Dendritic cells

Dendritic cells (DC) are the most effective or 'professional' of the antigen-presenting cells (APC) that initiate primary immune responses. They are located at surveillance sites where they capture and process antigens. They then initiate and regulate T- and B-cell responses by expressing lymphocyte costimulatory molecules, migrating to lymphoid organs and secreting biologically active molecules. Dendritic cells not only activate lymphocytes to induce the immune response, but they also minimize autoimmune reactions by tolerizing T cells to self-antigens. Recent Phase I and II clinical studies have shown promise in the use of antigen-pulsed autologous DC for vaccination of cancer patients. Dendritic cells also have applications in preventing rejection after transplantation, immunization against viral infections and immunosuppression in autoimmune diseases.     

Dendritic cells in the kidney

Dendritic cells (DC) in nonlymphoid organs function at the crossroads of innate and adaptive immunity, self-tolerance, and tissue homeostasis. This review provides an overview of the study of DC in the kidney, tracing its history leading to the current knowledge of the origins, migration, and function of renal DC. Together, these studies suggest that renal DC play a critical role in the health and disease of the kidney, opening the way to direct targeting of renal DC for therapeutic benefit.     

Dendritic cells and macrophages in kidney disease

Recent studies on dendritic cells (DCs) and macrophages have greatly advanced our knowledge of glomerular immunopathology. This rapidly developing field most likely has considerable impact on our understanding of the major mediators of tissue injury and repair in kidney disease. The pivotal role of cytokine in the initiation, differentiation, and amplification of local immune response production by antigen-presenting cells (APC; DCs, macrophages, and so forth) has been well documented, but the precise biological role of the numerous APC-derived products as effectors in both renal inflammation and repair remains a topic of intense research. This review focuses on the activated DCs and macrophages for the development and resolution of kidney disease, and discusses mechanistic information on the inflammatory process, including tissue injury and healing. A multi-dimensional study may contribute to further clarification of the role of their cellular activation in the progression of human kidney disease.     

Dendritic cells as a target of immunosuppressive drugs

For a long time, it has been recognized that dendritic cells (DCs) play a pivotal role in the induction of immune responses, including alloimmunity. More recently, it has become clear that DCs are also central players in the other extreme end of immune regulation (ie, tolerance induction). Initially, it was proposed that different DC lineages might be responsible for these different activities. However, in addition, the differentiation/maturation stage of DCs determines its functional capacity. In recent years, it has been shown that several pharmacological agents have the capacity to control or direct these DC functions. In the present review, we will give an overview of these findings and especially discuss these in the view of strategies to induce allospecific tolerance in transplantation.     

Dendritic cells (I): Biological functions

Dendritic cells (DCs) are potent antigen presenting cells (APCs) that possess the ability to stimulate na?ve T cells. They comprise a system of leukocytes widely distributed in all tissues, especially in those that provide an environmental interface. DCs posses a heterogeneous haemopoietic lineage, in that subsets from different tissues have been shown to posses a differential morphology, phenotype and function. The ability to stimulate na?ve T cell proliferation appears to be shared between these various DC subsets. It has been suggested that the so-called myeloid and lymphoid-derived subsets of DCs perform specific stimulatory or tolerogenic function, respectively. DCs are derived from bone marrow progenitors and circulate in the blood as immature precursors prior to migration into peripheral tissues. Within different tissues, DCs differentiate and become active in the taking up and processing of antigens (Ags), and their subsequent presentation on the cell surface linked to major histocompatibility (MHC) molecules. Upon appropriate stimulation, DCs undergo further maturation and migrate to secondary lymphoid tissues where they present Ag to T cells and induce an immune response. DCs are receiving increasing scientific and clinical interest due to their key role in anti-cancer host responses and potential use as biological adjuvants in tumour vaccines, as well as their involvement in the immunobiology of tolerance and autoimmunity.     

树突细胞的免疫调节功能及其影响因素

树突细胞(DC)是体内功能最强的专职抗原呈递细胞,它在调控机体对自身或非自身抗原产生适当的免疫应答方面起非常重要的作用。DC是一群异质性的细胞,不同亚型的DC具有不同的功能。组织微环境、DC的成熟状态、DC表面的免疫分子以及局部组织基质细胞(如肝星状细胞)等与DC的功能有关。通过改变DC表面的一些关键分子的表达能够调控DC诱导的免疫反应。阐明决定DC诱导免疫耐受功能的关键分子以及DC选择性触发T细胞向辅助性T细胞(Th)1、Th2、Th17、调节性T细胞等不同方向分化的关键因素对寻找用新的方法来调控机体免疫反应具有重大意义。     

Dendritic cells modulate burn wound healing by enhancing early proliferation

Adequate wound healing is vital for burn patients to reduce the risk of infections and prolonged hospitalization. Dendritic cells (DCs) are antigen presenting cells that release cytokines and are central for the activation of innate and acquired immune responses. Studies have showed their presence in human burn wounds; however, their role in burn wound healing remains to be determined. This study investigated the role of DCs in modulating healing responses within the burn wound. A murine model of full‐thickness contact burns was used to study wound healing in the absence of DCs (CD11c promoter‐driven diphtheria toxin receptor transgenic mice) and in a DC‐rich environment (using fms‐like tyrosine kinase‐3 ligand, FL‐ a DC growth factor). Wound closure was significantly delayed in DC‐deficient mice and was associated with significant suppression of early cellular proliferation, granulation tissue formation, wound levels of TGFβ1 and formation of CD31⁺ vessels in healing wounds. In contrast, DC enhancement significantly accelerated early wound closure, associated with increased and accelerated cellular proliferation, granulation tissue formation, and increased TGFβ1 levels and CD31⁺ vessels in healing wounds. We conclude that DCs play an important role in the acceleration of early wound healing events, likely by secreting factors that trigger the proliferation of cells that mediate wound healing. Therefore, pharmacological enhancement of DCs may provide a therapeutic intervention to facilitate healing of burn wounds.     

应用热诱导凋亡法制备靶向胶质瘤细胞的树突状细胞疫苗

目的 应用热诱导凋亡U251细胞致敏树突状细胞,观察其诱导特异性细胞毒性T细胞的能力,探讨其对肿瘤细胞的杀伤机制.方法 应用改良Inaba法,从小鼠骨髓细胞中诱导出树突状细胞,应用电镜和流式细胞技术行表型鉴定,然后和经热诱导凋亡的胶质瘤细胞共培养获得树突状细胞疫苗,细胞计数试剂盒( CCK-8)检测疫苗在体外促T细胞增殖和杀伤肿瘤细胞作用,将疫苗经尾静脉注入荷瘤裸鼠体内,检测体内肿瘤生长抑制作用.结果 44℃孵育3h能有效诱导胶质瘤细胞凋亡,凋亡率达(40.10±1.08)％.负载凋亡细胞抗原的树突状细胞在体外能有效促进T细胞增殖,增加干扰素(IFN)-γ的分泌,并随效靶比增加,对胶质瘤细胞的杀伤率增大.体内注射疫苗4周后,治疗组肿瘤体积(301.704±21.659) mm3,空白对照组为(487.116 ±65.975) mm3,差异有统计学意义(P＜0.01).结论 热诱导凋亡胶质瘤细胞致敏的树突状细胞能在体外有效促进T细胞增殖,诱导特异性细胞毒性T细胞杀伤胶质瘤细胞,有效抑制体内肿瘤生长.     

Dendritic branch typing and spine expression patterns in cortical nonpyramidal cells

To understand the dendritic differentiation in various types of cortical nonpyramidal cells, we analyzed quantitatively their dendritic branching and spine expression. The dendritic internode and interspine interval obeyed exponential distributions with type-specific decay constants. The initial branching pattern, internode interval and spine density at the light microscopic level divided nonpyramidal cells into three dendritic types, correlated with axonal, neurochemical and firing types. The initial branching pattern determined the overall vertical spread of dendrites. Basket cell subtypes with different firing and chemical expression patterns were distinct in the vertical and horizontal spatial spread, providing diverse input territories. Internode densities of dendritic spines, as well as those of axonal synaptic boutons, did not correlate with the tortuosities and intervals, suggesting a tendency to distribute synapses homogeneously over the arbor. Dendritic spines identified at the electron microscopic level were different in length and shape among subtypes. Although the density was lower than that of pyramidal cells, spines themselves were also composed of several morphological types such as mushroom and multihead ones, which were expressed differentially among subtypes. Correlation of dendritic branching characteristics with differences in spine structure suggests distinct ways to receive specific inputs among the subtypes.     

Dendritic cells pulsed with pancreatic cancer total tumor RNA generate specific antipancreatic cancer T cells

RNA-based dendritic cell immunotherapy with the use of total tumor RNA provides the potential to generate a polyclonal immune response to multiple known and unknown tumor antigens without HLA restriction. Our study evaluated this approach as potential immunotherapy for patients with pancreatic cancer. Dendritic cells were generated using adherent monocytes isolated from peripheral blood of patients with pancreatic cancer and evaluated phenotypically by flow cytometry to determine whether dendritic cells could be generated from the blood of patients with pancreatic cancer. Immature dendritic cells were transfected with mRNA encoding full-length carcinoembryonic antigen (CEA) or pancreatic cancer total tumor messenger RNA, and then matured. Matured dendritic cell phenotypes were also analyzed by flow cytometry. Transfected, matured dendritic cells were used to stimulate autologous T cells, and the resultant antigen-specific effector T cells were analyzed by interferon-γ Elispot assay. Immature dendritic cells with characteristic phenotypic markers CD40, CD80, and CD86 were successfully isolated from the blood of patients with pancreatic cancer. Incubation with maturation agents increased expression of CD80 and CD83, demonstrating the induction of a mature antigen-presenting phenotype. Dendritic cells transfected with a pancreatic cancer-associated antigen (CEA) generated antigen-specific T cells (P < 0.05). Dendritic cells transfected with autologous total tumor pancreatic cancer RNA generated T cells that specifically recognized HLA-matched pancreatic cancer cell lines (P < 0.05 compared to control cell lines). Dendritic cells from patients with pancreatic cancer maintain the ability to translate and process transfected RNA and serve as mature antigen-presenting cells. These RNA-transfected dendritic cells from pancreatic cancer patients successfully generate specific T cells against the pancreatic cancer-associated antigen CEA as well as T cells that specifically recognize pancreatic cancer cells. These data suggest that total tumor RNA-pulsed dendritic cells may have potential as an adjuvant immunotherapy for patients with pancreatic cancer. Presented at the Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 19–22, 2003 (oral presentation). Supported by a National Research Service Award (M.F.K.) and by a grant from the Lustgarten Foundation (D.S.T.).     

Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction

Acute urinary obstruction causes interstitial inflammation with leukocyte accumulation and the secretion of soluble mediators. Here we show that unilateral ureteral ligation caused a progressive increase in renal F4/80(+) and F4/80(-) dendritic cells, monocytes, neutrophils and T-cells 24-72 h following obstruction. Depletion of dendritic cells by clodronate pretreatment showed these cells to be the most potent source of tumor necrosis factor and other pro-inflammatory mediators in the obstructed kidney. F4/80(+) dendritic cells and T-cells co-localized in the cortico-medullary junction and cortex of the obstructed kidney. Cytokine secretion patterns and surface phenotypes of T-cells from obstructed kidneys were found to include interferon-gamma-secreting CD4(+) and CD8(+) memory T-cells as well as interleukin 17 (IL-17)-secreting CD4(+) memory T-cells. Depletion of the intra-renal dendritic cells prior to ligation did not numerically reduce T-cells in obstructed kidneys but attenuated interferon-gamma and IL-17-competent T-cells. Our study shows that intra-renal dendritic cells are a previously unidentified early source of proinflammatory mediators after acute urinary obstruction and play a specific role in recruitment and activation of effector-memory T-cells including IL-17-secreting CD4(+) T-cells.     

胰腺癌黏蛋白4基因修饰的树突状细胞疫苗构建及对胰腺癌细胞的免疫效应

Objective To obtain the dendritic cells ( DC)-based vaccine modified by adenovirus containing MUC4 gene , and evaluate the anti-tumor efficacy of DC vaccine to pancreatic tumor cells. Meth-ods The mRNA sequence of tumor associated antigen, MUC4, was obtained from NCBI, and MUC4 se-quence was acquired through the restriction enzyme sites and over lap PCR, then subcloned into adenovirus plasmid to create recombinant adenovirus ( rAd-MUC4) . The DCs were infected by rAd-MUC4 virus and then stimulated the lymph cells from the same donor to induce MUC4 specific cytotoxicity T lympbocytes ( CTL) . The efficacy of CTL was analyzed by LDH releasing assay. Elispot was used to detect the IFN-γ release. Results The recombinant adenovirus containing MUC4 ( sv12) gene was obtained. The MUC4-induced CTL could specifically kill the Capan-1 pancreatic tumor cells [ ( 13. 7±6.0)% , ( 21.4± 4. 7)% , (36.1±9. 5)% at ratios of 10: ,20: ,40: ] , higher than MCF-7 and Bxpc-3 cells respectively, P < 0. 05. The spots number of CTL induced by rAd-MUC4 was ( 139.1±23.3) , more than GFP and PBS control group,P<0.05. Conclusion The Muc4 gene modified DC vaccine could induce the proliferation of CTL, which provided a significant cytotoxicity to HLA-matched MUC4 positive tumor cell lines in vitro.     

胰腺癌黏蛋白4基因修饰的树突状细胞疫苗构建及对胰腺癌细胞的免疫效应

Objective To obtain the dendritic cells ( DC)-based vaccine modified by adenovirus containing MUC4 gene , and evaluate the anti-tumor efficacy of DC vaccine to pancreatic tumor cells. Meth-ods The mRNA sequence of tumor associated antigen, MUC4, was obtained from NCBI, and MUC4 se-quence was acquired through the restriction enzyme sites and over lap PCR, then subcloned into adenovirus plasmid to create recombinant adenovirus ( rAd-MUC4) . The DCs were infected by rAd-MUC4 virus and then stimulated the lymph cells from the same donor to induce MUC4 specific cytotoxicity T lympbocytes ( CTL) . The efficacy of CTL was analyzed by LDH releasing assay. Elispot was used to detect the IFN-γ release. Results The recombinant adenovirus containing MUC4 ( sv12) gene was obtained. The MUC4-induced CTL could specifically kill the Capan-1 pancreatic tumor cells [ ( 13. 7±6.0)% , ( 21.4± 4. 7)% , (36.1±9. 5)% at ratios of 10: ,20: ,40: ] , higher than MCF-7 and Bxpc-3 cells respectively, P < 0. 05. The spots number of CTL induced by rAd-MUC4 was ( 139.1±23.3) , more than GFP and PBS control group,P<0.05. Conclusion The Muc4 gene modified DC vaccine could induce the proliferation of CTL, which provided a significant cytotoxicity to HLA-matched MUC4 positive tumor cell lines in vitro.     

胰腺癌黏蛋白4基因修饰的树突状细胞疫苗构建及对胰腺癌细胞的免疫效应

Objective To obtain the dendritic cells ( DC)-based vaccine modified by adenovirus containing MUC4 gene , and evaluate the anti-tumor efficacy of DC vaccine to pancreatic tumor cells. Meth-ods The mRNA sequence of tumor associated antigen, MUC4, was obtained from NCBI, and MUC4 se-quence was acquired through the restriction enzyme sites and over lap PCR, then subcloned into adenovirus plasmid to create recombinant adenovirus ( rAd-MUC4) . The DCs were infected by rAd-MUC4 virus and then stimulated the lymph cells from the same donor to induce MUC4 specific cytotoxicity T lympbocytes ( CTL) . The efficacy of CTL was analyzed by LDH releasing assay. Elispot was used to detect the IFN-γ release. Results The recombinant adenovirus containing MUC4 ( sv12) gene was obtained. The MUC4-induced CTL could specifically kill the Capan-1 pancreatic tumor cells [ ( 13. 7±6.0)% , ( 21.4± 4. 7)% , (36.1±9. 5)% at ratios of 10: ,20: ,40: ] , higher than MCF-7 and Bxpc-3 cells respectively, P < 0. 05. The spots number of CTL induced by rAd-MUC4 was ( 139.1±23.3) , more than GFP and PBS control group,P<0.05. Conclusion The Muc4 gene modified DC vaccine could induce the proliferation of CTL, which provided a significant cytotoxicity to HLA-matched MUC4 positive tumor cell lines in vitro.