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.
引用
收藏
页码:243 / 250
页数:8
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