently you can say that it blocks the CD25 positive memory B cell population and so you don’t have to build T regs into your argument.

Alternatively you spin a story that the high affinity CD25 interleukin two receptor is blocked so that the interleukin two that can’t bind to CD25 stimulates the intermediate affinity interleukin 2 receptor and make natural killer cells, which block MS maybe by killing the MS virus:-)

But one way people con themselves is that daclizumab only regulates T reg function a very little bit, but it doesn’t really fit with the reality as it blocks Tregs a lot more. 

This study says that T regs aren’t stable in a test tube and turn into normal T cells. (Conventional T cells). 

It was suggested that Treg cells that express high levels of CD25 are not properly blocked by anti-CD25 but the conventional T cells that have lower CD25 are completely blocked and so allows growth of T reg so if this happened in vivo then daclizumab would inhibit disease. 

Is this the explanation?

This happens for transforming growth factor beta induced T regs but natural T regs lack stability. 

So what is important in MS?

Wilkinson DS, Ghosh D, Nickle RA, Moorman CD, Mannie MD. Partial CD25 Antagonism Enables Dominance of Antigen-Inducible CD25high FOXP3+Regulatory T Cells As a Basis for a Regulatory T Cell-Based Adoptive Immunotherapy. Front Immunol. 2017  14;8:1782

FOXP3+ regulatory T cells (Tregs) represent a promising platform for effective adoptive immunotherapy of chronic inflammatory disease, including autoimmune diseases such as multiple sclerosis. Successful Treg immunotherapy however requires new technologies to enable long-term expansion of stable, antigen-specific as FOXP3+ Tregs in cell culture. Antigen-specific activation of naïve T cells in the presence of TGF-β elicits the initial differentiation of the FOXP3+ lineage, but these Treg lines lack phenotypic stability and rapidly transition to a conventional T cell (Tcon) phenotype during in vitro propagation. Because Tregs and Tcons differentially express CD25, we hypothesized that anti-CD25 monoclonal antibodies (mAbs) would only partially block IL-2 signaling in CD25high FOXP3+ Tregs while completely blocking IL-2 responses of CD25low-intermediate Tcons to enable preferential outgrowth of Tregs during in vitro propagation. Indeed, murine TGF-β-induced MOG-specific Treg lines from 2D2 transgenic mice that were maintained in IL-2 with the anti-CD25 PC61 mAb rapidly acquired and indefinitely maintained a FOXP3high phenotype during long-term in vitro propagation (>90% FOXP3+ Tregs), whereas parallel cultures lacking PC61 rapidly lost FOXP3. These results pertained to TGF-β-inducible “iTregs” because Tregs from 2D2-FIG Rag1/ mice, which lack thymic or natural Tregs, were stabilized by continuous culture in IL-2 and PC61. MOG-specific and polyclonal Tregs upregulated the Treg-associated markers Neuropilin-1 (NRP1) and Helios (IKZF2). Just as PC61 stabilized FOXP3+ Tregs during expansion in IL-2, TGF-β fully stabilized FOXP3+ Tregs during cellular activation in the presence of dendritic cells and antigen/mitogen. Adoptive transfer of blastogenic CD25high FOXP3+ Tregs from MOG35-55-specific 2D2 TCR transgenic mice suppressed experimental autoimmune encephalomyelitis in pretreatment and therapeutic protocols. In conclusion, low IL-2 concentrations coupled with high PC61 concentrations constrained IL-2 signaling to a low-intensity range that enabled dominant stable outgrowth of suppressive CD25high FOXP3+Tregs. The ability to indefinitely expand stable Treg lines will provide insight into FOXP3+ Treg physiology and will be foundational for Treg-based immunotherapy.

Do you buy the idea?

Also if T regs are so unstable, is this a plausible mechanism of immune control?

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  • Are they sugesting " Adoptive transfer of blastogenic CD25high FOXP3+ Tregs "

    Into humans?

    May not work so well 🙁

    "Further work has shown that T cells are more plastic in nature than originally thought.[17][18][19] This means that the use of regulatory T cells in therapy may be risky, as the T regulatory cell transferred to the patient may change into T helper 17 (Th17) cells, which are pro-inflammatory rather than regulatory cells.[17] Th17 cells are proinflammatory and are produced under similar environments as a/iTregs.[17] Th17 cells are produced under the influence of TGF-β and IL-6 (or IL-21), whereas a/iTregs are produced under the influence of solely TGF-β, so the difference between a proinflammatory and a pro-regulatory scenario is the presence of a single interleukin. IL-6 or IL-21 is being debated by immunology laboratories as the definitive signaling molecule"

    "Of note, although Tregs
    are thought to play a key role in maintaining
    self-tolerance, their adoptive
    transfer after immunoablation together
    with the stem cell graft did not elicit
    additional clinical improvement in a
    murine model of ASCT, but conversely
    resulted in a delayed reconstitution of
    the graft-derived T cell compartment.
    Therefore, Treg therapy should be applied
    with caution as it may hamper
    immune renewal (39).

    Resetting the immune system with immunoablation and
    autologous haematopoietic stem cell transplantation in
    autoimmune diseases


  • Blocking Tregs doesn't seem to be good in MS, and before that Daclizumab can detonate the liver…

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