Thursday, 19 June 2014

Treg function depleted by Daclizumab but functional activity remains

Oh U, Blevins G, Griffith C, Richert N, Maric D, Lee CR, McFarland H, Jacobson S.Regulatory T cells are reduced during anti-CD25 antibody treatment of multiple sclerosis.Arch Neurol. 2009 Apr;66(4):471-9. doi: 10.1001/archneurol.2009.16.

OBJECTIVE:Maintenance therapy with anti-CD25 antibody has emerged as a potentially useful treatment for multiple sclerosis (MS). Constitutive CD25 expression on CD4+CD25+ regulatory T cells (Treg) suggests that anti-CD25 antibody treatment may potentially target a subset of T cells that exhibit immune suppressive properties. We examined changes to CD4+CD25+ Treg in patients with MS receiving maintenance anti-CD25 monoclonal antibody treatment to determine the effect of treatment on Treg and, consequently, on immunological tolerance.
DESIGN:Peripheral blood and cerebrospinal fluid samples obtained from a before-and-after trial of anti-CD25 antibody monotherapy were examined to compare baseline and treatment differences in CD4+CD25+ Treg.
RESULTS: Sustained reduction of the frequency of CD4+CD25+ Treg was observed during treatment. Anti-CD25 antibody treatment led to evidence of impaired in vivo Treg proliferation and impaired ex vivo Treg suppression. Inflammatory MS activity was substantially reduced with treatment despite reduction of circulating Treg, and there was no correlation between changes in the frequency of Treg and changes in brain inflammatory activity. However, new-onset inflammatory disease, notably dermatitis, was also observed in a number of subjects during treatment.
CONCLUSION:The reduction in Treg did not negatively affect maintenance of central nervous system tolerance during anti-CD25 antibody treatment. The incidence of new-onset inflammatory disease outside of the central nervous system in a subset of patients, however, warrants further studies to examine the possibility of compartmental differences in the capacity to maintain tolerance in the setting of reduced CD4+CD25+ Treg.


Huss et al. CD25 blockade with daclizumab alters regulatory T cell dynamics in RRMS patients (THER3P.880) The Journal of Immunology, 2014; no. 1 Supplement136.6

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 indicating that the effect of daclizumab on Treg dynamics may be independent of the therapeutic mechanism of action.
T reg cells are thought to limit the degree of autoimmunity. They express some markers like foxhead P3 and the low affinitiy interleukin2 receptor (CD25). Daclizumab blocks CD25 and would be thought to block T reg function as has been shown, however despite this it seems that they remain a functional regulatory population, However the mechanism of how this antibodiy works is believed to be an action on natural killer cells.

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