• IMMUNE NETWORK
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• v.11 no.6
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• pp.399-405
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• 2011

Background: Endogenous uveitis is a chronic inflammatory eye disease of human, which frequently leads to blindness. Experimental autoimmune uveoretinitis (EAU) is an animal disease model of human endogenous uveitis and can be induced in susceptible animals by immunization with retinal antigens. EAU resembles the key immunological characteristics of human disease in that both are $CD4^+$ T-cell mediated diseases. Dendritic cells (DCs) are specialized antigen-presenting cells that are uniquely capable of activating naive T cells. Regulation of immune responses through modulation of DCs has thus been tried extensively. Recently our group reported that donor strain-derived immature DC pretreatment successfully controlled the adverse immune response during allogeneic transplantation. Methods: EAU was induced by immunization with human interphotoreceptor retinoid-binding protein (IRBP) $peptide_{1-20}$. Dendritic cells were differentiated from bone marrow in the presence of recombinant GM-CSF. Results: In this study, we used paraformaldehyde-fixed bone marrow-derived DCs to maintain them in an immature state. Pretreatment with fixed immature DCs, but not fixed mature DCs, ameliorated the disease progression of EAU by inhibiting uveitogenic $CD4^+$ T cell activation and differentiation. Conclusion: Application of iBMDC prepared according to the protocol of this study would provide an important treatment modality for the autoimmune diseases and transplantation rejection.

• IMMUNE NETWORK
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• v.15 no.3
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• pp.111-120
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• 2015

Dendritic cells (DCs) play a significant role in establishing self-tolerance through their ability to present self-antigens to developing T cells in the thymus. DCs are predominantly localized in the medullary region of thymus and present a broad range of self-antigens, which include tissue-restricted antigens expressed and transferred from medullary thymic epithelial cells, circulating antigens directly captured by thymic DCs through coticomedullary junction blood vessels, and peripheral tissue antigens captured and transported by peripheral tissue DCs homing to the thymus. When antigen-presenting DCs make a high affinity interaction with antigen-specific thymocytes, this interaction drives the interacting thymocytes to death, a process often referred to as negative selection, which fundamentally blocks the self-reactive thymocytes from differentiating into mature T cells. Alternatively, the interacting thymocytes differentiate into the regulatory T (Treg) cells, a distinct T cell subset with potent immune suppressive activities. The specific mechanisms by which thymic DCs differentiate Treg cells have been proposed by several laboratories. Here, we review the literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation, and discusses its potential mechanisms and future directions.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.1
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• pp.11-14
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• 2010

Human tumors, including those of the hepatobiliary system, express a number of specific antigens that can be recognized by T cells, and may provide potential targets for cancer immunotherapy. Dendritic cells (DCs) are rare leucocytes that are uniquely potent in their ability to capture, process and present antigens to T cells. The ability to culture sufficient numbers of DCs from human bone marrow or blood progenitors has attracted a great deal of interest in their potential utilization in human tumor vaccination. $CD34^+$ peripheral blood stem cells (PBSCs) were obtained from a patient with a hepatocellular carcinoma. The PBSCs were cultured in the X-VIVO 20 medium supplemented with the Flt-3 Ligand (FL), GM-CSF, IL-4 and TNF-$\alpha$ for 12 days. The morphology and functions of the cells were examined. The generated cells had the typical morphology of DCs. When the DCs were reinjected into the same patient, an augmentation of the cytotoxic T lymphocyte (CTL) activity was observed. Concomitantly, an increase in the natural killer (NK) cell activity was also detected in the patient. These results suggest that DCs-based cancer immunotherapy may become an important treatment option for cancer patients in the future.

• BMB Reports
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• v.54 no.1
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• pp.31-43
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• 2021

Dendritic cells (DC), which consist of several different subsets, specialize in antigen presentation and are critical for mediating the innate and adaptive immune responses. DC subsets can be classified into conventional, plasmacytoid, and monocyte-derived DC in the tumor microenvironment, and each subset plays a different role. Because of the role of intratumoral DCs in initiating antitumor immune responses with tumor-derived antigen presentation to T cells, DCs have been targeted in the treatment of cancer. By regulating the functionality of DCs, several DC-based immunotherapies have been developed, including administration of tumor-derived antigens and DC vaccines. In addition, DCs participate in the mechanisms of classical cancer therapies, such as radiation therapy and chemotherapy. Thus, regulating DCs is also important in improving current cancer therapies. Here, we will discuss the role of each DC subset in antitumor immune responses, and the current status of DC-related cancer therapies.

• BMB Reports
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• v.43 no.3
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• pp.188-192
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• 2010

Inflammatory reactology has become increasingly important in diabetic kidney disease. In this study, we estabilished STZ-induced diabetic rat model to investigate whether dendritic cells (DCs) mediated tubulointerstitial damages, and whether the effects by DCs were mediated by P-selectin expression and can be inhibited by atorvastatin. The study demonstrated that there was an accumulation of DCs in diabetic rats mediated by P-selectin. It also showed the accumulation of DCs and expression of P-selectin was closely correlated with the degree of renal tubulointerstitial injury. These effects were markedly attenuated by atorvastatin. Thus, DCs play a role in tubulointerstitial damages, atorvasttin can prevent renal tubulointerstitium from damage by inhibiting the P-selectin expression and DCs migration.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.5
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• pp.255-259
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• 2003

Dendritic cells (DCs) play a critical role in various immune responses involving $CD4^+$ T cells and have been used to generate anti-tumor immunity. Chemotherapy induces severe side effects including immunosuppression in patients with cancer. Although immunosuppression has been studied, the effects of anticancer drugs on DCs are not fully determined. In this study, we demonstrated that CD40 activation strongly protected DCs from 5-fluorouracil (5-FU) or mitomycin C-induced apoptosis. DCspecific surface markers, including CD11c and major histocompatibility complex (MHC) class II, were used for identifying DCs. CD 40 activation with anti-CD40 mAb significantly enhanced the viability of DCs treated with 5-FU or mitomycin C, assayed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). Fluorescence staining and analysis clearly confirmed the enhancing effect of anti-CD40 mAb on the viability of DCs, suggesting that CD40 activation may transduce critical signals for the viability of DCs. Annexin V staining assay showed that CD40 significantly protected DCs from 5-FU or mitomycin C-induced apoptosis. Taken together, this study shows that CD40 activation with anti-CD40 mAb has strong anti-apoptosis effect on DCs, suggesting that CD40 activation may overcome the immunosuppression, especially downregulation of number and function of DCs in chemotherapy-treated cancer patients.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.4
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• pp.243-247
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• 2012

Recent studies suggest that immunization with autologous dendritic cells (DCs) results in protective immunity and rejection of established tumors in various human malignancies. The purpose of this study is to determine whether DCs are generated from peripheral blood mononuclear cells (PBMNs) by using cytokines such as F1t-3 ligand (FL), granulocyte macrophage-colony stimulating factor (GM-CSF), IL-4, and TNF-${\alpha}$, and whether cytotoxic T cells activated against the thyroid cancer tissues by the DCs. Peripheral blood was obtained from 2 patients with thyroid cancer. DCs were established from PBMNs by culturing in the presence of FL, GM-CSF, IL-4, and TNF-${\alpha}$ for 14 days. At day 14, the differentiated DCs was analyzed morphologically. The immunophenotypic features of DCs such as CDla, CD83, and CD86 were analyzed by immunofluorelescence microscopy. At day 18, DCs and T cells were incubated with thyroid cancer tissues or normal thyroid tissues for additional 4 days, respectively. DCs generated from the PBMNs showed the typical morphology of DCs. Activated cytotoxic T lymphocytes (CTLs) were observed also. DCs and the CTLs were attached to the cancer tissues on scanning electron microscope. The DCs activated the CTLs, which able to specifically attack the thyroid cancer. This study provides morphologic evidence that the coculture of T cells/cancer tissues activated the T cells and differentiated CTLs. The CTLs tightly adhered to cancer tissues and lysed cancer tissues vigorously. Therefore DCs could be used as potential vaccines in the immunotherapy.

• KSBB Journal
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• v.27 no.5
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• pp.295-300
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• 2012

Matured dendritic cells (DCs) begin migration with their release from the bone marrow (BM) into the blood and subsequent traffic into peripheral lymphoid and non-lymphoid tissues. Throughout this long movement, migrating DCs must apply specialized skills to reach their target destination. Non-invasive in vivo cell-tracking techniques are necessary to advance immune cell-based therapies. In this study, we used a DiD cell-tracking solution for in vivo dendritic cell tracking in naive mice. We tracked DiD (non-invasive fluorescence dye)-labeled mature dendritic cells using the Near Infrared (NIR) imaging system in normal mice. We examined the immunophenotype of DiD-labeled cells compared with non-labelled mature DCs, and obtained time-serial images of NIR-DC trafficking after mouse footpad injection. In conclusion, we confirmed that DiD-labeled DCs migrated into the popliteal lymph node 24 h after the footpad injection. Here, these data suggested that the cell tracking system with the stable fluorescence dye DiD was useful as a cell tracking tool to advance dendritic cell-based immunotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.611-616
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• 2014

Objectives: Dendritic cell (DC)-based tumor immunotherapy needs an immunogenic tumor associated antigen (TAA) and an effective approach for its presentation to lymphocytes. In this study we explored whether transduction of DCs with lentiviruses (LVs) expressing the human interleukin-12 gene could stimulate antigen-specific cytotoxic T cells (CTLs) against human lung cancer cells in vitro. Methods: Peripheral blood monocyte-derived DCs were transduced with a lentiviral vector encoding human IL-12 gene (LV-12). The anticipated target of the human IL-12 gene was detected by RT-PCR. The concentration of IL-12 in the culture supernatant of DCs was measured by ELISA.Transduction efficiencies and CD83 phenotypes of DCs were assessed by flow cytometry. DCs were pulsed with tumor antigen of lung cancer cells (DC+Ag) and transduced with LV-12 (DC-LV-12+Ag). Stimulation of T lymphocyte proliferation by DCs and activation of cytotoxic T-lymphocytes (CTL) stimulated by LV-12 transduced DCs pulsed with tumor antigen against A549 lung cancer cells were assessed with methyl thiazolyltetrazolium (MTT). Results: A recombinant lentivirus expressing the IL-12 gene was successfully constructed. DC transduced with LV-12 produced higher levels of IL-12 and expressed higher levels of CD83 than non-transduced. The DC modified by interleukin -12 gene and pulsed with tumor antigen demonstrated good stimulation of lymphocyte proliferation, induction of antigen-specific cytotoxic T lymphocytes and antitumor effects. Conclusions: Dendritic cells transduced with a lentivirus-mediated interleukin-12 gene have an enhanced ability to kill lung cancer cells through promoting T lymphocyte proliferation and cytotoxicity.

• IMMUNE NETWORK
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• v.12 no.3
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• pp.104-112
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• 2012

Silica is one of the most abundant compounds found in nature. Immoderate exposure to crystalline silica has been linked to pulmonary disease and crystalline silica has been classified as a Group I carcinogen. Ultrafine (diameter <100 nm) silica particles may have different toxicological properties compared to larger particles. We evaluated the effect of ultrafine silica nanoparticles on mouse bone marrow-derived dendritic cells (BMDC) and murine dendritic cell line, DC2.4. The exposure of dendritic cells (DCs) to ultrafine silica nanoparticles showed a decrease in cell viability and an induction of cell death in size- and concentration-dependent manners. In addition, in order to examine the phenotypic changes of DCs following co-culture with silica nanoparticles, we added each sized-silica nanoparticle along with GM-CSF and IL-4 during and after DC differentiation. Expression of CD11c, a typical DC marker, and multiple surface molecules such as CD54, CD80, CD86, MHC class II, was changed by silica nanoparticles in a size-dependent manner. We also found that silica nanoparticles affect inflammatory response in DCs in vitro and in vivo. Finally, we found that p38 and NF-${\kappa}B$ activation may be critical for the inflammatory response by silica nanoparticles. Our data demonstrate that ultrafine silica nanoparticles have cytotoxic effects on dendritic cells and immune modulation effects in vitro and in vivo.