Plasticity Of Dendritic Cells Research Articles

Dendritic Cell Plasticity, Radiation, and Newton's Third Law.

Regulatory T cells protect damaged tissues but can undermine the effects of cancer treatments, including radiotherapy (RTx). Intratumoral immunostimulatory dendritic cells (type 1 conventional dendritic cells) respond to RTx with the production of regulatory T cell-attracting MDC/CCL22, undermining RTx effects. That effect can be reversed by EGFR-targeted IFNα, highlighting cDC1 plasticity and relevance as therapeutic targets. See related article by Bugno et al., p. 4450.

Possibilities of using dendritic cell vaccine in treatment of radiation injury of the bladder

Background . Radiation therapy for patients with cervical and endometrial cancer is often associated with the development of radiation cystitis which is treated mainly symptomatically. Objective was the rationale for dendritic cell vaccines in the treatment of the bladder damage after radiation therapy. Materials and methods . The treatment effectiveness of late radiation damage to the bladder in 26 oncogynecologic patients after chemoradiotherapy was analyzed in the article. Results . The effectiveness of 25.000.000 autologous dendritic cells vaccine introduced into all the tops of the rhombus of Michaelis for 5 cycles with 2-week intervals was proved. Mucosal erosions, ulcerous defects and telangiectasia during dendritic cell therapy were managed in 100, 81.8 and 78.6 % of cases, respectively, while in control — in 66.7, 50 and 30 % of cases, respectively (p <0.05). One of the mechanisms of action of dendritic cell vaccines in the treatment of radiation injuries may comprise a high phenotypic plasticity of dendritic cells and macrophages and their ability to regulate inflammatory and anti-inflammatory functions and regenerate and repair damaged tissues. Conclusion . The results of treatment for radiation cystitis resistant to the standard anti-inflammatory therapies demonstrate the obvious benefits of immunotherapy.

Sphingosine 1-Phosphate Receptor 3-Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury.

The plasticity of dendritic cells (DCs) permits phenotypic modulation ex vivo by gene expression or pharmacologic agents, and these modified DCs can exert therapeutic immunosuppressive effects in vivo through direct interactions with T cells, either inducing T regulatory cells (T(REG)s) or causing anergy. Sphingosine 1-phosphate (S1P) is a sphingolipid and the natural ligand for five G protein-coupled receptors (S1P1, S1P2, S1P3, S1P4, and S1P5), and S1PR agonists reduce kidney ischemia-reperfusion injury (IRI) in mice. S1pr3(-/-)mice are protected from kidney IRI, because DCs do not mature. We tested the therapeutic advantage of S1pr3(-/-) bone marrow-derived dendritic cell (BMDC) transfers in kidney IRI. IRI produced a rise in plasma creatinine (PCr) levels in mice receiving no cells (NCs) and mice pretreated with wild-type (WT) BMDCs. However, S1pr3(-/-) BMDC-pretreated mice were protected from kidney IRI. S1pr3(-/-) BMDC-pretreated mice had significantly higher numbers of splenic T(REG)s compared with NC and WT BMDC-pretreated mice. S1pr3(-/-) BMDCs did not attenuate IRI in splenectomized, Rag-1(-/-), or CD11c(+) DC-depleted mice. Additionally, S1pr3(-/-) BMDC-dependent protection required CD169(+)marginal zone macrophages and the macrophage-derived chemokine CCL22 to increase splenic CD4(+)Foxp3(+) T(REG)s. Pretreatment with S1pr3(-/-) BMDCs also induced T(REG)-dependent protection against IRI in an allogeneic mouse model. In summary, adoptively transferred S1pr3(-/-) BMDCs prevent kidney IRI through interactions within the spleen and expansion of splenic CD4(+)Foxp3(+) T(REG)s. We conclude that genetically induced deficiency of S1pr3 in allogenic BMDCs could serve as a therapeutic approach to prevent IRI-induced AKI.

MicroRNAs and dendritic cell-based vaccination in melanoma patients

MicroRNAs are increasingly being recognized to play an important role in finely tuning gene expression; therefore, their dysregulation in cancer has been investigated extensively. In terms of melanoma, they are involved in the regulation of many genes and pathways impacting invasiveness, dissemination, and disease progression. Many microRNAs also target genes regulating ontogenesis and functions of the immune system. Indeed, fine-tuning of gene expression by microRNAs is necessary for normal differentiation of the various components of the immune system and for mounting an effective innate and cell-mediated response, which has been shown to be able to control tumor growth. Dendritic cells, by presenting antigens to and activating naive T cells, constitute a critical aspect and have been therefore been used in many studies of cancer vaccination with promising results. Many genes regulating functions and plasticity of dendritic cells are indeed targeted by microRNAs, whose expression is also dependent on maturation status. Therefore, microRNAs could provide new potential therapeutic targets both on the tumor and on the immune system, and could also be used to characterize dendritic cells utilized in immunotherapy trials.

Dendritic Cell Plasticity in Tumor-Conditioned Skin: CD14+ Cells at the Cross-Roads of Immune Activation and Suppression

Tumors abuse myeloid plasticity to re-direct dendritic cell (DC) differentiation from T cell stimulatory subsets to immune-suppressive subsets that can interfere with anti-tumor immunity. Lined by a dense network of easily accessible DC the skin is a preferred site for the delivery of DC-targeted vaccines. Various groups have recently been focusing on functional aspects of DC subsets in the skin and how these may be affected by tumor-derived suppressive factors. IL-6, Prostaglandin-E2, and IL-10 were identified as factors in cultures of primary human tumors responsible for the inhibited development and activation of skin DC as well as monocyte-derived DC. IL-10 was found to be uniquely able to convert fully developed DC to immature macrophage-like cells with functional M2 characteristics in a physiologically highly relevant skin explant model in which the phenotypic and functional traits of “crawl-out” DC were studied. Mostly from mouse studies, the JAK2/STAT3 signaling pathway has emerged as a “master switch” of tumor-induced immune suppression. Our lab has additionally identified p38-MAPK as an important signaling element in human DC suppression, and recently validated it as such in ex vivo cultures of single-cell suspensions from melanoma metastases. Through the identification of molecular mechanisms and signaling events that drive myeloid immune suppression in human tumors, more effective DC-targeted cancer vaccines may be designed.

Clinical and fundamental aspects of monocyte, macrophage and dendritic cell plasticity

The scientists gathering at the EMDS 2011meeting did not need to await theannouncement of the Nobel Prize inPhysiology Medicine to Bruce Beutler,Jules Hoffmann and Ralph Steinman [1]to be convinced of the crucial roleof TLRs and myeloid cells (MCs),such as DCs, in both innate and adaptiveimmune responses. Indeed, cells of themyeloid lineage – in particular monocytes,macrophages and DCs – are centralorchestrators of inflammation and innateand adaptive immunity, but, conversely,can also contribute to the resolutionphase of inflammation and woundhealing and thus play an important rolein a range of normal physiologicalprocesses and diseases. Hereto, MCs areamong the most versatile cells of theimmune system and exhibit a highdegree of functional and phenotypicplasticity in response to the micro-envir-onmental triggers to which they areexposed. The importance of these cellshas been highlighted recently in thisJournal with a Viewpoint series on dendri-tic cells introduced by Ralph Steinman [2]and a Viewpoint series on macrophagesintroduced by Siamon Gordon andAlberto Mantovani [3]; the latter beingpublished to coincide with the EMDS 2011meeting.

Plasticity of dendritic cells during differentiation and maturation

In general, there are two major immunotherapeuticstrategies for the induction of the immunological response:1) active immunotherapy based on the use of dendritic cells(DCs) for the activation of the immunological system and 2)passive immunotherapy based on the use of antigen-specificT lymphocytes or of components of the immunological systemsuch as anti-tumor antibodies.In contrast to standard vaccines used for diseaseprevention, vaccines based on DCs used for anti-tumortreatment or against infectious agents are developedexclusively in order to induce the immunological system toreact vigorously against diseases already installed.

The Plasticity of Dendritic Cells at the Host/Fungal Interface

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