In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Abstract

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 demethylated 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.

Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis

“…Careful monitoring of possible autoimmunity (antinuclear antibodies, cutaneous reactions) should be performed if daclizumab treatment is to be used in chronic HCV patients. Interestingly, it has recently been shown that daclizumab therapy maintains a limited population of regulatory T cells in humans and did not lead to adverse cutaneous events [76]. …”

Targeting Monoclonal Antibodies to the Tumor Microenvironment for Cancer Therapy/Immunotherapy

“…In this regard, the in vivo biological activity of nondepleting antibodies to CD25 seems to reinforce rather than inhibit the function of regulatory T cells in mice and humans [14,20] . Additionally, new approaches, including in vivo administration of IL-2 or complexes of IL-2/anti-IL-2 to increase the numbers and functional activity of regulatory T cells are also desired [16,21] .…”

Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases

“…IL-2 is a prime example: the importance of this cytokine in promoting immune tolerance through upregulation of FOXP3 protein would seem to indicate that IL-2 inhibition might induce, rather than treat, autoimmunity, 33 but the efficacy of targeting IL-2 in MS provides a very different view 9, 10 . Whilst daclizumab is efficacious in the treatment of MS, this therapy can be complicated by rash and alopecia, indicative of exacerbation of autoimmunity 9, 10, 34 .…”