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.
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.