title: 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 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.
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: David J
authors.initials: DJ
authors.lastname: Huss
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: Devangi S
authors.initials: DS
authors.lastname: Mehta
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: Akanksha
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: Xiaojun
authors.initials: X
authors.lastname: You
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Riester
authors.affiliation: AbbVie Biotherapeutics, Redwood City, CA 94063
authors.forename: James P
authors.initials: JP
authors.lastname: Sheridan
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Amaravadi
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Elkins
authors.affiliation: Biogen Idec, Cambridge, MA 02142
authors.forename: Jason D
authors.initials: JD
authors.lastname: Fontenot
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D000077561:Daclizumab; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D053631:Interleukin Receptor Common gamma Subunit / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000276:immunology; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050799:STAT5 Transcription Factor / Q000378:metabolism; D017634:Self Tolerance / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508594:IL2 protein, human; C508017:IL2RA protein, human; C508020:IL2RB protein, human; C507941:IL2RG protein, human; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053631:Interleukin Receptor Common gamma Subunit; D020381:Interleukin-17; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma; D000077561:Daclizumab