肝脏树突状细胞研究进展

人肝脏ＤＣ主要存在于肝脏门脉基质，胆管及肝窦附近，与脾脏及骨髓来源的ＤＣ相比，肝脏ＤＣ表面ＭＨＣⅡ类抗原表达水平较低，不能诱导初始型同种Ｔ细胞增殖，但具有体外增殖能力和向次级淋巴组织定向迁移能力，此外，肝脏ＤＣ与病毒性肝炎，自身免疫性肝病及同种肝移植排斥的发生关系密切。     

树突状细胞的研究近况

树突状细胞为一种重要的免疫辅佐细胞。本文列举了该种细胞的诱导、表面标志、分泌功能及在肿瘤免疫方面的研究近况。     

树突状细胞和滤泡树突状细胞的研究进展

树突状细胞作为一种专职性抗原递呈细胞，在免疫应答起着很重要的作用。近年来人们对两类ＣＤ，即与Ｔ细胞相关的指突太ＤＣ和与Ｂ细胞相关的滤泡ＤＣ有了较深入的了解。本文介绍各种ＤＣ的内在联系，在组织间的移行，功能上的成熟过程以及ＦＤＣ对Ｂ细胞介导的体液免疫作用的等研究进展作一介绍。     

慢性乙型肝炎患者树突状细胞表型的研究

目的探讨慢性乙型肝炎患者外周血来源树突状细胞（Dendritic cell，DC）数量及表型的改变，并对其与肝功能、乙肝病毒复制水平的关系进行研究。方法检测37例慢性乙肝患者和21例健康人肝功能及血清HBV DNA水平，并提取外周血单个核细胞（Peripheral blood mononuclear cell，PBMC）进行体外诱导培养，促使其发育成DC，计数其数量并检测膜表面分子的变化。分析DC数量及表型与肝功能、乙肝病毒复制水平的关系。结果与正常对照组比较，慢性乙肝患者的树突状细胞数量明显减少（P〈0．05），且其膜表面分子CD83、CD86的表达均明显降低（P〈0．05）。在慢性乙肝患者中，DC数量、DC膜表面分子CD83和CD86与血清HBV DNA之间呈负相关关系，而与肝功能之间无明显相关关系。结论慢性乙肝患者体内存在DC数量减少及成熟障碍，这种改变与肝内炎症反应程度不相关，但与乙肝病毒（Hepatitis Bvirus，HBV）的复制水平呈负相关，提示DC参与慢性乙肝患者体内HBV的清除。     

树突状细胞和滤泡树突状细胞的研究进展

树突状细胞（ＤＣ）作为一种专职性抗原递呈细胞，在免疫应答起着很重要的作用。近年来人们对两类ＣＤ，即与Ｔ细胞相关的指突状ＤＣ（ＩＤＣ）和与Ｂ细胞相关的滤泡ＤＣ（ＦＤＣ）有了较深入的了解。本文介绍各种ＤＣ的内在联系，在组织间的移行、功能上的成熟过程以及ＦＤＣ对Ｂ细胞介导的体液免疫的作用等研究进展作一介绍。     

树突状细胞影响肝移植

据Supter TL[Hepatology，2007，46（6）：2021-2031]报道，肝脏树突状细胞对肝移植有重要影响。 树突状细胞（dendritic cells，DC）是近年来倍受人们关注的专职抗原呈递细胞（antigen presenting cells，APC），能摄取、加工及呈递抗原，启动T淋巴细胞介导的免疫反应。     

树突状细胞的抗肿瘤实验研究

树突状细胞 (ｄｅｎｄｒｉｔｉｃｃｅｌｌｓ ,ＤＣ)ＤＣ是一类具有独特形态的新型细胞群体 ,是目前发现的功能最强的一类专职性抗原提呈细胞 ,也是体内唯一能激活初始型Ｔ细胞的抗原提呈细胞。ＤＣ可以通过ＭＨＣⅡ类分子和ＭＨＣⅠ类分子途径提呈抗原 ,并提供充分的共刺激信号 ,因而在肿瘤免疫中起着举足轻重的作用。90年代以来 ,随着体外大量分离和扩增培养ＤＣ方法的建立和不断改进 ,人们已从分析实体瘤内ＤＣ浸润密度与患者预后的相关性转向应用ＤＣ进行肿瘤免疫治疗的研究 ,尤其是在如何提高肿瘤细胞的免疫原性、促使ＤＣ更有效地提呈…     

Th细胞的活化与树突状细胞

树突状细胞（dendritic,DC)是体内功能最强的专职抗原提呈细胞（APC），具有很强的抗原呈递能力，并能有效激发T细胞应答。DC在免疫学及肿瘤学乃至其它各学科中的作用也日益受到重视。选择性激活Th1和Th2是许多免疫反应发生的关键，而Th的分化由DC所控制，本文就免疫应答中DC和T细胞相互作用方面的最新研究作一综述。     

树突状细胞介导的肿瘤免疫治疗研究

树突状细胞是抗原递呈能力最强的抗原递呈细胞。树突状细胞可通过交叉致敏途径呈递外源性抗原如肿瘤抗原，诱导CD8 的CTL应答。应用不同形式的肿瘤抗原负载DC，将致敏DC作为疫苗回输体内可诱导机体产生有效的抗肿瘤免疫应答。     

Suppressive role of hepatic dendritic cells in concanavalin A-induced hepatitis

Concanavalin A (Con A)‐induced hepatitis is a mouse model of acute autoimmune hepatitis. The aim of this study was to investigate the role of hepatic dendritic cells (DC) in the immune modulation of tissue damage. Almost all hepatic DC were plasmacytoid DC (CD11c⁺ I‐A^low B220⁺); however, conventional DC were CD11c⁺ I‐A^high B220^–. At an early stage (3–6 h) after Con A administration, the number of DC in both the liver and spleen decreased, increasing thereafter (12–24 h) in parallel with hepatic failure. The hepatic CD11c⁺ DC population contained many CD11b^‐ cells, while the majority of splenic CD11c⁺ DC were CD11b⁺. After Con A administration, the proportion of I‐A⁺ and CD11b⁺ cells within the CD11c⁺ DC population tended to increase in the liver, but not in the spleen. Similarly, expression of the activation markers CD80, CD86 and CD40 by CD11c⁺ DC increased in the liver, but not in the spleen. Next, adoptive transfer of DC isolated from the liver and spleen was performed 3 h after Con A administration to examine the immunomodulatory function of DC. Only hepatic DC had the ability to suppress hepatic failure. Analysis of cytokine production and subsequent identification of the effector cells showed that hepatic DC achieved this by suppressing the production of interleukin (IL)‐12 and IL‐2, rather than modulating effector cell function.     

Impairment of circulating myeloid dendritic cells in immunosuppressed liver transplant recipients

The aim of the present study was to elucidate the impact of liver transplantation (LTX) on myeloid dendritic cell (MDC) homeostasis. We observed a threefold reduction of circulating CD1c(+) MDC immediately after LTX (n = 16; P < 0.01), and normalization between 3 and 12 months after LTX. This decline was not due to recruitment of MDC into the liver graft, as numbers of MDC in post-LTX liver graft biopsies were not increased compared to pre-LTX biopsies (n = 7). Moreover, no change in chemokine receptor expression on circulating MDC was observed, suggesting that their homing properties were not altered. Normalization of circulating MDC was associated with withdrawal of corticosteroid therapy, and not with changes in calcineurin inhibitor intake, indicating that corticosteroids are responsible for the observed changes in numbers of circulating MDC. During high-dose corticosteroid treatment early after LTX, circulating MDC showed a lowered maturation status with decreased expression of human leucocyte antigen D-related (HLA-DR) and CD86 compared to pre-LTX values (P < 0.01). However, when MDC from blood of LTX recipients were matured ex vivo, they up-regulated HLA-DR and co-stimulatory molecules to a comparable extent as MDC from healthy individuals. In addition, ex vivo matured MDC from both groups had equal allogeneic T cell stimulatory capacity. In conclusion, during the first months after LTX numbers and maturational status of circulating MDC are impaired significantly, probably due to a suppressive effect of corticosteroids on MDC. However, corticosteroid therapy does not imprint MDC with an intrinsic resistance to maturation stimuli.     

Interdigitating and dendritic reticulum cells in chronic active hepatitis

An ultrastructural study of the cytology of piecemeal necrosis in 12 liver biopsies from patients with chronic active (aggressive) hepatitis revealed a variety of cell types. This communication deals with two particular cell types, only observed in areas of severe piecemeal necrosis—interdigitating reticulum cells (IDRCs) and dendritic reticulum cells (DRCs). IDRCs are typical components of T-cell regions in lymphoid organs. Cells with the characteristics of IDRCs were found in severe piecemeal necrosis at the periphery of portal tracts and in periportal areas. This suggests that areas of periportal piecemeal necrosis are analogous to the T-cell regions of lymphoid organs during immune reactions. DRCs are typical components of B-cell regions in lymphoid organs. Cells with the characteristics of DRCs were found in the central parts of portal tracts with follicle-like aggregations of lymphocytes, as seen in some cases with pronounced piccemeal necrosis. This finding suggest that follicle-like lymphocytic aggregates in portal tracts are analogous to the B-cell regions of lymphoid organs during immune reactions. A mesenchymal origin of DRCs is suggested. The finding of IDRCs and DRCs in severe piecemeal necrosis emphasizes the fundamental similarity of immune reactions in the liver to those in lymphoid organs. These data are discussed in relation to immunological findings in chronic active hepatitis.     

Recent advances in the study of dendritic cells and follicular dendritic cells

The role of dendritic cells in the initiation of immune responses, and of follicular dendritic cells in the presentation of antigen to B cells, is fundamental to our understanding of the immune system. A recent symposium* was convened in order to review progress in the study of the pathophysiology of these two cell types.     

The current immune function of hepatic dendritic cells

While only a small percentage of the liver as dendritic cells, they play a major role in the regulation of liver immunity. Four major types of dendritic cell subsets include myeloid CD8α^-B220^-, lymphoid CD8α^＋B220^-, plasmacytoid CD8α^-B220^＋, and natural killer dendritic cell with CD8α^-B220^-NK1.1^＋ phenotype. Although these subsets have slightly different characteristics, they are all poor naive T cell stimulators. In exchange for their reduced capacity for allostimulation, hepatic DCs are equipped with an enhanced ability to secrete cytokines in response to TLR stimulation. In addition, they have increased level of phagocytosis. Both of these traits suggest hepatic DC as part of the innate immune system. With such a high rate of exposure to the dietary and commensal antigens, it is important for the hepatic DCs to have an enhanced innate response while maintaining a tolerogenic state to avoid chronic inflammation. Only upon secondary infectivity does the hepatic DC activate memory T cells for rapid eradication of recurring pathogen. On the other hand, overly tolerogenic characteristics of hepatic DC may be responsible for the increase prevalence of autoimmunity or liver malignancies.     

体外诱导成熟树突状细胞的研究

目的：探讨在体外从干细胞中诱导出成熟DC的适宜环境。方法：分别将人胎肝、骨髓和脾细胞以及小鼠骨髓和脾细胞在体外用GM－CSF和TNF－α诱导,观察了第3、5、7天DC的收获情况。进一步用S－P免疫细胞化学染色检测了mBmDC和fLDC有关分子表达。结果：在体外通过GM－CSF和TNF－α的作用,小鼠骨髓、人胎肝、骨髓细胞呈典型的毛刺状胞浆突起,第5天的收获率分别为：39.5％、67.2％、12.9％,而基本不能从脾细胞中诱导出成熟DC,获得的DC能与MAbCD80、MAbCD40呈强阳性反应。结论：在GM－CSF和TNF－α的共同作用下,能在体外从人胎肝、 骨髓和小鼠骨髓干细胞中获得成熟DC,其DC能表达高高水平的B7－1和CD40分子,这为大量获得DC提供了一种简便可行的手段,为研究DC的生物学特征及其抗原提呈功能提供了丰富的材料,为开展以DC为基础的各种免疫治疗研究奠了良好的基础。     

Human hepatic lymph nodes contain normal numbers of mature myeloid dendritic cells but few plasmacytoid dendritic cells

We investigated whether the hyporesponsiveness of the adaptive arm of the liver immune system is related to the composition of the dendritic cell (DC) population in hepatic lymph nodes. Noninflamed human hepatic lymph nodes (LN) were obtained from multiorgan donors, inflamed hepatic LN from liver transplant recipients with autoimmune cholestatic liver diseases, and inguinal LN from kidney transplant recipients. Quantitative immunohistochemistry showed that all three types of LN contained comparable numbers of mature and immature myeloid DC, but that noninflamed and inflamed hepatic LN contained significantly fewer plasmacytoid DC as compared to inguinal LN. Likewise, DC-enriched cell preparations from hepatic LN contained relatively few plasmacytoid DC. The difference in numbers of plasmacytoid DC was confirmed in comparisons of hepatic LN and ileacal LN from the same organ-donors. Myeloid DC from hepatic LN showed similar expressions of HLA-DR, CD83, and CD86, and higher expression of CD80 compared to myeloid DC from inguinal LN. In conclusion, hepatic LN contain similar numbers of myeloid DC as muscle/skin lymph-draining LN, with no signs of immaturity, but relatively few plasmacytoid DC.     

Monocyte-derived dendritic cell function in chronic hepatitis C is impaired at physiological numbers of dendritic cells

Monocyte-derived dendritic cells (MoDCs) are a promising cellular adjuvant for effector immune responses against tumours and chronic viral infections, including hepatitis C virus (HCV). If autologous DC therapeutic approaches are to be applied in persistent HCV infections in patients, it is important to have an unambiguous understanding of the functional status of the cell type used, namely MoDCs from patients with chronic hepatitis C (CHC) infection. Because of conflicting published reports of either impaired or normal MoDC function in CHC infection, we re-examined the ability of MoDCs from CHC and normal healthy donors (NHD) to mature to an inflammatory stimulus [tumour necrosis factor (TNF)-alpha] and their subsequent functional capabilities. Expression of maturation-associated phenotypic markers [human leucocyte antigen (HLA)-DR, CD83, CD86, CD40], allostimulatory capacity in mixed lymphocyte reactions (MLRs) and CD40-ligand-induced cytokine and chemokine generation were compared in CHC- versus NHD-MoDCs. TNF-alpha-stimulated CHC-MoDCs up-regulated phenotypic markers, but to significantly lower levels than NHD-MoDCs. At physiological ratios of DCs to T cells, CHC-MoDCs were less allostimulatory than NHD-MoDCs, but not when DC numbers were substantially increased. CHC- and NHD-MoDCs generated equivalent amounts of cytokines [TNF-alpha, interleukin (IL)-1beta, IL-6, IL-12p70, IL-15, IL-10] and chemokines [interferon-inducible protein (IP)-10, macrophage inflammatory protein (MIP)-1alpha, regulated upon activation, normal T expressed and secreted (RANTES)] after CD40 ligation. Because the functional defect was not apparent at high MoDC : T cell ratios, autologous MoDC therapy with sufficiently high numbers of DCs could, in theory, overcome any impairment of MoDC function in CHC.     

HBsAg脉冲的树突状细胞对CIK细胞功能的影响

目的:探讨HBsAg脉冲的树突状细胞(DC),对细胞因子诱导的杀伤细胞(CIK)的增殖和杀伤作用的影响。方法:选择慢性乙肝患者23例,用常规方法分离外周血单个核细胞(PBMC),经HBsAg脉冲后培养为特异性的DC,用3H-TdR掺入法检测该细胞对CIK细胞增殖的刺激作用,用乳酸脱氢酶释放法检测特异性CIK细胞对HepG2215细胞的特异性杀伤作用。结果:HBsAg脉冲的DC对CIK细胞的增殖具有刺激作用。由HBsAg脉冲的DC所诱导的特异性CIK细胞对HepG2215细胞的特异性杀伤作用增强。结论:HBsAg脉冲的DC可增强CIK细胞的杀伤活性。     

小鼠肝B220~+/DEC205~+树突状细胞对结肠癌肝转移的影响

目的:研究小鼠肝内B220~+/DEC205~+树突状细胞对结肠癌肝转移的影响.方法:小鼠尾静脉大容量快速注射重组质粒plasmid-IL-3/CD40L,诱导肝B220~+/DEC205~+树突状细胞增殖,小鼠脾内接种结肠腺癌CT26细胞,检测肝表面转移癌结节数量及脾内癌结节大小和重量、血清癌胚抗原含量及小鼠生存期.结果:处理组小鼠肝非实质细胞较对照组明显增多.小鼠脾包膜下接种CT26细胞后第14天,脾均有癌结节形成,仅肝表面见癌转移结节,转移率为100%.处理组肝表面转移癌结节数量明显多于对照组.脾内癌结节的大小、重量,处理组与对照组比较无明显差别.处理组较对照组血清癌胚抗原水平显著升高,小鼠生存期较对照组缩短.结论:小鼠肝内经重组质粒plasmid-IL-3/CD40L诱导扩增的B220~+/DCE205~+树突状细胞对结肠癌肝转移具有促进作用.