PMID- 21274874
OWN - NLM
STAT- MEDLINE
DCOM- 20110318
LR  - 20220410
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 53
IP  - 2
DP  - 2011 Feb
TI  - Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance 
      reconstitution in type-2 autoimmune hepatitis.
PG  - 536-47
LID - 10.1002/hep.24039 [doi]
AB  - Effector CD4 and CD8 T cell immune responses to cytochrome P450IID6 (CYP2D6), the 
      autoantigen of autoimmune hepatitis type 2 (AIH-2), are permitted by a numerical 
      and functional impairment of CD4(pos) CD25(high) regulatory T cells (T-regs). We 
      aimed to investigate whether T-regs specific for CYP2D6 immunodominant regions 
      and restricted by the appropriate human leukocyte antigen (HLA)-DR molecule can 
      be generated in patients with AIH-2 and can control CD4 and CD8 T cell effectors 
      targeting identical or overlapping CYP2D6 regions. CYP2D6-specific regulatory T 
      cells (CYP2D6 T-regs) were obtained from peptide-pulsed monocyte-depleted 
      peripheral blood mononuclear cells of 17 patients with AIH-2, who were positive 
      for the predisposing HLA-DR7 and/or HLA-DR3 alleles. Their antigen specificity 
      was assessed by cytofluorimetry using HLA class II tetramers and their cytokine 
      profile by intracellular staining. T-reg ability to suppress was ascertained by 
      measuring reduction of CD4(pos) CD25(neg) cell proliferation/effector cytokine 
      secretion and of CD8 T cell cytotoxicity. The most efficient suppression of 
      effector T cell proliferation, inflammatory cytokine release, and cytotoxicity 
      was obtained by coculturing T-regs with CYP2D6-peptide-loaded semimature 
      dendritic cells (smDCs), and smDC-CYP2D6 T-regs also expressed high levels of 
      FOXP3 (forkhead box P3). Possession of the appropriate HLA-DR molecule and 
      recognition of the CYP2D6 autoantigenic sequence were critical to the synergistic 
      smDC-CYP2D6 T-reg immunoregulatory functions, and lack of either element led to 
      poor control of responder cell proliferation and cytokine secretion. Moreover, 
      interferon-gamma neutralization significantly boosted the suppressive ability of 
      CYP2D6 T-regs. CONCLUSION: T-regs generated under CYP2D6-specific conditions and 
      cocultured with smDCs are highly effective at controlling autoreactive T cells, 
      thus providing the basis for a powerful and tailored form of immunotherapy for 
      AIH-2.
CI  - Copyright (c) 2010 American Association for the Study of Liver Diseases.
FAU - Longhi, Maria Serena
AU  - Longhi MS
AD  - Institute of Liver Studies, King's College London School of Medicine at King's 
      College Hospital, Denmark Hill, London, UK.
FAU - Hussain, Munther J
AU  - Hussain MJ
FAU - Kwok, William W
AU  - Kwok WW
FAU - Mieli-Vergani, Giorgina
AU  - Mieli-Vergani G
FAU - Ma, Yun
AU  - Ma Y
FAU - Vergani, Diego
AU  - Vergani D
LA  - eng
GR  - G0902288/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101228
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Autoantibodies)
RN  - 0 (Autoantigens)
RN  - 0 (Cytokines)
RN  - 0 (HLA-DR7 Antigen)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
SB  - IM
CIN - Hepatology. 2011 Feb;53(2):385-8. PMID: 21274860
MH  - Adolescent
MH  - Adult
MH  - Autoantibodies/metabolism
MH  - Autoantigens/*immunology
MH  - CD4-Positive T-Lymphocytes/immunology/pathology/physiology
MH  - CD8-Positive T-Lymphocytes/immunology/pathology/physiology
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Child
MH  - Child, Preschool
MH  - Cytochrome P-450 CYP2D6/*immunology
MH  - Cytokines/metabolism
MH  - Dendritic Cells/immunology/pathology/physiology
MH  - Female
MH  - HLA-DR7 Antigen/metabolism
MH  - Hepatitis, Autoimmune/*immunology/physiopathology/therapy
MH  - Humans
MH  - Immune Tolerance/*immunology
MH  - Immunotherapy
MH  - Infant
MH  - Male
MH  - T-Lymphocytes, Regulatory/*immunology/pathology/physiology
MH  - Young Adult
EDAT- 2011/01/29 06:00
MHDA- 2011/03/19 06:00
CRDT- 2011/01/29 06:00
PHST- 2009/08/19 00:00 [received]
PHST- 2010/10/05 00:00 [accepted]
PHST- 2011/01/29 06:00 [entrez]
PHST- 2011/01/29 06:00 [pubmed]
PHST- 2011/03/19 06:00 [medline]
AID - 10.1002/hep.24039 [doi]
PST - ppublish
SO  - Hepatology. 2011 Feb;53(2):536-47. doi: 10.1002/hep.24039. Epub 2010 Dec 28.