Bhopale MK, Hilliard B, Constantinescu CS, Phillips SM, Rostami A. DAB389IL-2 recombinant fusion toxin effect on lymphocyte- and macrophage-producing cytokine subpopulation cells in experimentally induced demyelinating disease in mice. Immunopharmacol Immunotoxicol. 2017 :1-12
CONTEXT: We have reported previously that DAB389IL-2 recombinant fusion toxin targets IL-2R bearing CD4+ cells, and suppresses demyelinating disease in acute (A) - and chronic (C) - experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis.
OBJECTIVES: The present study was undertaken to investigate the effect of DAB389IL-2 treatment on various cytokine-secreting cell populations in A-EAE and C-EAE mice.
MATERIALS AND METHODS:The effects of DAB389IL-2 at doses of 200-, 800-, or 1600 kU administered i.v. on days 11-13 and 15 on the clinical score and cytokine-secreting cell populations were examined using flow cytometry.
RESULTS:C-EAE mice treated with 1600kU DAB389IL-2, but not A-EAE mice treated with 800 kU had significantly reduced disease. The CD3+CD25+ sub-population in spleens and spinal cords of A-EAE mice treated with 800 kU DAB389IL-2 a was increased, whereas in C-EAE mice treated with 1600 kU this population was increased. DAB389IL-2 treatment reduced CD3+CD4+, CD3+CD8+, CD4+CD8+, CD3+IL-2+, CD3+IFN-γ+ and CD3+TNF-α+ T cell subpopulations in the spinal cord in A-EAE, and C-EAE mice on day 16. CD11b+ macrophages that were IL-2-, IFN-γ-, and TNF-α- positive were reduced in A-EAE mice. DAB389IL-2 treatment reduced CD19+ B-cells positive for IL-2 or CD11b+ in the spinal cord in acute and chronic disease. DAB389IL-2 treatment also reduced lymph node CD3+CD8+, CD4+CD8+, CD3+CD25+ populations on day 16, and lymph node CD3+IL-10+ and peripheral blood CD3+CD25+ populations on day 24.
DISCUSSION AND CONCLUSIONS: Our study demonstrates that DAB389IL-2 fusion toxin suppresses EAE in a dose-dependent manner, and alters inflammatory cell sub-populations during disease development
One of the flavors of the decade in terms of disease mechanisms has been the identification of Fox3P, CD25+, CD4 T regulatory cells. You can't see a paper these days where this is not the mechanism of action of EAE inhibition.
This is all well and dandy, but in terms of MS there is one nasty fact.
People ignore from their world view.
This is daclizumab.
This antibody blocks CD25 which is the high affinity interleukin2 (T cell growth factor) receptor. Block this and natural killer subsets increase and MS goes away, but a problem is so do the T reg cells as these are depleted.
I was always of a mind-set that that the inhibitory effect is not surprising because the action of daclizumab is because it is simply killing or blocking activated T cells and have more recently switched to thinking it is because it kills activated memory B cells. The NK story is a smoke screen. ProfG disagrees he thinks that this creates and better anti-viral response, due to more NK cells.
However T regs are dogma. They are there to stop autoimmunity developing, which I totally understand. However, one question I have always posed is why would we want to spend a lot of effort to generate an immune response, outside the control of T reg control to give you life long protection, only to have it reeled back in by T regs.
Since T regs were discovered, most studies give the interleukin 2 blocker before disease induction and low and behold it blocks T reg function and autoimmunity gets worse.....Hurrah for dogma.
What happens when this is done after disease has become established?
I have often thought of doing this for a student project, we could by the antibody with their lab expenses and see what happens I predicted nothing or it makes EAE better because EAE is driven by T cells and the blocker blocks activated T cells.
Now I have found a few examples where people block the CD25 molecule after disease has developed and disease gets worse...so hoorah for dogma again.
However I have also seen studies where cladribine stops mouse EAE, however someone forgot to tell the authors that cladribine does not work properly on rodents (don't believe me ask Merck..I did and they should know) and is not T cell immunosuppressive. This could be deduced by reading the early cladribine studies that showed that rodent metabolise cladribine in a different way to humans. We knew this years ago (experiments done in 2004).
So on first read of the manuscript I thought has this had been done
and it didn't block the early acute phase but blocked the chronic phase, but on re-read whilst writing this....I must say uuurgh,
In this study they used a toxin linked to interleukin2 so when it binds to the the CD25 it kills the target. Do this and Eh.....the number of T reg cells increases but T cells decrease and EAE is reduced so hooray dogma persists.
Should I do that study project?