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本帖最后由 cwy121 于 2012-12-10 12:59 编辑
日前，中科大免疫所田志刚教授课题组在乙肝病毒（HBV）耐受及天然免疫研究领域取得重要进展。他们发现乙肝患者NK细胞高表达抑制性受体NKG2A，抗体阻断NKG2A信号能够使NK细胞功能恢复从而达到清除乙肝病毒的目的。
HBV感染是世界范围内的科学难题，目前依赖于干扰素与核苷类似物常规治疗方法不能彻底清除病毒。本研究发现，活化期的慢性乙肝携带者外周血NK细胞表面NKG2A受体的表达明显高于健康人，而抗体阻断NKG2A可以显著提高乙肝携带者NK细胞的体外细胞毒性。为了进行更深入的机制研究，本研究引入HBV携带小鼠模型, 此小鼠模型展示出与人类HBV携带者非常类似的现象—其NK细胞特别是肝脏NK细胞表面NKG2A分子高表达。进一步的机制研究发现，HBV感染会诱导小鼠肝脏局部产生一群具有调节功能的CD4+T细胞，其分泌的IL-10能够显著上调NK细胞NKG2A的表达进而抑制NK细胞的功能。更为重要的是，在HBV携带小鼠体内利用抗体阻断NKG2A信号可以显著促进小鼠清除HBV病毒。
该研究成果于2012年10月以题为“Blocking the Natural Killer (NK) Cell Inhibitory Receptor NKG2A Increases Activity of Human NK Cells and Clears HBV Infection in Mice”发表在国际著名学术期刊Gastroenterology上。杂志编委指出“本研究揭示了通过阻断NKG2A进而清除HBV感染的生物学原理，具有重要的科研及临床意义）
doi: 10.1053/j.gastro.2012.10.039
PMC:
PMID:
Blocking the Natural Killer (NK) Cell Inhibitory Receptor NKG2A Increases Activity of Human NK Cells and Clears HBV Infection in Mice
Li F, Wei H, Wei H, Gao Y, Xu L, Yin W, Sun R, Tian Z.
BACKGROUND & AIMS:: We studied the functions of natural killer (NK) cells and the role of the NK cell inhibitory receptor (NKG2A) during hepatitis B virus (HBV) infection in patients and mice. METHODS:: We analyzed levels of NKG2A on peripheral blood NK cells from 42 patients with active chronic hepatitis B (CHB), 31 patients with inactive CHB, and 35 healthy volunteers (controls). Five patients with CHB treated with anti-viral therapy were also included, to evaluate changes in NK cells after HBV titers decreased. We examined the effects of blocking antibodies against NKG2A, or its ligand Qa-1 (equivalent to HLA-E in humans), in immunocompetent mice that express HBV from a plasmid and are positive for serum hepatitis B surface antigen (a mouse model of HBV infection). RESULTS:: A higher percentage of NK cells from patients with active CHB were positive for NKG2A (38.47%) than from patients with inactive CHB (19.33%; P <.01) or controls (27.96%, P <.05). The percentage of NKG2A+ cells correlated with serum viral load (r=0.5457, P <.001). The percentage of NKG2A+ cells decreased along with HBV load in patients that received anti-viral therapy ( P <.05). Blocking NKG2A interaction with HLA-E in peripheral NK cells from patients with active CHB increased their cytotoxicity in vitro. NK cells of HBV carrier mice also had higher percentages of NK cells that expressed NKG2A compared with control mice; NKG2A was likely to be upregulated by production of interleukin-10 by hepatic regulatory CD4+CD25+ T cells. Blocking Qa-1 in these mice promoted viral clearance in an NK cell-dependent manner. CONCLUSIONS:: Infection with HBV increases levels of the inhibitory receptor NKG2A on NK cells in mice and humans, and reduces their ability to clear HBV. Reagents designed to block the interaction between NKG2A and HLA-E might be developed to treat CHB infection
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发表于 2012-12-10 12:58
