李呼伦
致力于神经免疫学和干细胞与组织工程学的研究。
个性化签名
- 姓名:李呼伦
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学术头衔:
博士生导师
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学科领域:
神经生物学
- 研究兴趣:致力于神经免疫学和干细胞与组织工程学的研究。
李呼伦,教授,博士生导师;神经生物学教研室主任、学科带头人、学术带头人;中国微生物学会医学微生物学及免疫学专业委员会委员、黑龙江省神经科学会理事;1996-2000年瑞典卡罗林斯卡皇家医学院神经科客座研究员,归国后致力于神经免疫学和干细胞与组织工程学的研究。
从事科研工作以来,共发表国内、外学术论文100余篇,其中SCI收录25篇,最高影响因子27.783。承担国家及省课题7项,其中国家"十五"攻关课题1项,国家自然基金课题2项,省重大攻关课题1项,省国际合作项目1项,省教育厅和卫生厅课题各1项。参与国家及省科研课题10项,获得省政府及厅局级奖20项。培养博士研究生5名、硕士研究生13名;联合培养博士研究生11名、硕士研究生20名。
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【期刊论文】Experimental autoimmune myasthenia gravis induction in B cell-deficient mice
李呼伦, Hulun Li, Fu-Dong Shi, Bing He, Moiz Bakheit, Britta Wahren, Anna Berglo
International Immunology Vol. 10 No.9 (1998) 1359-1365,-0001,():
-1年11月30日
Experimental autoimmune myasthenia gravis (EAMG) is an animal model for human myasthenia gravis (MG). Autoantibody-induced functional loss of nicotinic acetylcholine receptor (AChR) at the postsynaptic membrane is an important pathogenic feature of both MG and EAMG. To evaluate the extent at which the humoral immune response against AChR operates in the pathogenesis of EAMG, we immunized B cell knockout (mMT) and wild-type C57BL/6 mice with AChR and complete Freund’s adjuvant. The ability of AChR-primed lymph node cells to proliferate and secrete IFN-g in response to AChR and its dominant peptide a146-162 were intact in mMT mice as in wild-type mice. Similar amounts of mRNA for IFN-g, IL-4 and IL-10 in AChR-reactive lymph node cells were detected in mMT and wild-type mice. However, mMT mice had no detectable anti-AChR antibodies and remained completely free from clinical EAMG. We conclude that B cells are critically required for the genesis of clinical EAMG, but not for AChR-specific T cell priming.
autoantibody, autoimmunity., experimental autoimmune myasthenia gravis, B cell knockoutmice
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李呼伦, Hu-Lun Li, * Fu-Dong Shi, *, Xue-Feng Bai, * Yu-Min Huang, * Peter H. van der Meide, Bao-Guo Xiao, * and Hans Link*
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY Vol. 87 No.1 (1998) 15-22,-0001,():
-1年11月30日
Tolerance to B cell-mediated experimental autoim-mune myasthenia gravis (EAMG), an animal model for myasthenia gravis (MG) in human s, can be achieved byn asal adminis tra tion of the autoantigen acetylcholin ereceptor (AChR). Nasal tolerance induction requiresonly l/1000 0f the amount of AChR used for oral toler-ance in ductio n, but is as effe ctive in preventing EAMG.To investigate whether nasally induced tolerance toEAMG can be inOuenced by nasal administration ofcytokin es, recom bin ant rat IFN -y (total 5000 U/ra t), acombination of AChR and IFN-'y or AChR alone was given nasally to Lewis rats before immunization withAChR and complete Freun d's adjuvant (CFA). One ad-ditional group of rats received the same amount ofAChR nasally in conjunction with IFN-y (total5000 Ulrat) intraperitoneally. AChR given alone nasally in-duced effective tolerance to EAMG whereas rats re-ceiving AChR + IFN-y by the nasal route exhibited asimilar disease pattern, and similarly escalated T andB cell responses to AChR when compared to controlEAMG rats. In contrast, administration of IFN-y ip to-gether with AChR nasally did not affect the inductionof tolerance to EAMG. IFN-'y given alone nasally didnot affect clinic al EAMG. This study demonstrates th at nasal tolerance can be modulated by nasal administra-tion of minute amounts of IFN- y. Nas al adminis trationof certain cytokines with benemial effects mightbroaden the effectiveness of applying nasal toleranceas a poten tial therapeu tic means of preventing au toim-mune diseases..
experimentalgravis, oral tolerance, nasal munity.,
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李呼伦, H.-L. LI, * J.-Q. LIU, * X.-F. BAI*, P. H. VAN DER MEIDEt & H. LINK*
Immunology 9(1998)4431-437,-0001,():
-1年11月30日
Nasal administration of soluble antigens is an exciting means of specifically down-regulating pathogenic T-cell reactivities in autoimmune diseases. The mechanisms by which nasal administration of soluble antigens suppresses autoimmunity are poorly understood. To define further the principles of nasal tolerance induction, we studied the effects of nasal administration of myelin basic protein (MBP) on experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE is a CD4+ T-cell-mediated animal model for human multiple sclerosis. Nasal administration of guinea-pig (gp)-MBP at a dose as low as 30 gtg/rat can completely prevent gp-MBP-induced EAE, whereas nasal administration of bovine (b)-MBP is not effective even at a much higher dosage. Cellular immune responses, as reflected by T-cell proliferation and interferon-y (IFN-y)- ELISPOT, were suppressed in rats receiving the two different doses (30 and 600 Jig/rat) of gp-MBP, but not after administration of b-MBP. Rats tolerized with both doses of gp-MBP had also abrogated MBP-induced IFN-y mRNA expression in popliteal and inguinal lymph node mononuclear cells compared with rats receiving phosphate-buffered saline nasally. However, adoptive transfer revealed that only spleen mononuclear cells from rats pretreated with a low dose, but not from those pretreated with a high dose, of gp-MBP transferred protection to actively induced EAE. Low-dose (30 Jg/rat) gp-MBP-tolerized rats also had high numbers of interleukin-4 (IL-4) mRNA-expressing lymph node cells, while high-dose (600 Jg/rat) gp-MBP-tolerized rats had low numbers of IL-4 mRNA-expressing lymph node cells. Our data suggest an exquisite specificity of nasal tolerance. Dose-dependent mechanisms also relate to nasal tolerance induction and protection against EAE in the Lewis rat.
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李呼伦, Nikolaos Kostulas, PhD; Hu-Lun Li, BSci; Bao-Guo Xiao, PhD; Yu-Min Huang, MD, PhD; Vasilios Kostulas, PhD; Hans Link, PhD
Stroke April (2000) 1129-1134,-0001,():
-1年11月30日
Background and Purpose—Cerebral ischemia is associated with inflammation involving accumulation of polymorphonuclearneutrophils. T cells have been suggested to contribute to the secondary progression of ischemic braininjury. Dendritic cells (DC) are potent regulators of immunity by activating and tolerizing T cells. DC have previouslybeen detected in rat meninges and choroid plexus. Hypothesizing that DC are involved in inflammation associated withcerebral ischemia, we investigated DC in the brain of Sprague-Dawley rats after permanent middle cerebral arteryocclusion (pMCAO) versus sham operation.Methods-All experimental rats (n 24) had the right MCA permanently occluded by inserting a nylon monofilamentthrough the right external carotid artery. Immunohistochemistry was used to detect DC (OX62), microglia/macrophages (OX42) that developed into DC, and activated DC expressing major histocompatibility complex class II (OX6) in the brain hemispheres at 1 hour to 6 days after pMCAO or sham operation.Results—Levels of DC were elevated at 1 hour in the ischemic versus sham hemispheres (P 0.001) and ischemic versusnonischemic hemispheres (P 0.001). Activated DC expressing major histocompatibility complex class II(OX62 OX6 ) were still elevated at 6 days after pMCAO in the ischemic versus nonischemic hemispheres (P 0.01).The area of brain lesion correlated with numbers of OX62 DC per 100-mm2 brain tissue section (r 0.79; P 0.0001). Conclusions-Increased levels of DC inthe brain after pMCAO and correlation between DC numbers and brain lesion areaindicate a role for DC in cerebral ischemia. This observation could constitute a basis for further studies on the role ofDC in inflammation related to cerebral ischemia.
cerebral ischemia, focal, cytokines, dendritic cells, microglia, rats
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李呼伦, Hua-Bing Wang, Hulun Li, Fu-Dong Shi, , Benedict J. Chambers, Hans Link and Hans-Gustaf Ljunggren
International Immunology Vol. 12 No.10 (2000) 1381-1388 ,-0001,():
-1年11月30日
Tumor necrosis factor receptor-1 (TNFR1, CD120a) has been implicated in the pathogenesis of several experimental models of T cell-mediated autoimmune disorders, but its role in antibodymediated autoimmune diseases has not been addressed. Experimental autoimmune myastheniagravis (EAMG), an autoantibody-mediated T cell-dependent neuromuscular disorder, representsan animal model for myasthenia gravis in human. To investigate the role of TNFR1 in thepathogenesis of EAMG, TNFR1-/- and wild-type mice were immunized with Torpedo acetylcholinereceptor (AChR) in complete Freund's adjuvant. TNFR1-/- mice failed to develop EAMG. Lymphoidcells from TNFR1-/- mice produced low amounts of Th1 (IFN-γ, IL-2 and IL-12)-type cytokines, butelevated levels of Th2 (IL-4 and IL-10)-type cytokines compared with lymphoid cells of wild-typemice. Accordingly, the levels of anti-AChR IgG2 antibodies were severely reduced and the level ofanti-AChR IgG1 antibodies were moderately reduced. Co-injection of recombinant mouse IL-12 withAChR in adjuvant restored T cell responses to AChR and promoted development of EAMG inTNFR1-/-mice. These results demonstrate that the TNF/TNFR1 system is required for thedevelopment of EAMG. The lack of a functional TNF/TNFR1 system can, at least in part, besubstituted by IL-12 at the stage of initial priming with AChR and adjuvant. Introduction.
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【期刊论文】The role of B-cells in experimental myasthenia gravis in mice
李呼伦, H.B. Wang', H. Li', B. He', M.Bakheit, M.Levi', B.Wahren, A.Bergliif, K.Sandstedt, H.Link', ED.Shil, *
B-cells and experimental myasthenia gravis (1999) 227-233,-0001,():
-1年11月30日
Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused by auto-antibodies against thenicotinic acetylcholine receptor (AChR) at the postsynaptic membrane. To evaluate the extent to which the humoral immune response againstAChR opcratcs in the pathogenesis of EAMG, we immunized B-cell knockout(儿MT) and wild type C57BL/6 mice with AChR in complete Freund's adjuvant. The ability of AChR-primed lymph node cells to proliferate and secreteIFN-/in response to AChR and itsdominant peptide a146-162 were intact in ktMT as in wild type mice. Similar levels of mRNA for IFN- IL-4 and IL-IO in AChR-reactivelymph node cells were detected in ktMT and wild type mice. However, htMT mice had no detectable anti-AChR antibodies and never devel-oped clinical EAMG. We conclude that B-cells are critically required for the genesis of clinical EAMG, but not for AChR-specific T-cellpriming
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李呼伦, Fu-Dong Shi, * Hulun Li, † Huabing Wang, † Xuefeng Bai, † Peter H.van der Meide, Hans Link, † and Hans-Gustaf Ljunggren*
The Journal of Immunology 162(1999)5757-5763,-0001,():
-1年11月30日
Autoantigen administration via nasal mucosal tissue can induce systemic tolerance more effectively than oral administration in anumber of experimental autoimmune diseases, including Ab-mediated experimental autoimmune myasthenia gravis, a murinemodel of myasthenia gravis. The mechanisms underlying nasal tolerance induction are not clear. In this study, we show that nasaladministration of acetylcholine receptor (AChR) in C57BL/6 mice, before immunizations with AChR in adjuvant, results in delayed onset and reduced muscle weakness compared with control mice. The delayed onset and reduced muscle weakness wereassociated with decreased AChR-specific lymphocyte proliferation and decreased levels of anti-AChR Abs of the IgG2a and IgG2bisotypes in serum. The clinical and immunologicalchanges in the AChR-pretreated C57BL/6 wild-type (wt) mice were comparable with those observed in AChR-pretreated CD82/2 mice, indicating that CD81 T cells were not requiredfor the generation of nasaltolerance. AChR-pretreated wt and CD82/2 mice showed augmented TGF-b and reduced IFN-g responses, whereas levels of IL-4were unaltered. Splenocytes from AChR-pretreated wt and CD82/2 mice, but not from CD42/2 mice, suppressed AChR-specificlymphocyte proliferation. This suppression could be blocked by Abs against TGF-b. Thus, our results demonstrate that the suppression induced in the present model is independent of CD81 T cells and suggest the involvementof Ag-specific CD41 Th3cells producing TGF-b.
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李呼伦, Hua-Bing Wang, *, Fu-Dong Shi, †, Hulun Li, * Peter H. van der Meide, ‡ Hans-Gustaf Ljunggren, † and Hans Link*
Clinical Immunology Vol. 95 No.2 (2000) 156-162,-0001,():
-1年11月30日
Experimental autoimmune myasthenia gravis(EAMG) is caused by autoantibodies against the nicotinicacetylcholine receptor (AChR) at the neuromuscularpostsynaptic membrane and represents an animalmodel of myasthenia gravis in human. Recentstudies highlighted the roles of TH1 cytokines (IFN-g,IL-12), rather than TH2 cytokines (IL-4), in the pathogenesisof EAMG by using homozygous (2/2) knockoutmice with an EAMG-susceptible genetic background.To further evaluate a role for IFN-g, we injected recombinantrat IFN-g (rrIFN-g) at the time of immunizationwith AChR in complete Freund’s adjuvant toEAMG-susceptible Lewis rats and EAMG-resistantWistar Furth (WF) rats. RrIFN-g enhanced Lewis ratEAMG. The exacerbated muscular weakness was associatedwith higher levels of anti-AChR IgG and enhancedTNF-a responses. Anti-AChR IgG antibody levelswere augmented to a similar extent as in Lewirats, however, the identical immunization and IFN-ginjection induced only mild and transient EAMG inWF rats due to the default TH3 phenotype developmentand inherent low TH1 responses. We conclude that IFN-g plays a major role in the pathogenesis ofEAMG in the Lewis rat, but fails to break disease resistancein the WF rat.
autoantibody, autoimmunity, EAMG, interferon-g, T helper cells
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李呼伦, Hua-Bing Wang, * Fu-Dong Shi, , ‡ Hulun Li, * Benedict J.Chambers, ‡ Hans Link, * and Hans-Gustaf Ljunggren
The Journal of Immunology, (2001) 166: 6430-6436.,-0001,():
-1年11月30日
CTLA-4 appears to be a negative regulator of T cell activation and is implicated in T cell-mediated autoimmune diseases.Experimental autoimmune myasthenia gravis (EAMG), induced by immunization of C57BL/6 mice with acetylcholine receptor(AChR) in adjuvant, is an autoantibody-mediated disease model for human myasthenia gravis (MG). The production of anti-AChR Abs in MG and EAMG is T cell dependent. In the present study, we demonstrate that anti-CTLA-4 Ab treatment enhancesT cell responses to AChR, increases anti-AChR Ab production, and provokes a rapid onset and severe EAMG. To address possible mechanisms underlying the enhanced autoreactive T cell responses after anti-CTLA-4 Ab treatment, mice were immunized withthe immunodominant peptide a146–162 representing an extracellular sequence of the AChR. Anti-CTLA-4 Ab, but not control Ab,treatment subsequent to peptide immunization results in clinical EAMG with diversification of the autoantibody repertoire as wellas enhanced T cell proliferation against not only the immunizing a146–162 peptide, but also against other subdominant epitopes.Thus, treatment with anti-CTLA-4 Ab appears to induce determinant spreading, diversify the autoantibody repertoire, andenhance B cell-mediated autoimmune disease in this murine model of MG.
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