In vivo maintenance of human regulatory T cells during CD25 blockade.
J Immunol
; 194(1): 84-92, 2015 Jan 01.
Article
in En
| MEDLINE
| ID: mdl-25416807
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 a subunit (IL-2R a 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- g, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2R bg 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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Immunoglobulin G
/
Interleukin-2
/
T-Lymphocytes, Regulatory
/
Multiple Sclerosis, Relapsing-Remitting
/
Interleukin-2 Receptor alpha Subunit
/
Antibodies, Monoclonal, Humanized
/
Immunosuppressive Agents
Type of study:
Clinical_trials
Limits:
Humans
Language:
En
Journal:
J Immunol
Year:
2015
Type:
Article