M-DC8+leukocytes - A novel human dendritic cell population

Dendritic cells (DC) constitute a heterogeneous leukocyte population having in common a unique capacity to induce primary T cell responses and are therefore most attractive candidates for immunomodulatory strategies. Two populations of blood DC (CD11c+ CD123(dim) and CD11c- CD123(high)) have been defined so far. However, their direct isolation for experimental purposes is hampered by their low frequency and by the lack of selective markers allowing large scale purification from blood. Here we describe the monoclonal antibody (mAb) M-DC8, which was generated by immunizing mice with highly enriched blood DC. This mAb specifically reacts with 0.2-1% of blood leukocytes and enables their direct isolation by a one-step immunomagnetic procedure from fresh mononuclear cells. These cells can be differentiated from T cells, B cells, NK cells and monocytes using lineage-specific antibodies. M-DC8+ cells express HLA class It molecules, CD33 and low levers of the costimulatory molecules CD86 and CD40. Upon in vitro culture M-DC8+ cells spontaneously mature into cells with the phenotype of highly stimulatory cells as documented by the upregulation of HLA-DR, CD86 and CD40; in parallel CD80 expression is induced. M-DC8+ cells display an outstanding capacity to present antigen. In particular, they proved to be excellent stimulators of autologous mixed leukocyte reaction and to activate T cells against primary antigens such as keyhole limpet hemocyanin. Furthermore, they induce differentiation of purified allogeneic cytotoxic T cells into alloantigen-specific cytotoxic effector cells. While the phenotypical analysis reveals similarities with the two known blood DC populations, the characteristic expression of Fc gamma RIII (CD16) and the M-DC8 antigen clearly defines them as a novel population of blood DC. The mAb M-DC8 might thus be a valuable tool to determine circulating DC for diagnostic purposes and to isolate these cells for studies of antigen-specific T cell priming. Copyright (C) 2000 S. Karger AG, Basel

SPRACHGEWAND(T) : sprachkritische Schreibweisen in der DDR-Lyrik von Bert Papenfuß-Gorek und Stefan Döring

Die vorliegende Studie, ein überarbeiteter und erweiterter Teil meiner Magisterarbeit "Der Mythos des Anderen. Sprechakte und Sprachräume jenseits des Herrschaftsdiskurses in der DDR-Lyrik der siebziger und achtziger Jahre", beschäftigt sich mit der sogenannten "jungen" ostdeutschen Literatur aus der späten DDR, die unter der irreführenden Chiffre "Prenzlauer- Berg-Literatur" in die Forschung eingegangen ist. Sie konzentriert sich auf eine Strömung innerhalb dieser Literatur, die sich vorläufig mit dem Begriff "Sprachkritik" umschreiben läßt. Stefan Döring und Bert Papenfuß-Gorek gehören zu den bekanntesten Vertretern dieser Strömung. In exemplarischen Textanalysen gilt es, charakteristische Merkmale ihrer Dichtung herauszuarbeiten und einen Zugang zu den mitunter sperrigen Texten anzubieten. Bert Papenfuß-Gorek ist einer der wenigen Prenzlauer-Berg-Literaten, der sich auch auf dem westdeutschen Buchmarkt etablieren konnte - bis heute erschienen von ihm mehr als zwölf Gedichtbände sowie zahlreiche Beiträge in Zeitschriften und Anthologien. 1989 wurde er mit dem Erich Fried-Preis ausgezeichnet. Grund genug, abschließend einen Blick auf die Nach-Wende-Lyrik dieses Autors zu werfen.The present study, a revised and extended part of my thesis "Der Mythos des Anderen. Sprechakte und Sprachräume jenseits des Herrschaftsdiskurses in der DDR-Lyrik der siebziger und achtziger Jahre", deals with the so-called "young" East German literature of the seventies and eighties, better known as "Prenzlauer-Berg-Literature". It is focused on a subject, that can preliminarily be described as "language criticism". Stefan Döring and Bert Papenfuß-Gorek were and are still considered to be two of the well known and most productive representatives of this movement. Some examplary analyses represent the important characteric features of their lyrics. In addition it is the intention to give an idea, how these sometimes hermetic textes "could" be read. Bert Papenfuß-Gorek is one of a small group of "Prenzlauer-Berg-Poets", who could establish himself on the western book market. Up to now, he has published more than twelve collections of poems and a countless number of lyrics in magazines, artist books and anthologies. In 1998 he was honoured with the famous "Erich Fried-Preis". Reason enough to take at least a short look on his poetry after the year 1989

Einbindung von Erzeugungsanlagen mit Vollumrichter in das Überlagerungsverfahren zur Kurzschlussstromberechnung

This article presents an expansion of the superposition method for short circuit current calculations to take the voltage-dependent fault ride through behavior of power plants with a full-scale converter into account. Furthermore, it shows the physical limits of the short circuit current contribution to the grid required by the German Technical Connection Rules. Exceeding these physical limits through the short circuit current contribution of power plants with a full-scale converter leads to convergence problems of the developed iterative short circuit current calculation method. In order to identify the power plants with an impermissible short circuit contribution, the permissible operating points depending on the short circuit voltage are derived. An illustrative short circuit current calculation shows the influence of the pre-fault load flow as well as the effects of an active current feed-in during the short circuit on the initial short circuit current.In diesem Aufsatz wird eine Erweiterung des Überlagerungsverfahrens vorgestellt, um das spannungsabhängige Fault Ride Through-Verhalten von Erzeugungsanlagen mit Vollumrichter zur Berechnung des betriebspunktabhängigen Anfangs-Kurzschlusswechselstroms zu berücksichtigen. Zudem werden die physikalischen Grenzen des in den Technischen Anschlussregeln in Deutschland geforderten Kurzschlussstrombeitrags aufgezeigt. In dem entwickelten iterativen Kurzschlussstromberechnungsverfahren führt das Überschreiten der physikalischen Grenzen durch den Kurzschlussstrombeitrag der Erzeugungsanlagen mit Vollumrichter zu Konvergenzproblemen. Zur Identifikation der betroffenen Anlagen werden die zulässigen bzw. unzulässigen Betriebspunkte in Abhängigkeit von der Kurzschlussspannung hergeleitet. Eine exemplarische Kurzschlussstromberechnung zeigt den Einfluss des Vorfehlerzustandes der Erzeugungsanlagen mit Vollumrichter sowie die Auswirkungen einer Wirkstromeinspeisung im Kurzschlusszustand auf den Anfangs-Kurzschlusswechselstrom

Auricular Oedema and Dyshidrotic Eczema in a Patient with Acute Myeloid Leukaemia Treated with Cytarabine

Cytarabine is an effective drug in the treatment of haematological malignancies. The therapy is associated with various complications. Frequencies of dermatological side-effects range from 2–72% and occur most commonly after high-dose regimens. Although most cutaneous reactions are mild and resolve spontaneously within several days, they may result in an increased risk of infection and alterations in comfort. In some cases, severe life-threatening reactions have been reported. Here we describe the case of a patient with acute myeloid leukaemia, who developed severe exceptional skin toxicity in terms of auricular oedema and palmar dyshidrotic eczema after the application of low-dose cytarabine. Re-administration of the drug resulted in reduced skin toxicity during further cycles of chemotherapy. Negative epicutaneous patch-testing supported the existence of cytarabine-provoked toxicity

Impact of p38 mitogen-activated protein kinase inhibition on immunostimulatory properties of human 6-sulfo LacNAc dendritic cells

p38 Mitogen-activated protein kinase (MAPK) plays a crucial role in the induction and regulation of innate and adaptive immunity. Furthermore, p38 MAPK can promote tumor invasion, metastasis, and angiogenesis. Based on these properties, p38 MAPK inhibitors emerged as interesting candidates for the treatment of immune-mediated disorders and cancer. However, the majority of p38 MAPK inhibitor-based clinical trials failed due to poor efficacy or toxicity. Further studies investigating the influence of p38 MAPK inhibitors on immunomodulatory capabilities of human immune cells may improve their therapeutic potential. Here, we explored the impact of the p38 MAPK inhibitor SB203580 on the pro-inflammatory properties of native human 6-sulfo LacNAc dendritic cells (slanDCs). SB203580 did not modulate maturation of slanDCs and their capacity to promote T-cell proliferation. However, SB203580 significantly reduced the production of pro-inflammatory cytokines by activated slanDCs. Moreover, inhibition of p38 MAPK impaired the ability of slanDCs to differentiate naïve CD4(+) T cells into T helper 1 cells and to stimulate interferon-γ secretion by natural killer cells. These results provide evidence that SB203580 significantly inhibits various important immunostimulatory properties of slanDCs. This may have implications for the design of p38 MAPK inhibitor-based treatment strategies for immune-mediated disorders and cancer

The CD16+ (FcγRIII+) Subset of Human Monocytes Preferentially Becomes Migratory Dendritic Cells in a Model Tissue Setting

Much remains to be learned about the physiologic events that promote monocytes to become lymph-homing dendritic cells (DCs). In a model of transendothelial trafficking, some monocytes become DCs in response to endogenous signals. These DCs migrate across endothelium in the ablumenal-to-lumenal direction (reverse transmigration), reminiscent of the migration into lymphatic vessels. Here we show that the subpopulation of monocytes that expresses CD16 (Fcγ receptor III) is predisposed to become migratory DCs. The vast majority of cells derived from CD16+ monocytes reverse transmigrated, and their presence was associated with migratory cells expressing high levels of CD86 and human histocompatibility leukocyte antigen (HLA)-DR, and robust capacity to induce allogeneic T cell proliferation. A minority of CD16− monocytes reverse transmigrated, and these cells stimulated T cell proliferation less efficiently. CD16 was not functionally required for reverse transmigration, but promoted cell survival when yeast particles (zymosan) were present as a maturation stimulus in the subendothelial matrix. The cell surface phenotype and migratory characteristics of CD16+ monocytes were inducible in CD16− monocytes by preincubation with TGFβ1. We propose that CD16+ monocytes may contribute significantly to precursors for DCs that transiently survey tissues and migrate to lymph nodes via afferent lymphatic vessels

Draft Genome Sequences of Three Porcine Streptococcus suis Isolates Which Differ in Their Susceptibility to Penicillin

The draft genome sequences of three Streptococcus suis isolates, IMT40343, IMT40201, and IMT40738, are presented here. These isolates were obtained from bronchoalveolar lavage fluid of healthy and diseased weaners from different German piglet-producing farms and differed in their susceptibility to penicillin

A Novel Modular Antigen Delivery System for Immuno Targeting of Human 6-sulfo LacNAc-Positive Blood Dendritic Cells (SlanDCs)

Previously, we identified a major myeloid-derived proinflammatory subpopulation of human blood dendritic cells which we termed slanDCs (e.g. Schäkel et al. (2006) Immunity 24, 767-777). The slan epitope is an O-linked sugar modification (6-sulfo LacNAc, slan) of P-selectin glycoprotein ligand-1 (PSGL-1). As slanDCs can induce neoantigen-specific CD4+ T cells and tumor-reactive CD8+ cytotoxic T cells, they appear as promising targets for an in vivo delivery of antigens for vaccination. However, tools for delivery of antigens to slanDCs were not available until now. Moreover, it is unknown whether or not antigens delivered via the slan epitope can be taken up, properly processed and presented by slanDCs to T cells.Single chain fragment variables were prepared from presently available decavalent monoclonal anti-slan IgM antibodies but failed to bind to slanDCs. Therefore, a novel multivalent anti-slanDC scaffold was developed which consists of two components: (i) a single chain bispecific recombinant diabody (scBsDb) that is directed on the one hand to the slan epitope and on the other hand to a novel peptide epitope tag, and (ii) modular (antigen-containing) linker peptides that are flanked at both their termini with at least one peptide epitope tag. Delivery of a Tetanus Toxin-derived antigen to slanDCs via such a scBsDb/antigen scaffold allowed us to recall autologous Tetanus-specific memory T cells.In summary our data show that (i) the slan epitope can be used for delivery of antigens to this class of human-specific DCs, and (ii) antigens bound to the slan epitope can be taken up by slanDCs, processed and presented to T cells. Consequently, our novel modular scaffold system may be useful for the development of human vaccines

Human innate immune cell crosstalk induces melanoma cell senescence

Mononuclear phagocytes and NK cells constitute the first line of innate immune defense. How these cells interact and join forces against cancer is incompletely understood. Here, we observed an early accumulation of slan$^{+}$ (6-sulfo LacNAc) non-classical monocytes (slanMo) in stage I melanoma, which was followed by an increase in NK cell numbers in stage III. Accordingly, culture supernatants of slanMo induced migration of primary human NK cells in vitro via the chemotactic cytokine IL-8 (CXCL8), suggesting a role for slanMo in NK cell recruitment into cancer tissues. High levels of TNF-α and IFN-γ were produced in co-cultures of TLR-ligand stimulated slanMo and NK cells, whereas much lower levels were contained in cultures of slanMo and NK cells alone. Moreover, TNF-α and IFN-γ concentrations in slanMo/NK cell co-cultures exceeded those in CD14$^{+}$ monocyte/NK cell and slanMo/T cell co-cultures. Importantly, TNF-α and IFN-γ that was produced in TLR-ligand stimulated slanMo/NK cell co-cultures induced senescence in different melanoma cell lines, as indicated by reduced melanoma cell proliferation, increased senescence-associated β-galactosidase expression, p21 upregulation, and induction of a senescence-associated secretory phenotype (SASP). Taken together, we identified a role for slanMo and NK cells in a collaborative innate immune defense against melanoma by generating a tumor senescence-inducing microenvironment. We conclude that enhancing the synergistic innate immune crosstalk of slanMo and NK cells could improve current immunotherapeutic approaches in melanoma

Current Concepts on 6-sulfo LacNAc Expressing Monocytes (slanMo)

The human mononuclear phagocytes system consists of dendritic cells (DCs), monocytes, and macrophages having different functions in bridging innate and adaptive immunity. Among the heterogeneous population of monocytes the cell surface marker slan (6-sulfo LacNAc) identifies a specific subset of human CD14− CD16+ non-classical monocytes, called slan+ monocytes (slanMo). In this review we discuss the identity and functions of slanMo, their contributions to immune surveillance by pro-inflammatory cytokine production, and cross talk with T cells and NK cells. We also consider the role of slanMo in the regulation of chronic inflammatory diseases and cancer. Finally, we highlight unresolved questions that should be the focus of future research