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Nat Commun. 2014 Sep 3;5:4741. doi: 10.1038/ncomms5741.

Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy.

Author information

1
School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
2
Computational Genomics Group, Department of Computer Science, University of Bristol, Bristol BS8 1UB, UK.
3
Division of Biomedical Sciences, Institute of Child Health, University College London, London WC1N 1EH, UK.

Abstract

Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4(+) T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4(+) T cells. Analysis of the CD4(+) T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4(+) T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy.

PMID:
25182274
PMCID:
PMC4167604
DOI:
10.1038/ncomms5741
[Indexed for MEDLINE]
Free PMC Article

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