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?
Labels: T regs