In vivo maintenance of human regulatory T cells during CD25 blockade

J Immunol. 2015 Jan 1;194(1):84-92. doi: 10.4049/jimmunol.1402140.

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.

Trial registration: ClinicalTrials.gov NCT00390221.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • CD4 Lymphocyte Count
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Daclizumab
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immunoglobulin G / therapeutic use*
  • Immunosuppressive Agents / therapeutic use*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin Receptor Common gamma Subunit / immunology
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / immunology
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / blood
  • Interleukin-2 / immunology*
  • Interleukin-2 Receptor alpha Subunit / antagonists & inhibitors*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-2 Receptor beta Subunit / immunology
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Phosphorylation
  • Promoter Regions, Genetic
  • STAT5 Transcription Factor / metabolism
  • Self Tolerance / drug effects
  • Self Tolerance / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Antibodies, Monoclonal, Humanized
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2 protein, human
  • IL2RA protein, human
  • IL2RB protein, human
  • IL2RG protein, human
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-17
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-2 Receptor beta Subunit
  • STAT5 Transcription Factor
  • Interferon-gamma
  • Daclizumab

Associated data

  • ClinicalTrials.gov/NCT00390221