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Modulation of CD4+ T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis
被引:37
作者:
Hashimoto, N.
[2
]
Shimoda, S.
[1
]
Kawanaka, H.
[2
]
Tsuneyama, K.
[3
]
Uehara, H.
[2
]
Akahoshi, T.
[2
]
Kinjo, N.
[2
]
Taketomi, A.
[2
]
Shirabe, K.
[2
]
Akashi, K.
Lleo, A.
[4
]
Ansari, A. A.
[5
]
Gershwin, M. E.
[6
]
Maehara, Y.
[2
]
机构:
[1] Kyushu Univ, Dept Med & Biosystem Sci, Grad Sch Med Sci, Higashi Ku, Fukuoka 8128582, Japan
[2] Kyushu Univ, Dept Surg & Sci, Fukuoka 8128582, Japan
[3] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Toyama 930, Japan
[4] IRCCS Ist Clin Humanitas, Ctr Autoimmune Liver Dis, Dept Internal Med, Milan, Italy
[5] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA
[6] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Sch Med, Davis, CA 95616 USA
关键词:
HCV;
liver cirrhosis;
PD-1;
ligand;
splenectomy;
ADAPTIVE IMMUNE-RESPONSES;
PEGINTERFERON ALPHA-2A;
EXPRESSION;
PD-L1;
THROMBOCYTOPENIA;
PERSISTENCE;
BLOCKING;
THERAPY;
LIGAND;
D O I:
10.1111/j.1365-2249.2011.04393.x
中图分类号:
R392 [医学免疫学];
Q939.91 [免疫学];
学科分类号:
100102 ;
摘要:
Dysfunction of T cells is a common feature in chronic persistent viral infections, including hepatitis C virus (HCV), and although hepatic and peripheral T cells have been studied extensively in chronic HCV hepatitis, the role of splenic T cell responses in such patients is poorly defined. This is an important issue, as thrombocytopenia is a complication of HCV-related liver cirrhosis (LC), due to splenic platelet sequestration and bone marrow suppression; splenectomy has been proposed to treat such patients. Herein, we studied peripheral blood mononuclear cells (PBMC) and splenic lymphoid subpopulations from a total of 22 patients, including 15 with HCV-related LC with marked thrombocytopenia treated with splenectomy, and seven controls. CD4(+) T cells from peripheral blood and spleen were isolated and phenotype and function evaluated. Splenic CD4(+) T cells in patients with LC expressed molecules associated with inhibitory signalling, including increased frequency of negative markers such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) and decreased production of cytokines. Patients with LC manifest higher levels of splenic CD4(+) regulatory T cells and PD-L1- and PD-L2-expressing cells than controls. Blocking of PD-1/PD-1 ligand interaction reconstituted proliferative and cytokine responses of splenic mononuclear cells (SMC) from patients with LC. Splenectomy was followed by an increase in the ratio of interferon (IFN)-gamma to interleukin (IL)-10 and a reduction of PD-1-expressing CD4(+) T cells in peripheral blood. Our data suggest that peripheral tolerance is promoted by the spleen in LC via the up-regulated expression of PD-1 ligands.
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页码:243 / 250
页数:8
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