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Cancer Vaccine by Fusions of Dendritic and Cancer Cells  [PDF]
Shigeo Koido,Eiichi Hara,Sadamu Homma,Yoshihisa Namiki,Toshifumi Ohkusa,Jianlin Gong,Hisao Tajiri
Clinical and Developmental Immunology , 2009, DOI: 10.1155/2009/657369
Abstract: Dendritic cells (DCs) are potent antigen-presenting cells and play a central role in the initiation and regulation of primary immune responses. Therefore, their use for the active immunotherapy against cancers has been studied with considerable interest. The fusion of DCs with whole tumor cells represents in many ways an ideal approach to deliver, process, and subsequently present a broad array of tumor-associated antigens, including those yet to be unidentified, in the context of DCs-derived costimulatory molecules. DCs/tumor fusion vaccine stimulates potent antitumor immunity in the animal tumor models. In the human studies, T cells stimulated by DC/tumor fusion cells are effective in lysis of tumor cells that are used as the fusion partner. In the clinical trials, clinical and immunological responses were observed in patients with advanced stage of malignant tumors after being vaccinated with DC/tumor fusion cells, although the antitumor effect is not as vigorous as in the animal tumor models. This review summarizes recent advances in concepts and techniques that are providing new impulses to DCs/tumor fusions-based cancer vaccination.
Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice  [PDF]
Guangming Li,Menglan Cheng,Jun-ichi Nunoya,Liang Cheng,Haitao Guo,Haisheng Yu,Yong-jun Liu,Lishan Su ,Liguo Zhang
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004291
Abstract: The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.
Absence of vaccine-enhanced RSV disease and changes in pulmonary dendritic cells with adenovirus-based RSV vaccine
Anja Krause, Yaqin Xu, Sara Ross, Wendy Wu, Ju Joh, Stefan Worgall
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-375
Abstract: RSV is a leading cause of severe viral respiratory disease in infants and children [1]. A major obstacle in the development of an RSV vaccine has been vaccine-enhanced disease triggered by immunization with inactivated virus antigen [2,3]. This aberrant immune-mediated response is characterized by infiltration of neutrophils and eosinophils, increased complement-fixing antibody titers and lymphoproliferative responses [4-7]. The exact mechanism has not been fully elucidated. An altered pattern of CD4 lymphocyte activation with eosinophil recruitment and Th2-type-predominant cytokine production (IL-4, IL-5, IL-13 and eotaxin) suggests an aberrant immune-mediated response skewed towards Th2 responses [4,8-10]. This is supported by data demonstrating that the disease following RSV infection can be transferred by RSV G protein-specific CD4 T cells and also occurs in the absence of CD8 T cells or IFN-γ [11-13]. RSV-specific CD8 T cells can even inhibit the disease [7,13,14]. Initially, the RSV G protein itself was implicated based on studies using vaccinia virus expressing the membrane-anchored part or the entire G protein for immunization [15-17]. Recently, it has been suggested that the pathway of antigen processing, rather than the antigenic content, is responsible [4,7]. In addition, low avidity anti-RSV antibodies, which may have resulted from poor activation of toll-like receptors, have been observed in mice following immunization with FIRSV [18], the most commonly used model to study vaccine-enhanced RSV disease [4,19-21].The RSV F protein, one of the main capsid proteins that confers protective immunity against RSV, has been a major target in RSV vaccine development [22]. Vaccination with the F protein generates helper T cell responses that are Th1 in character [23]. Adenovirus (Ad)-based gene delivery systems are promising platforms for genetic vaccines due to their ability to act as immune system adjuvants and to induce strong cellular and humoral responses aga
Specific targeting of whole lymphoma cells to dendritic cells ex vivo provides a potent antitumor vaccine
Christian Adam, Josef Mysliwietz, Ralph Mocikat
Journal of Translational Medicine , 2007, DOI: 10.1186/1479-5876-5-16
Abstract: We compare various loading reagents including whole parental and modified tumor cells and a single tumor-specific antigen, namely the lymphoma idiotype (Id). Bone marrow-derived DC were pulsed in vitro and used for therapy of established A20 lymphomas.We show that a vaccine with superior antitumor efficacy can be generated when DC are loaded with whole modified tumor cells which provide both (i) antigenic polyvalency and (ii) receptor-mediated antigen internalization. Uptake of cellular material was greatly enhanced when the tumor cells used for DC pulsing were engineered to express an anti-Fc receptor immunoglobulin specificity. Upon transfer of these DC, established tumor burdens were eradicated in 50% of mice. By contrast, pulsing DC with unmodified lymphoma cells or with the lymphoma Id, even when it was endowed with the anti-Fc receptor binding arm, was far less effective. A specific humoral anti-Id response could be detected, particularly following delivery of Id protein-pulsed DC, but it was not predictive of tumor protection. Instead a T-cell response was pivotal for successful tumor protection. Interaction of the transferred DC with CD8+ T lymphocytes seemed to play a role for induction of the immune response but was dispensable when DC had received an additional maturation stimulus.Our analyses show that the advantages of specific antigen redirection and antigenic polyvalency can be combined to generate DC-based vaccines with superior antitumor efficacy. This mouse model may provide information for the standardization of DC-based vaccination protocols.Dendritic cells (DC) are professional antigen-presenting cells (APC) that are effective at presenting immunogenic peptides in the context of major histocompatibility complex (MHC) molecules and providing the costimulatory signals necessary for efficient T-cell stimulation [1-3]. DC-based vaccination against tumor-associated antigens (TAA) has received much interest in experimental cancer therapy. To allow TAA
Preparation of Triple-Negative Breast Cancer Vaccine through Electrofusion with Day-3 Dendritic Cells  [PDF]
Peng Zhang, Shuhong Yi, Xi Li, Ruilei Liu, Hua Jiang, Zenan Huang, Yu Liu, Juekun Wu, Yong Huang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0102197
Abstract: Dendritic cells (DCs) are professional antigen-presenting cells (APCs) in human immune system. DC-based tumor vaccine has met with some success in specific malignancies, inclusive of breast cancer. In this study, we electrofused MDA-MB-231 breast cancer cell line with day-3 DCs derived from peripheral blood monocytes, and explored the biological characteristics of fusion vaccine and its anti-tumor effects in vitro. Day-3 mature DCs were generated from day-2 immature DCs by adding cocktails composed of TNF-α, IL-1β, IL-6 and PEG2. Day-3 mature DCs were identified and electofused with breast cancer cells to generate fusion vaccine. Phenotype of fusion cells were identified by fluorescence microscope and flow cytometer. The fusion vaccine was evaluated for T cell proliferation, secretion of IL-12 and IFN-γ, and induction of tumor-specific CTL response. Despite differences in morphology, day-3 and day-7 DC expressed similar surface markers. The secretion of IL-12 and IFN-γ in fusion vaccine group was much higher than that in the control group. Compared with control group, DC-tumor fusion vaccine could better stimulate the proliferation of allogeneic T lymphocytes and kill more breast cancer cells (MDA-MB-231) in vitro. Day-3 DCs had the same function as the day-7 DCs, but with a shorter culture period. Our findings suggested that day-3 DCs fused with whole apoptotic breast cancer cells could elicit effective specific antitumor T cell responses in vitro and may be developed into a prospective candidate for adoptivet immunotherapy.
Mechanism of Ad5 Vaccine Immunity and Toxicity: Fiber Shaft Targeting of Dendritic Cells  [PDF]
Cheng Cheng equal contributor,Jason G. D Gall equal contributor,Wing-pui Kong,Rebecca L Sheets,Phillip L Gomez,C. Richter King,Gary J Nabel
PLOS Pathogens , 2007, DOI: 10.1371/journal.ppat.0030025
Abstract: Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs) was independent of the coxsackievirus and adenovirus receptor (CAR), its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines.
An effective vaccine against colon cancer in mice: Use of recombinant adenovirus interleukin-12 transduced dendritic cells  [cached]
Xiao-Zhou He, Liang Wang, Yan-Yun Zhang
World Journal of Gastroenterology , 2008,
Abstract: AIM: To investigate the effect of a vaccine with recombinant adenovirus interleukin-12 (AdVIL-12) transduced dendritic cells (DCs) against colon cancer in mice.METHODS: DCs and AdVIL-12 were incubated together at different time intervals and at different doses. Supernatant was collected and tested for IL-12 by enzyme-linked immunosorbent assay (ELISA). In order to determine whether tumor cell lysate-pulsed (TP) AdVIL-12/DCs enhance therapeutic potential in the established tumor model, CT26 colon tumor cells were implanted subcutaneously (s.c.) in the midflank of na ve BALB/c mice. Tumor-bearing mice were injected with a vaccination of CT26 TP AdVIL-12/DCs on d 3 and 10. As a protective colon tumor model, na ve BALB/c mice were immunized s.c. in their abdomens with CT26 TP AdVIL-12/DCs twice at seven day intervals. After the immunization on d 7, the mice were challenged with a lethal dose of CT26 tumor cells and survival times were evaluated. Subsequently, cytotoxic T lymphocyte (CTL) activity and interferon gamma (IFNγ) secretion was evaluated in the immunized mice, and assayed CTL ex vivo.RESULTS: Murine DCs were retrovirally transduced with AdVIL-12 efficiency, and the AdVIL-12 transduced DCs secreted a high level of IL-12 (AdVIL-12/DCs, 615.27 ± 42.3 pg/mL vs DCs, 46.32 ± 7.29 pg/mL, P < 0.05). Vaccination with CT26 TP AdVIL-12/DCs could enhance anti-tumor immunity against CT26 colon tumor in murine therapeutic models (tumor volume on d 19: CT26 TP AdVIL-12/DCs 107 ± 42 mm3 vs CT26 TP DCs 383 ± 65 mm3, P < 0.05) and protective models. Moreover, the CT26 TP AdVIL-12/DC vaccination enhances tumor-specific CTL activity, producing high levels of IFNγ in immunized mice. Ex vivo primed T cells with AdVIL-12/DCs were able to induce more effective CTL activity than in primed T cells with CT26 TP/DCs (E:T = 100:1, 69.49% ± 6.11% specific lysis vs 37.44% ± 4.32% specific lysis, P < 0.05).CONCLUSION: Vaccination with recombinant AdVIL-12 transduced DC pulsed tumor cell lysate enhance anti-tumor immunity specific to colon cancer in mice.
A Novel Cancer Vaccine Strategy Based on HLA-A*0201 Matched Allogeneic Plasmacytoid Dendritic Cells  [PDF]
Caroline Aspord,Julie Charles,Marie-Therese Leccia,David Laurin,Marie-Jeanne Richard,Laurence Chaperot,Joel Plumas
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010458
Abstract: The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy.
Preventing autoimmune arthritis using antigen-specific immature dendritic cells: a novel tolerogenic vaccine
Igor Popov, Mu Li, Xiufen Zheng, Hongtao San, Xusheng Zhang, Thomas E Ichim, Motohiko Suzuki, Biao Feng, Costin Vladau, Robert Zhong, Bertha Garcia, Gill Strejan, Robert D Inman, Wei-Ping Min
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar2031
Abstract: The natural function of immature dendritic cells (DC) is to provide conditions for self-tolerance, either through the generation of regulatory T cells or through the induction of apoptosis or anergy of autoreactive effector cells [1-3]. Several attempts have been made to utilize immature DC therapeutically. Some hurdles unfortunately still exist that prevent the therapeutic use of immature DC: first, only limited protocols are available for generating immature DC; and second, there is a danger that once immature DC are introduced into the host, a maturation event may occur that would actually cause immunogenicity instead of tolerance [4,5]. A direct method of targeting DC maturation involves blocking signal transduction pathways that are necessary for the DC to differentiate. A pathway known to be involved in DC maturation is the cascade that leads to activation of the transcription factor NF-κB. Zanetti and colleagues established that the RelB component of NF-κB is critical for DC maturation in vivo [6].LF 15-0195 (LF) is a chemically synthesized analog of the immune suppressant 15-deoxyspergualin that possesses higher immunosuppressive activity and less in vivo degradation than its parent compound [7]. It has been demonstrated that part of the immune suppressive effects of LF are due to activation of caspases in reactive T cells [8].Our laboratory has focused on the antigen-presenting cell arm of the immune system. We have been the first to demonstrate that LF specifically interferes with DC maturation through inhibiting the activity of IκB kinase (IKK) on its target IKB [9]. The unique ability of LF to target IKK in DC therefore suggests that it may possess distinctive properties allowing the generation of immature tolerogenic DC. Supporting the role of LF as a tolerogenic agent are studies describing induction of 'active' long-term tolerance in situations of autoimmunity, as illustrated in models of experimental autoimmune encephalomyelitis [10,11] and of myasth
Three-day dendritic cells for vaccine development: Antigen uptake, processing and presentation
Maja Bürdek, Stefani Spranger, Susanne Wilde, Bernhard Frankenberger, Dolores J Schendel, Christiane Geiger
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-90
Abstract: In this study, we addressed the properties of antigen uptake, processing and presentation by monocyte-derived DC prepared in three days (3d mDC) compared with conventional DC prepared in seven days (7d mDC), which represent the most common form of DC used for vaccines to date.Although they showed a reduced capacity for spontaneous antigen uptake, 3d mDC displayed higher capacity for stimulation of T cells after loading with an extended synthetic peptide that requires processing for MHC binding, indicating they were more efficient at antigen processing than 7d DC. We found, however, that 3d DC were less efficient at expressing protein after introduction of in vitro transcribed (ivt)RNA by electroporation, based on published procedures. This deficit was overcome by altering electroporation parameters, which led to improved protein expression and capacity for T cell stimulation using low amounts of ivtRNA.This new procedure allows 3d mDC to replace 7d mDC for use in DC-based vaccines that utilize long peptides, proteins or ivtRNA as sources of specific antigen.The benefit of dendritic cells (DC) as adjuvants to induce tumor-specific cytotoxic T cells as well as helper T cells has been demonstrated in animal experiments and initial human trials [1,2]. In different tumor vaccines that were successfully applied in mice, mature DC (mDC) were used that were loaded with tumor antigens, supplied in various forms, including tumor extracts, short peptides or antigen-encoding RNA [3,4]. Several clinical trials using DC as tumor-vaccines have also been performed, where an increased T cell response against tumor-associated antigens could be observed [5].DC are the most potent antigen-presenting cells for the stimulation of na?ve T cells [6]. Immature DC (iDC) patrol peripheral tissues and take up antigens via macropinocytosis, phagocytosis or receptor-mediated endocytosis. After uptake of antigen, iDC process and present antigen-derived peptides on their MHC molecules. Since DC ha
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