他克莫司处理供者树突状细胞在诱导大鼠同种心脏移植免疫耐受中的作用(英文)

背景:诱导供者特异性免疫耐受被认为是最终克服器官移植后排斥反应的有效途径,近年来关于未成熟树突状细胞在诱导免疫耐受中的重要作用日益受到关注。目的:观察他克莫司处理的供者未成熟树突状细胞对大鼠同种异体心脏移植免疫耐受的影响,分析未成熟树突状细胞诱导免疫耐受的作用途径。设计:随机对照动物实验。材料:实验于2006-04/2006-12在青岛大学医学院附属医院动物实验中心完成。以45只Wistar大鼠为供体,45只SD大鼠为受体,行颈部心脏移植45例次。按随机数字表法分为3组,每组15例次,进行不同的预处理。方法:对照组、未经他克莫司处理组及他克莫司处理组移植前7d分别经尾静脉注射生理盐水、供者未成熟树突状细胞和他克莫司处理的未成熟树突状细胞。分别测定移植后SD大鼠与Wistar大鼠及第3品系Lewis大鼠的单向混合淋巴细胞反应。主要观察指标:各组受体大鼠移植心脏存活时间、心肌病理及血清白细胞介素2、白细胞介素4、白细胞介素10、γ-干扰素含量变化。结果:①未经他克莫司处理组大鼠的移植心脏存活时间较对照组明显延长(P<0.01),他克莫司处理组大鼠的移植心脏存活时间进一步延长(P<0.05)。②混合淋巴细胞培养结果显示为供者特异性。③各组大鼠血清白细胞介素2、γ-干扰素、白细胞介素4、白细胞介素10含量差异具有显著性意义(P<0.01)。代表Th1的白细胞介素2、γ-干扰素水平明显降低,代表Th2的白细胞介素4、白细胞介素10水平明显增高。结论:未成熟树突状细胞能够诱导同种异体大鼠心脏移植免疫耐受;他克莫司处理的未成熟树突状细胞能够加强这种免疫耐受,且这种耐受是供者特异性的。其可能主要通过调节T细胞免疫应答类型(Th1至Th2的免疫偏移)、诱导调节性T细胞和诱导T细胞失能等途径来参与免疫耐受的形成。     

Cytokine-conditioned dendritic cells induce humoral tolerance to protein therapy in mice

A major obstacle in the genetic therapy of inherited metabolic disease is host immune responses to the therapeutic protein. This is best exemplified by inhibitor formation in the protein therapy for hemophilia A. An approach to overcoming this is induction of immunological tolerance to the therapeutic protein. Tolerogenic dendritic cells (DCtols) have been reported to induce tolerance. In addition, cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β(1) are known to induce tolerance. To model protein therapy, we used ovalbumin (OVA) as antigen in BALB/c mice and their transgenic derivative, DO11.10 mice. In this study we show that adoptive transfer of antigen-pulsed dendritic cells (DCs) treated with a combination of IL-10 and TGF-β(1) can suppress the antibody response in mice. Adoptive transfer of cytokine-conditioned DCs in preimmunized mice results in reduction of antibody response in the mice. Furthermore, the effect is antigen specific, as the recipient mice were able to mount a potent antibody response to the control antigen. Last, we show that TGF-β(1) and IL-10-conditioned DCs are able to inhibit anti-FVIII antibody responses in FVIII knockout (KO) mice. Analysis of the contribution of IL-10 and TGF-β(1) to the DCtol phenotype shows that IL-10 treatment of DCs is sufficient for inducing OVA-specific tolerance in BALB/c mice, but we observed a requirement for treatment with both human TGF-β(1) and human IL-10 to significantly inhibit anti-FVIII antibody responses in FVIII KO mice. This paper demonstrates that autologous cell therapy for antigen-targeted immune suppression may be developed to facilitate long-term therapy.     

"Pathogen-mimicking" nanoparticles for vaccine delivery to dendritic cells

A clinically relevant delivery system that can efficiently target and deliver antigens and adjuvant to dendritic cells (DCs) is under active investigation. Immunization with antigens and immunomodulators encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles elicits potent cellular immune responses; but understanding how this mode of delivery affects DCs and priming of naive T cells needs further investigation. In the current study, we assessed the extent of maturation of DCs after treatment with monophosphoryl lipid A (MPLA) encapsulated in PLGA nanoparticles and the generation of primary T-cell immune responses elicited by DCs loaded with antigens using this approach. Results indicated that DCs up-regulated the expression of surface maturation markers and demonstrated an enhanced allostimulatory capacity after treatment with MPLA containing PLGA nanoparticles. Treatment of DCs with MPLA containing nanoparticles released high amounts of proinflammatory and TH1 (T helper 1) polarizing cytokines and chemokines greater than that achieved by MPLA in solution. The delivery of ovalbumin in PLGA nanoparticles to DCs induced potent in vitro and in vivo antigen-specific primary TH1 immune responses that were furthermore enhanced with codelivery of MPLA along with the antigen in the nanoparticle formulation. Delivery of MUC1 lipopeptide (BLP25, a cancer vaccine candidate) and MPLA in PLGA nanoparticles to human DCs induced proliferation of MUC1 reactive T cells in vitro demonstrating the break in tolerance to self-antigen MUC1. These results demonstrated that targeting antigens along with toll-like receptor ligands in PLGA nanoparticles to DCs is a promising approach for generating potent TH1 polarizing immune responses that can potentially override self-tolerance mechanisms and become beneficial in the immunotherapy of cancer and infectious diseases.     

Potent maturation of monocyte-derived dendritic cells after CD40L lentiviral gene delivery

Dendritic cells (DCs) are being evaluated in immunization protocols to enhance immunity against infectious diseases and cancer. Interaction of T-helper cells expressing CD40 ligand (CD40L) with its cognate CD40 receptor on DCs leads to a mature DC phenotype, characterized by increased capacity of antigen presentation to cytotoxic T cells. The authors examined the ability of third-generation self-inactivating lentiviral vectors expressing CD40L to induce autonomous maturation of ex vivo expanded human monocyte-derived dendritic cells. Transduction with lentiviral vectors achieved a highly efficient gene transfer of CD40L to DCs, which correlated with phenotypic maturation as shown by the expression of immunologic relevant markers (CD83, CD80, MHCI) and secretion of IL-12, whereas DC phenotype was not affected by a control vector expressing only the green fluorescent protein marker. Addition of recombinant IFN-gamma to DCs at the time of CD40L transduction further enhanced IL-12 production, and when co-cultured with allogeneic and autologous CD8+ and CD4+ T cells, a potent activation was observed. Autologous responses against an HLA-A2-restricted influenza peptide (Flu-M1) and a tumor-associated antigenic peptide (gp100 210M) were significantly enhanced when CD40L transduced DCs were used as antigen-presenting cells for in vitro stimulation of CD8+ cytotoxic T lymphocytes. These results demonstrate that endogenous expression of CD40L by lentivirally transduced DCs induced their autonomous maturation to a phenotype comparable to that induced by optimal concentrations of soluble CD40L, providing a novel tool for genetic manipulation of DCs.     

Cell-based therapy approaches using dying cells: from tumour immunotherapy to transplantation tolerance induction

Cell-based therapies are promising approaches to treat uncontrolled pathologies, such as tumours. Apoptotic tumour cells have recently been proposed as a source of tumour-associated antigens to stimulate an efficient immune response. However, a complex relationship exists between apoptosis and the immune system. In this review, the different factors that may influence immune responses against apoptotic cells are detailed and discussed in the light of recent publications. These factors include the nature of the phagocytes and the receptors involved in apoptotic cell uptake, as well as the environment in which cells are dying. A possible distinction between apoptosis and necrosis by immune system sentinels adds a further level of complexity. The potential use of the immunomodulatory properties associated with apoptosis to favour engraftment and induce tolerance in transplantation is then discussed. In conclusion, this review will suggest appropriate conditions to efficiently and safely use apoptotic cells as a new cell therapy product.     

Cell-based therapy approaches using dying cells: from tumour immunotherapy to transplantation tolerance induction

Cell-based therapies are promising approaches to treat uncontrolled pathologies, such as tumours. Apoptotic tumour cells have recently been proposed as a source of tumour-associated antigens to stimulate an efficient immune response. However, a complex relationship exists between apoptosis and the immune system. In this review, the different factors that may influence immune responses against apoptotic cells are detailed and discussed in the light of recent publications. These factors include the nature of the phagocytes and the receptors involved in apoptotic cell uptake, as well as the environment in which cells are dying. A possible distinction between apoptosis and necrosis by immune system sentinels adds a further level of complexity. The potential use of the immunomodulatory properties associated with apoptosis to favour engraftment and induce tolerance in transplantation is then discussed. In conclusion, this review will suggest appropriate conditions to efficiently and safely use apoptotic cells as a new cell therapy product.     

Specialized role of migratory dendritic cells in peripheral tolerance induction

Harnessing DCs for immunotherapies in vivo requires the elucidation of the physiological role of distinct DC populations. Migratory DCs traffic from peripheral tissues to draining lymph nodes charged with tissue self antigens. We hypothesized that these DC populations have a specialized role in the maintenance of peripheral tolerance, specifically, to generate suppressive Foxp3⁺ Tregs. To examine the differential capacity of migratory DCs versus blood-derived lymphoid-resident DCs for Treg generation in vivo, we targeted a self antigen, myelin oligodendrocyte glycoprotein, using antibodies against cell surface receptors differentially expressed in these DC populations. Using this approach together with mouse models that lack specific DC populations, we found that migratory DCs have a superior ability to generate Tregs in vivo, which in turn drastically improve the outcome of experimental autoimmune encephalomyelitis. These results provide a rationale for the development of novel therapies targeting migratory DCs for the treatment of autoimmune diseases.     

间充质干细胞诱导糖尿病小型猪同种异体胰岛移植的免疫耐受

背景：胰岛移植为有望根治糖尿病的一种方法,而移植排斥问题阻碍了移植的开展,诱导受体对供体移植物的免疫耐受是解决同种异体移植排斥反应的关键。目的：观察骨髓间充质干细胞输注对糖尿病小型猪同种异体胰岛移植物存活时间的影响。方法：无菌条件下抽取动物骨髓,离心弃上清。取单核细胞层,洗涤后加入L-DMEM培养基,调整细胞浓度为1×10^9L^-1。培养48h后换液去除未贴壁的细胞,依据贴壁培养法分离和扩增间充质干细胞。取第5代细胞作为移植供源,调整细胞浓度为1×10^10L^-1。四氧嘧啶制备糖尿病小型猪模型,随机分为骨髓细胞组和干细胞＋骨髓细胞组,经肝门静脉分别植入胰岛细胞、骨髓细胞,胰岛细胞、骨髓细胞和骨髓间充质干细胞。结果与结论：骨髓间充质干细胞联合骨髓细胞输注较单纯骨髓细胞输注能显著延长同种异体小型猪胰岛移植物存活时间（P〈0．05）,同时受体血清胰岛素能较长时间维持较高水平。提示骨髓间充质干细胞输注能显著延长猪胰岛移植物存活时间,并促进胰岛移植物正常功能的发挥。     

Stable cationic microparticles for enhanced model antigen delivery to dendritic cells.

The objectives of this work were (i) to prepare physically stable cationic microparticles and (ii) to study the impact of the surface properties on microparticle phagocytosis and the phenotype of dendritic cells (DC). Protein loaded biodegradable microparticles from poly(lactic-co-glycolic acid) [PLGA] were produced in a micromixer-based w/o/w solvent evaporation procedure. Anionic particles were obtained by using polyvinyl alcohol (PVA) as stabilizing agent; for cationic surfaces cetyltrimethylammonium bromide (CTAB) and chitosan/PVA or DEAE-dextran/PVA blends were evaluated. In phagocytosis studies human monocytes and monocyte-derived DC were incubated with microparticles and analysed by flow cytometry. While CTAB modified microparticles lost their positive charge and aggregated due to CTAB desorption from the particle surface, the modification with chitosan and DEAE-dextran resulted in stable microparticles without cell toxicity. Due to a very low endotoxin content, phagocytosis of anionic and cationic microparticles did not induce an upregulation of maturation-associated surface markers on DC. DEAE-dextran modified microparticles showed an enhanced model protein delivery into phagocytic cells. Overall, PLGA microparticles are suitable vehicles for protein delivery to DC, which might be used for DC-based cell therapies.     

预输注RelB shRNA慢病毒修饰树突细胞诱导大鼠肝移植免疫耐受

背景:肝移植后的排斥反应是威胁患者和移植物长期存活的主要原因。诱导受者产生特异性免疫耐受是解决排斥反应的理想措施。目的:探讨RNAi RelB树突状细胞预输注诱导大鼠肝移植特异性免疫耐受的可能性。方法:将近交系雄性清洁级DA(RT1a)大鼠和近交系雄性SPF级Lewis(RT11)大鼠分别作为供、受体,行原位肝移植手术。术前随机配对分为4组:①对照组,受体鼠移植前不做预输注。②治疗组:受体鼠移植前7d静脉输注供体大鼠RNAi RelB树突状细胞(5×106)。③未成熟树突状细胞组:受体鼠移植前7d静脉输注供体大鼠未成熟树突状细胞(5×106)。④成熟树突状细胞组:受体鼠移植前7d静脉输注供体大鼠成熟树突状细胞(5×106)。结果与结论:与对照组、未成熟树突状细胞组以及成熟树突状细胞组相比,治疗组移植肝的平均生存时间显著延长。移植后第7天,治疗组天冬氨酸转氨酶,总胆红素水平低于对照组、成熟树突状细胞组、未成熟树突状细胞组(P<0.01),移植后第14天治疗组、未成熟树突状细胞组天冬氨酸转氨酶,总胆红素均有轻微下降,两组比较差异仍有显著性意义(P<0.01)。移植后第7天,与治疗组比较,对照组、成熟树突状细胞组、未成熟树突状细胞组γ-干扰素、白细胞介素2水平升高(P<0.01),而白细胞介素4、白细胞介素10下降(P<0.01);移植后第14天治疗组、未成熟树突状细胞组γ-干扰素、白细胞介素2水平均有下降,白细胞介素4、白细胞介素10水平均有升高,两组比较差异仍有显著性意义(P<0.01)。对照组、成熟树突状细胞组、未成熟树突状细胞组移植后第7天排斥活动指数为8.0-9.0。未成熟树突状细胞组第14天肝细胞、内皮细胞坏死及汇管区炎性细胞浸润进一步增多。治疗组移植后第7天排斥活动指数为6.0-8.0,第14天时排斥活动指数为4.0-5.0。结果提示RNAi RelB树突状细胞预输注可以减轻移植肝排斥程度,延长移植肝生存时间,这是通过间接途径实现的,其机制可能与T细胞的调节和无能有关。     

In situ induction of dendritic cell-based T cell tolerance in humanized mice and nonhuman primates

Induction of antigen-specific T cell tolerance would aid treatment of diverse immunological disorders and help prevent allograft rejection and graft versus host disease. In this study, we establish a method of inducing antigen-specific T cell tolerance in situ in diabetic humanized mice and Rhesus monkeys receiving porcine islet xenografts. Antigen-specific T cell tolerance is induced by administration of an antibody ligating a particular epitope on ICAM-1 (intercellular adhesion molecule 1). Antibody-mediated ligation of ICAM-1 on dendritic cells (DCs) led to the arrest of DCs in a semimature stage in vitro and in vivo. Ablation of DCs from mice completely abrogated anti-ICAM-1-induced antigen-specific T cell tolerance. T cell responses to unrelated antigens remained unaffected. In situ induction of DC-mediated T cell tolerance using this method may represent a potent therapeutic tool for preventing graft rejection.     

Enhanced lentiviral transduction of monocyte-derived dendritic cells in the presence of conditioned medium from dying monocytes

Lentiviral vectors (LVs) are attractive vehicles for the transduction of human dendritic cells (DCs) in order to mobilize their endogenous antigen presentation pathways. We analyzed here how to improve the efficiency of LV transduction, which we performed at the initial stages of the differentiation of purified monocytes into dendritic cells (Mo-DCs). Using LVs pseudotyped with the vesicular stomatitis virus envelope G glycoprotein (VSV-G), we found that a conditioned medium derived from dying monocytes (MCM) improved by 2- to 10- fold the proportion of transduced Mo-DCs. This enhanced transduction efficiency requires the presence of MCM during the initial stage of LV transduction and does not affect the phenotype and antigen presentation function of terminally differentiated Mo-DCs. Importantly, we found that MCM derived from a human acute monocytic leukemia cell line, THP-1, was equally effective. The MCM activity was heat stable (56 degrees C) and was present in the soluble fraction after high-speed centrifugation. Altogether our results show that a soluble factor present in dying monocyte cultures can replace advantageously facilitating agents such as Polybrene, to achieve high LV transductions levels. This protocol can be performed with autologous monocytes and is therefore applicable in clinical settings.     

The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo

Dendritic cells (DCs) are able in tissue culture to phagocytose and present antigens derived from infected, malignant, and allogeneic cells. Here we show directly that DCs in situ take up these types of cells after fluorescent labeling with carboxyfluorescein succinimidyl ester (CFSE) and injection into mice. The injected cells include syngeneic splenocytes and tumor cell lines, induced to undergo apoptosis ex vivo by exposure to osmotic shock, and allogeneic B cells killed by NK cells in situ. The CFSE-labeled cells in each case are actively endocytosed by DCs in vivo, but only the CD8+ subset. After uptake, all of the phagocytic CD8+ DCs can form major histocompatibility complex class II-peptide complexes, as detected with a monoclonal antibody specific for these complexes. The CD8+ DCs also selectively present cell-associated antigens to both CD4+ and CD8+ T cells. Similar events take place with cultured DCs; CD8+ DCs again selectively take up and present dying cells. In contrast, both CD8+ and CD8- DCs phagocytose latex particles in culture, and both DC subsets present soluble ovalbumin captured in vivo. Therefore CD8+ DCs are specialized to capture dying cells, and this helps to explain their selective ability to cross present cellular antigens to both CD4+ and CD8+ T cells.     

Distinct mechanisms of neonatal tolerance induced by dendritic cells and thymic B cells

To assess the role of different types of antigen-presenting cells (APC) in the induction of tolerance, we isolated B cells, macrophages, and dendritic cells from thymus and spleen, and injected these into neonatal BALB/c mice across an Mls-1 antigenic barrier. One week after injection of APC from Mls-1-incompatible mice or from control syngeneic mice, we measured the number of thymic, Mls-1a-reactive, V beta 6+ T cells and the capacity of thymocytes to induce a graft-vs.-host (GVH) reaction in popliteal lymph nodes of Mls-1a mice. Injection of thymic but not spleen B cells deleted thymic, Mls-1a-reactive V beta 6+ T cells and induced tolerance in the GVH assay. The thymic B cells were primarily of the CD5+ type, and fluorescence-activated cell sorter-purified CD5+ thymic B cells were active. Injection of dendritic cells from spleen or thymus also induced tolerance, but the V beta 6 cells were anergized rather than deleted. Macrophages from thymus did not induce tolerance. Dendritic cells and thymic B cells were also effective in inducing tolerance even when injected into Mls-, major histocompatibility complex-incompatible, I-E- mice, but only thymic B cells depleted V beta 6-expressing T cells. Therefore, different types of bone marrow-derived APC have different capacities for inducing tolerance, and the active cell types (dendritic cells and CD5+ thymic B cells) can act by distinct mechanisms.     

移植免疫耐受的研究现状及进展

目前,器官移植已经成为终末期器官功能衰竭患者的有效治疗手段,但长期使用免疫抑制剂可引起许多不良反应,而且免疫抑制剂无助于移植慢性排斥反应和移植物的长期存活.器官移植后最理想的措施是针对供体移植物建立特异性免疫耐受,树突状细胞、CD4+CD25+调节性T细胞及嵌合现象等在免疫耐受过程中都扮演了重要的角色.目前为止还未形成一种成熟的可以在临床广泛应用的移植免疫耐受模式,理想的免疫耐受模式还有待进一步探索.     

腺相关病毒介导癌胚抗原转染树突状细胞对免疫功能的调节作用

目的:近年来,树突状细胞参与调节作用的研究较多。实验拟验证重组腺相关病毒(rAAV)介导癌胚抗原基因转染树突状细胞后其的免疫调节作用的变化。方法:实验于2006-06/2006-11在美国阿肯色大学医学院基因治疗中心完成。①实验方法:取健康人外周血(自愿捐献),采用改良Ficoll密度梯度离心的方法分离外周血单个核细胞,取贴壁细胞,分为rAAV/CEA转染组和空白对照组,均采用重组人粒细胞巨噬细胞集落刺激因子、白细胞介素4、肿瘤坏死因子-α诱导树突状细胞前体细胞成熟,将成熟树突状细胞与末梢血淋巴细胞按比例混合培养,可得到激活的细胞毒性T淋巴细胞。②实验评估:采用流式细胞仪检测树突状细胞表面标志表达,细胞毒性T淋巴细胞的免疫表型变化,细胞毒性T淋巴细胞γ-干扰素表达。采用酶联免疫吸附法(ELISA法)检测树突状细胞的白细胞介素12和白细胞介素10表达。结果:①rAAV/CEA转染树突状细胞的CD14较空白对照组降低,共刺激分子CD40、CD80、CD83、CD86表达均较空白对照组高。②成熟树突状细胞细胞因子表达中,rAAV/CEA转染组的白细胞介素12较空白对照组升高,白细胞介素10降低。③与空白对照组比较,rAAV/CEA转染组能高表达CD8 T细胞和其表型CD69,CD8/CD56的T细胞比例上调,CD25 CD4 的T细胞减少。④rAAV/CEA转染的细胞毒性T淋巴细胞表达相对较高水平的γ-干扰素,与杀伤实验结果相吻合。结论:rAAV/CEA转染树突状细胞能够激活细胞毒性T淋巴细胞的特异性杀伤作用,与树突状细胞和细胞毒性T淋巴细胞等免疫细胞表面标志变化和细胞内细胞因子水平变化相关。     

大鼠脑缺血后胶质细胞向树突状细胞转化的研究

目的探讨树突状细胞( dendritic cells,DC)是否参与脑缺血损伤过程及在缺血脑组织中 DC的来源. 方法用线栓方法封闭大鼠右侧大脑中动脉制作动物模型.用免疫组化方法检测脑缺血 1 h到第 6 天时,缺血脑 DC( OX62+)的存在,以及胶质细胞 /巨噬细胞( OX42+)转化成 DC( OX62+),同时检测活化后的 DC样细胞表达主要组织相容性复合分子Ⅱ( MHCⅡ)情况. 结果脑缺血半球和假手术半球比较,在 1 h DC数量增加 (t=7.143, P< 0.001),在脑缺血组中,缺血脑半球与非缺血脑半球比, DC的数量也增多 (t=4.968, P< 0.01).脑缺血第 6天缺血组与假手术组进行比较, DC表达 MHCⅡ( OX62+ OX6+)显著差异,每 100 mm2脑组织切片中 OX62+ OX6+细胞数量比为 (53± 3)比 (33± 2)个 (t=2.975, P< 0.05).脑缺血半球在 1 h到第 6天 OX42+转变成 OX62+ OX42+细胞逐渐增加,脑缺血第 6天脑缺血半球与非缺血半球比 t=9.875, P< 0.001.脑缺血损伤面积与以每 100 mm2脑组织片为单位的 OX62+数量呈正相关 (R2=0.891 4,P< 0.001). 结论脑缺血后,脑缺血组织中 DC的数量增加, DC数量增加与脑伤面积呈正相关,提示 DC参与了脑缺血过程,大鼠脑缺血后从胶质细胞向 DC样细胞转化是脑内 DC的来源之一.     

树突状细胞Toll样受体介导的免疫逃逸作用

目的:树突状细胞可借助其表面的一种模式识别受体Toll样受体对固有免疫及适应性免疫发挥免疫调节作用,Toll样受体是某些病原微生物借以逃逸机体免疫防御功能的靶分子,本文主要探讨Toll样受体的结构及功能、及其与病毒的相互作用。资料来源:应用计算机检索Pubmed 1980-01/2007-03期间有关树突状细胞表面Toll样受体及DC-SIGN受体结构、功能及相互关系文献,检索词“TLRs,DC-SIGN,antiviral immunity,HBV,HCV”,并限定文章语言种类为English。资料选择:选取树突状细胞表面Toll样受体和DC-SIGN及其抗感染免疫的相关文献,删除与Toll样受体或DC-SIGN抗感染免疫相关性不大的文献。资料提炼:共检索到65篇相关文献,33篇符合纳入标准。排除32篇文献中,12篇是与选取标准无关的研究,20篇属于重复研究。资料综合:目前已发现13种Toll样受体家族成员,其中11种表达于人类细胞。Toll样受体不同程度的表达于淋巴细胞、白细胞以及包括巨噬细胞和树突状细胞在内的单核吞噬细胞表面。巨噬细胞和树突状细胞等抗原提呈细胞上Toll样受体,构成一类独特的模式识别受体,是免疫应答的重要参与者,它能选择性识别侵入机体的病原微生物所携带的病原相关分子模式,诱导巨噬细胞和树突状细胞活化与成熟,产生细胞因子,引发针对病原微生物的适应性免疫应答。DC-SIGN与树突状细胞上Toll样受体之间有交叉联系,而这些交叉联系可导致免疫细胞活化或T细胞抑制。对于Toll样受体和DC-SIGN在人类肝炎病毒和艾滋病病毒-1感染过程中的作用了解尚浅。结论:Toll样受体在一些病毒感染过程中的作用还有待进一步研究。