Daclizumab and Tregs

Huss DJ, Mehta DS, Sharma A, You X, Riester KA, Sheridan JP, Amaravadi LS, Elkins JS, Fontenot JD.In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade. J Immunol. 2014. pii: 1402140. [Epub ahead of print]

First abstract on pubmed published

Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

Second Abstract on pubmed publish..what happened to the first

Regulatory T cells (Treg) mediate immune tolerance and depend on IL-2 for homeostasis and function. The biology of IL-2 is pleiotropic and complex. As a growth factor for both regulatory and conventional T cells, IL-2 is able to both potentiate and limit adaptive immune responses. Adding to this complexity, IL-2 can signal through a high-affinity (IL-2Rαβγ) and intermediate-affinity (IL-2Rβγ) receptor. Thus, the response to IL-2 at the single cell level is dependent on both receptor expression and local IL-2 concentration. Treg dysfunction is implicated in the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Daclizumab, a humanized monoclonal antibody that binds the IL-2 receptor alpha chain and prevents its association with IL-2, has demonstrated efficacy in patients with RRMS, despite causing a reduction in Tregs. These seemingly contradictory observations led us to investigate Treg dynamics in placebo- and daclizumab-treated RRMS patients in the SELECT clinical trial. We report that CD25 blockade reduces Treg numbers, yet Tregs that remain preserve IL-2 signaling capabilities through the intermediate affinity IL-2Rβγ and maintain epigenetic marks characteristic of a phenotypically stable and functional Treg population. Furthermore, Treg dynamics did not associate with treatment efficacy or development of cutaneous adverse events, indicating that the effect of daclizumab on Treg dynamics may be independent of the therapeutic mechanism of action.

CD25 is an interleukin-2 receptor and is stimulated by interleukin-2 which makes T cells grow and was originally thought to be a target to block activated T cells. Some studies showed that if you target this you can block neuroinflammatory disease.

However, then came along T regulatory cells which express foxhead P3 (Fox3P) transcription factor and CD25. Then all of a sudden all attempts to target this molecule resulted in disease worsening because you block Treg function and these cells are critical to the prevent development of autoimmunity.

However, then came along Daclizumab that blocks CD25, and low and behold, makes relapsing MS better!

So you ask the neuro-mafiosi wheeled out to present the trial data, how this equates to the Treg dogma?. You get some blank looks as they have not thought about it. Perhaps too busy thinking about spending the honorarium for doing the presentation that was probably made by the company slide makers:-)

This paper (coI by the manufacturers of daclizumab) investigates this conundrum and shows that over a year there is a 50% depletion of Treg cells. This is not associated with disease benefit but was not associated with worsening either. It is shown that Tregs remain and that interleukin-2 appears to signal via a different IL-2 receptor and so there function remains the same and so Treg alterations have nothing to do with action of daclizumab

So does this suggest they are critical for controlling immunity and 50% are enough? or are they unimportant once the immune response becomes manifest? 

Does it make a nice fudge such that the TregERS can live to fight another day. Will know more when one can actually read the paper on Journal Immunology as there seems to have been a bit of a mess up.

However, despite CD25 blockage RRMS is treated, probably because natural killer cells are stimulated…what do they do…kill virally infected cells?

This treat can lead to the development of some autoimmunities so maybe Tregs are being blocked?

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