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J Autoimmun. 2014 Sep;53:26-32. doi: 10.1016/j.jaut.2014.02.001. Epub 2014 Feb 22.

Retinoic acid stabilizes antigen-specific regulatory T-cell function in autoimmune hepatitis type 2.

Author information

1
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK; Section of Paediatrics, Division of Infectious Diseases, Imperial College London, London, UK.
2
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK.
3
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK; Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
4
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK; Paediatric Liver, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London, UK.
5
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK. Electronic address: maria.longhi@kcl.ac.uk.

Abstract

Imbalance between effector and regulatory T-cells (Treg) underlies the loss of immune-tolerance to self-antigens in autoimmune disease. In autoimmune hepatitis type 2 (AIH-2), effector CD4 T-cell immune responses to cytochrome P450IID6 (CYP2D6) are permitted by numerically and functionally impaired Treg. Restoration of CYP2D6-specific Treg in AIH-2 would enable control over effectors sharing the same antigen specificity, leading to re-establishment of immune-tolerance. We have previously developed a protocol for generating antigen-specific Treg through co-culture with semi-mature dendritic cells presenting CYP2D6 peptides. In this study, we aimed to explore phenotypic and functional features of patient Treg compared to health, to test Treg stability under pro-inflammatory conditions, and to investigate the potential benefit of supplementation with all-trans-retinoic acid (RA) or rapamycin (RP), agents proven to enhance Treg function. We show that antigen-specific Treg from patients have comparable phenotypic and functional features to those from healthy controls, suppressing both proliferation and pro-inflammatory cytokine production by effector cells. Treg exposure to inflammatory challenge results in decreased suppressive function and up-regulation of Th1/Th2/Th17 transcription factors both in health and AIH-2. The increase of Th1 and Th17 transcription factors is limited by addition of RA in controls and Th1 expression is decreased by RP in patients. Importantly, inflammation-induced decrease in Treg function is also abrogated by RA/RP in health and RA in patients. Our data provide important information for the optimization of protocols aiming at generating antigen-specific Treg for treatment of autoimmune disease and for understanding their biology upon pro-inflammatory challenge and RP/RA supplementation.

KEYWORDS:

Autoimmune liver disease; Liver autoantigen; Regulatory T-cell immunotherapy; Stability; Tolerance

PMID:
24566085
DOI:
10.1016/j.jaut.2014.02.001
[Indexed for MEDLINE]

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