栗占国
主要致力于类风湿关节炎发病机制及免疫治疗的研究。
个性化签名
- 姓名:栗占国
- 目前身份:
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学术头衔:
博士生导师
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学科领域:
临床医学
- 研究兴趣:主要致力于类风湿关节炎发病机制及免疫治疗的研究。
多年来主要致力于类风湿关节炎发病机制及免疫治疗的研究。先后承担多项国家自然科学基金、国家杰出青年基金、中华医学专项人才基金及教育部跨世纪优秀人才基金等研究项目。基金资助达487万元。在《Immunology》、《Eur J Immunology》、《Cell Immunology》、《Arthritis Rheumatism》、《中华内科杂志》、《中华风湿病杂志》及《中国免疫学杂志》等英美及国内免疫和风湿病学刊物上发表论文120篇,包括英文论文25篇。曾获澳大利亚及美国的研究基金两项。1993年获悉尼大学RNSH“突出成就奖”(Outstanding Achievment),1995获Westpac“全国年度医学奖”。先后获2001瑞士国际风湿病年会、欧洲抗风湿病联盟年会 (2002) 等国际性学术大会 “最佳论文奖”,《中华风湿病杂志》优秀论文一等奖 ( 2003),并多次获全国免疫及风湿病会议优秀论文奖。主编或参与编写了8部风湿病及免疫学专著。目前, 指导博士及硕士研究生近20名。现为《Scand J Immunology》、《中华医学杂志》、《中华内科杂志》、《中华医学杂志》(英文版)、《中国免疫学杂志》及《中华风湿病杂志》等七种刊物的编委或审稿人。现任中华医学会风湿病分会副主任委员;全国临床免疫学会副主任委员;北京免疫学会常务理事;国家自然科学基金委及北京市自然基金委评委。
研究工作主要集中在自身免疫反应的中心环节-HLA-DR、抗原及T细胞受体 (TCR) 三分子在类风湿关节炎 (RA) 发病中的作用,分别对RA的相关抗原、TCR抗原识别链 (α链和β链)及HLA-DRB1的RA共同表位进行了深入研究,并取得多项成果。近年来利用HLA-DR4/DR1转基因细胞系及RA患者PBMC的研究发现HLA-DRB1分子与抗原相互作用时存在模糊识别。为多种HLA-DRB1亚型及抗原参与RA发病的理论提供了试验依据。
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【期刊论文】小剂量激素治疗类风湿关节炎不良反应的回顾性临床分析
栗占国, MU Rong*, WANG Su-mei, LU Chuan-hui, LI ZHan-gou
中华风湿病学杂志,2005,9(5):303~305,-0001,():
-1年11月30日
目的 分析小剂量糖皮质激素(GCs)治疗类风湿关节炎(RA)的不良反应。为GCs的临床应用提供借鉴。方法 回顾性随机记录164例RA患者的用药史。并分析应用小剂量GCs(≤10m-d)与高血压、糖尿病、非外伤性骨折、消化道溃疡、白内障、青光眼和高脂血症等不良反应之间的相关性。结果164例RA患者中。曾使用过GCs治疗者68例。占4l.5%。其中。小剂量GCs治疗6个月以上者47例(287%)。长期应用中大剂量GCs治疗者8例(49%)。应用剂量不详者13例(79%)。与未用过GCs组相比。小剂量GCs组的高血压和糖尿病发生率无明显增加(P>0.05)。但高脂血症发生率明显较高(艮0.05)。发生非外伤性骨折、白内障及青光眼的患者例数较少。尚难评价其意义。结论初步研究提示。小剂量GCs治疗对血压和血糖的影响不显著。但可能增加高脂血症等不良反应的发生率。
糖皮质激素类, 关节炎.类风湿, 消炎药.非甾类, 不良反应
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【期刊论文】C反应蛋白在鉴别系统性红斑狼疮活动与合并感染中的意义
栗占国, AN Yuan, LI Ru, LI Zhan-guo. Departmeta of Rheumatology and Immunology
中华风湿病学杂志,2005,9(5):299~302,-0001,():
-1年11月30日
目的 通过分析系统性红斑狼疮(systemic lupus erythematosus, SLE)病情活动和合并感染患者的临床和血清学特点,发现对疾病活动和感染有鉴别意义的指标。方法 对2003-2004年在我科住院的110例SLE患者进行回顾性分析,比较病情活动未合并感染者87例(未感染组)和合并感染者23例(感染组)的发热、皮疹、口腔溃疡、脏器损害等临床表现。同时分析患者的C反应蛋白(CRP)。血沉(ESR),血清蛋白电泳(白蛋白、α1球蛋白、α2球蛋白、β球蛋白、γ球蛋白),补体(C3、C4),免疫球蛋白(IgA、IgM、IzG)及免疫复合物(CIC)的变化。结果 感染组CRP、ESR及α1球蛋白高于未感染组(P<01)。通过比较CRP、ESR及α1球蛋白与其他临床指标的相关性,发现CRP受感染之外的影响较少,在未感染组CRP浓度的均数在正常水平。合并感染后明显升高。感染组患者的发热、口腔溃疡、雷诺现象、心脏损害及糖皮质激素用量均高于未感染组(P<05)。结论 (1)sLE合并感染时大部分患者的cRP明显升高。②在狼疮活动时CRP大多正常或略高,但少数患者。尤其合并浆膜炎者的CRP水平可较高。CRP对于鉴别狼疮活动与合并感染有重要的临床应用价值。
红斑狼疮,, 系统性, 感染, C反应蛋白质
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【期刊论文】Altered collagen II peptides inhibited T-cell activation in rheumatoid arthritis
栗占国, Ru Li, Xia Li , Zhanguo Li *
Clinical Immunology 118(2006)317-323,-0001,():
-1年11月30日
It has been reported that collagen II (CII)-derived peptide induced T-cell activation via its amino acids responsible for T-cell receptor (TCR) recognition. In this study, three altered CII263–272 peptide ligands (APL) containing multiple substitutions of TCR contact residues were synthesized. Their roles in inhibition of T-cell activation were evaluated in peripheral blood lymphocytes (PBL) of rheumatoid arthritis (RA) in vitro. It was shown that 41% (25/61) of RA patients were responsive to the wild-type antigenic CII263-272. In contrast, marginal or silent T-cell responses to the three APLs were found, accompanied by inhibitory effects on secretion of Th1 type cytokines and expression of cell surface markers, CD69 and CD25. In addition, T-cell activation induced by the wild-type antigenic CII263-272 was inhibited by all the three APLs in a dose-dependent manner. It is demonstrated that APLs with substitutions of TCR contact residues are capable of down-regulating T-cell responses in PBLs of RA, suggesting that the CII-derived APLs are potentially therapeutic in RA. D 2005 Elsevier Inc. All rights reserved.
Collagen II peptides, T-cell activation, Rheumatoid arthritis
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栗占国, X. Li, , R. Li, * & Z. Li
Tissue Antigens 67(2006)45-52,-0001,():
-1年11月30日
Collagen (CII) 263-272 peptide, an autoantigen in rheumatoid arthritis, is a specific human leukocyte antigen (HLA)-DR1/4-binding peptide recognized by T-cell receptors (TCR). The affinity of influenza virus haemagglutinin (HA) 306- 318 peptide for the antigen-binding groove of HLA-DR1/4 molecules is higher than that of CII263-272. The HLA-DR1/4-binding residues of HA306-318 are located in the region 308-317. Altered HA308-317 peptides with substitutions of TCR-contact residues may inhibit HLA-DR1/4-specific T-cell activation by blocking the antigen-binding site of HLA-DR1/4 molecules. To evaluate the role of altered HA308-317 peptides in HLA-DR1-restricted T-cell activation, we synthesized three altered HA308-317 peptides. The specific binding of altered HA308-317 peptides to HLA-DR1 molecules was examined using flow cytometry. Effects of altered HA308-317 peptides on HLA-DR1-specific T-cell hybridoma were studied by measuring T-cell proliferation and surface expression of CD69 or CD25. The results showed that altered HA308-317 peptides were able to bind to HLA-DR1 molecules and competed with CII263-272 or wildtype HA308-317 peptide. Compared with wildtype CII263-272 or HA308-317, altered HA308-317 peptides did not stimulate significant T-cell proliferation and CD69 or CD25 expression. Furthermore, the altered HA308-317 peptides inhibited HLADR1-specific T-cell activation induced by CII263-272 or wildtype HA308-317 peptide, which may suggest an effective therapeutic strategy in inhibition of HLA-DR1-specific T-cell responses in autoimmunity.
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【期刊论文】Antibodies to a-fodrin derived peptide in Sjogren's syndrome
栗占国, J He, Q L Chen, Z G Li
Ann Rheum Dis 2006; 65: 549-550.,-0001,():
-1年11月30日
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【期刊论文】The Inhibitory Effect of Altered Collagen II Peptide on HLA-DRB1-Restricted T-Cell Activation
栗占国, Y. J. Cheng, Q. Zhou & Z. G. Li
2005 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 61, 260-265,-0001,():
-1年11月30日
It has been known that rheumatoid arthritis (RA)-associated antigenic peptides CII263–272 are coupled with human leucocyte antigen (HLA)-DRB1 and recognized by T-cell receptor (TCR), which in turn induced T-cell proliferation and pathogenesis of RA. Non-T-cell-stimulating type II collagen (CII) peptides might be generated by removing the amino acids responsible for TCR contact and keeping the HLA-DR-binding residues intact. In this study, a panel of altered CII peptides (APs) with consecutive or single substitutions of the TCRcontacting residues were synthesized. Through peptide binding and T-cell activation assays, we demonstrated that altered CII263–272 peptides with substitution of the TCR-contacting residues did not or barely induced T-cell activation; one of the best non-T-cell-stimulating peptide AP268–270 inhibited the binding of wild-type CII263-272 to HLA-DR1 and T-cell activation triggered by wild-type CII263–272 and HA306-318 in a dose-response manner. These data suggest that removal of the TCR-contacting residues of CII263-272 leads to HLA-DRB1 binding and low T-cell-stimulating peptides, which could potentially inhibit the T-cell response induced by HLA-DRB1-binding antigenic peptides.
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【期刊论文】T cell vaccination in systemic lupus erythematosus with autologous activated Tcells
栗占国, Z-G Li*, R Mu, Z-P Dai and X-M Gao
Lupus (2005) 14, 884-889,-0001,():
-1年11月30日
Systemic lupus erythematosus (SLE) is an autoreactive Tcell mediated autoimmune disease. Immunization with inactivated autoreactive Tcells may induce idiotype anti-idiotypic reaction to deplete specific subsets of autoreactive Tcells involved in SLE. Six SLE patients unsuitable or refused to use immunosuppressants were treated with Tcell vaccination. Their clinical manifestations and laboratory parameters including mixed lymphocyte reactions were evaluated. Autoreactive Tcell clones were derived from peripheral blood mononuclear cells of the patients and 1 107 irradiated Tcells were inoculated subcutaneously at 0, two, six and eight weeks, respectively. The enrolled patients were followed up for 32-40 months at an interval of three to six months. The clinical characteristics and laboratory abnormalities improved after inoculation without increasing the dose of corticosteroids and immunosuppressants in most patients. SLE disease activity index (SLEDAI) scores decreased. Proliferative responses against the Tcell vaccine were observed in four of six patients. At the time of this report, the six patients remain in clinical remission. No significant side effect from the vaccination was noticed during the follow-up period. The results of this pilot study indicate that T cell vaccination is a safe and effective treatment in SLE.
systemic lupus erythematosus, T cell vaccine, therapeutics
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栗占国, L Xia, L Ru, L Zhanguo
Ann Rheum Dis 2005; 64; 1790-1791,-0001,():
-1年11月30日
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【期刊论文】Inhibition of T-Cell Activition With HLA-DR1/DR4 Restricted Non-T-Cell Stimulating Peptides
栗占国, Qiang Zhou, Yongjing Cheng, Houshan Lu, Weihong Zhou, and Zhanguo Li
Human Immunology 64, 857-865 (2003),-0001,():
-1年11月30日
It has been reported that collagen II (CII) derived peptide CII263-272 induced T-cell activation via its amino acids responsible for T-cell receptor (TCR) recognition. The impact of substitution of the TCR contacting amino acids of CII263-272 on T-cell activation was evaluated in this study using a panel of altered CII263-272 peptides. Computer modeling revealed that the side chains of 263F and 266E in CII263-272 were coupled with amino acids on 1 and 1 chains of HLADR1 or-DR4, mainly via hydrogen bonds, whereas the side chains of 267Q and 270K protrude out of the cleft and might be recognized by TCR. Intracellular delivery of the altered peptides, and their binding to HLA-DR1 and DR4 molecules on cell surface, were demonstrated by confocal microscopy and flow cytometry. The results also revealed that the substitution of 267Q, 268G, 269P, and 270K individually or consecutively by alanine (A) or glycine (G) led to weak or non-T-cell responses. Furthermore, the altered peptides with 270K substitution (270A) or with consecutive substitution of 268G, 269P, and 270K (sub268-270) dramatically inhibited T-cell activation. It is suggested that the altered peptides derived from CII263-272 with substitution of amino acids responsible for TCR contact might be of inhibitory effect on T-cell responses.
activation, HLA-DR, altered peptides, collagen II, T cell
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栗占国, Z.-G. LI, W.-P. WU & N. MANOLIOS Sutton
1996 Blackwell Science Ltd, Immunotogy, 88, 524-530,-0001,():
-1年11月30日
The region responsible for T-cell receptor (TCR)a and chain assembly has previously been shown to reside in their extracellular domains. In an attempt to delineate further the structural requirements for TCRa and p chain assembly, chimeric TCR^ chains with increasing length of constant (C) region and mutant TCR/? chains with C-domain point mutations were constructed. Their ability to assemble with wild-type TCRa chain was evaluated in non-T (COS cells) or T cells. The results reveal that the C^ domain is the binding region to TCRa chain, whereas the intact variable (V), diversity (D) and joining (J) regions with a short C-domain of chain are not sufficient for the TCRa and p chain assembly. The unique interchain disulphide bond between TCRa and P chains is not required for the TCRa^ heterodimer formation.
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