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: David J Huss, Devangi S Mehta, Akanksha Sharma, Xiaojun You, Katherine A Riester, James P Sheridan, Lakshmi S Amaravadi, Jacob S Elkins, Jason D Fontenot
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 1 Pg. 84-92 (Jan 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25416807 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)

Chemical References

• 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

Topics

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