Development of a Neurotensin-Derived Ga-Labeled PET Ligand with High In Vivo Stability for Imaging of NTS Receptor-Expressing Tumors.

Overexpression of the neurotensin receptor type 1 (NTSR), a peptide receptor located at the plasma membrane, has been reported for a variety of malignant tumors. Thus, targeting the NTSR with F- or Ga-labeled ligands is considered a straightforward approach towards in vivo imaging of NTSR-expressing tumors via positron emission tomography (PET). The development of suitable peptidic NTSR PET ligands derived from neurotensin is challenging due to proteolytic degradation.

Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy.

Engineered regulatory T cell (Treg cell) therapy is a promising strategy to treat patients suffering from inflammatory diseases, autoimmunity, and transplant rejection. However, in many cases, disease-related antigens that can be targeted by Treg cells are not available. In this study, we introduce a class of synthetic biosensors, named artificial immune receptors (AIRs), for murine and human Treg cells.

BMP6-induced modulation of the tumor micro-milieu.

Melanoma is the deadliest form of skin cancer with rising incidence, creating a significant health problem. We discovered increased expression of bone morphogenetic protein 6 (BMP6) in melanoma cells and tissues, and observed that BMP6 deficiency caused significantly delayed tumor onset and decelerated tumor progression in a melanoma mouse model. Moreover, we determined that BMP6 inhibits dermal mast cell recruitment and found that mast cell-derived mediators significantly reduced melanoma growth in vitro.

TNF and regulatory T cells are critical for sepsis-induced suppression of T cells.

The immune system in sepsis is impaired as seen by reduced numbers and function of immune cells and impaired antigen-specific antibody responses. We studied T cell function in septic mice using cecal ligation and puncture (CLP) as a clinically relevant mouse model for sepsis. The proliferative response of CD4(+) and CD8(+) T cells was suppressed in septic mice.

High-Resolution Ultrasound Including Contrast-Enhanced Ultrasound (CEUS) for the Detection of Gas Formation during Aspergillus Fumigatus Infection in Mice.

Purpose: A. fumigatus infections represent a major threat for patients with a suppressed immune system. Early diagnosis is of importance for a favorable outcome but appears to be difficult due to limited diagnostic procedures.

Woronin bodies, their impact on stress resistance and virulence of the pathogenic mould Aspergillus fumigatus and their anchoring at the septal pore of filamentous Ascomycota.

Hyphae of filamentous Ascomycota consist of compartments that are connected via septal pores. To avoid a dramatic loss of cellular content after wounding, fungi developed mechanisms to occlude their septal pores. In most Pezizomycotina, so-called Woronin bodies are anchored in proximity to the pore.

TLR5 stop codon polymorphism is associated with invasive aspergillosis after allogeneic stem cell transplantation.

Single nucleotide polymorphisms (SNPs) have been associated with an increased incidence of invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT). We analyzed 41 patients with proven/probable IA after allo-SCT for an association of SNPs, within the TLR2, TLR4, TLR5, TLR9, and NOD2/CARD15 genes, with susceptibility to IA. The control group consisted of 130 patients who had allo-SCT but did not develop IA.

Hypoferraemia during the early inflammatory response is dependent on tumour necrosis factor activity in a murine model of protracted peritonitis.

On the grounds of clinical, in vitro and in vivo studies, tumour necrosis factor (TNF) is considered to be one of the inflammatory cytokines that contributes to to the generation of hypoferraemia and anaemia of inflammation (AI). We used a recently described murine model for AI and hypoferraemia, based on sublethal caecal ligation and puncture (CLP) with ensuing protracted peritonitis, to investigate the contribution of TNF to the generation of hypoferraemia. During the early inflammatory response to CLP, a marked decrease in serum iron concentration occurs within 8 h.

ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression.

Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3.

Studies on galactofuranose-containing glycostructures of the pathogenic mold Aspergillus fumigatus.

Galactofuranose is a hexose that is exclusively found in microbes and in particular in certain pathogenic species. In the mold Aspergillus fumigatus, it is the characteristic constituent of the cell wall component galactomannan. Detection of this carbohydrate is currently a widespread method used for diagnosis of systemic A.

Genetic variation determines mast cell functions in experimental asthma.

Mast cell-deficient mice are a key for investigating the function of mast cells in health and disease. Allergic airway disease induced as a Th2-type immune response in mice is employed as a model to unravel the mechanisms underlying inception and progression of human allergic asthma. Previous work done in mast cell-deficient mouse strains that otherwise typically mount Th1-dominated immune responses revealed contradictory results as to whether mast cells contribute to the development of airway hyperresponsiveness and airway inflammation.

Approaching the secrets of N-glycosylation in Aspergillus fumigatus: characterization of the AfOch1 protein.

The mannosyltransferase Och1 is the key enzyme for synthesis of elaborated protein N-glycans in yeast. In filamentous fungi genes implicated in outer chain formation are present, but their function is unclear. In this study we have analyzed the Och1 protein of Aspergillus fumigatus.

AfMkk2 is required for cell wall integrity signaling, adhesion, and full virulence of the human pathogen Aspergillus fumigatus.

The cell wall integrity (CWI) pathway, best characterized in S. cerevisiae, is strikingly conserved in Aspergillus species. We analyzed the importance of AfMkk2, a CWI signaling kinase, for virulence and antifungal therapy in the human pathogen A.

The mitA gene of Aspergillus fumigatus is required for mannosylation of inositol-phosphorylceramide, but is dispensable for pathogenicity.

GDP-mannose:inositol-phosphorylceramide (MIPC)-derived glycosphingolipids are important pathogen-associated molecular patterns (PAMP) of Candida albicans and according to recently published data also of Aspergillus fumigatus. MIPC transferases are essential for the synthesis of MIPC, but have so far been studied only in Saccharomyces cerevisiae and C. albicans.

Murine models of anaemia of inflammation: extramedullary haematopoiesis represents a species specific difference to human anaemia of inflammation that can be eliminated by splenectomy.

In contrast to humans, mice physiologically exhibit extramedullary haematopoiesis in the spleen. In spite of this crucial species specific difference not much is known about the contribution of extramedullary haematopoiesis to overall erythropoiesis in models of anaemia of inflammation (AI). The objective of this study is to characterize murine AI with respect to extramedullary haematopoiesis and to develop a model more closely resembling human AI.

The putative alpha-1,2-mannosyltransferase AfMnt1 of the opportunistic fungal pathogen Aspergillus fumigatus is required for cell wall stability and full virulence.

Proteins entering the eukaryotic secretory pathway commonly are glycosylated. Important steps in this posttranslational modification are carried out by mannosyltransferases. In this study, we investigated the putative alpha-1,2-mannosyltransferase AfMnt1 of the human pathogenic mold Aspergillus fumigatus.

Properdin plays a protective role in polymicrobial septic peritonitis.

Properdin is a positive regulator of complement activation so far known to be instrumental in the survival of infections with certain serotypes of Neisseria meningitidis. We have generated a fully backcrossed properdin-deficient mouse line by conventional gene-specific targeting. In vitro, properdin-deficient serum is impaired in alternative pathway-dependent generation of complement fragment C3b when activated by Escherichia coli DH5alpha.

Investigations on the involvement of the lectin pathway of complement activation in anaphylaxis.

Background: Systemic anaphylaxis is the most severe form of immediate hypersensitivity reaction. The activation of the complement system occurs during anaphylactic shock. The purpose of this study was to determine in a mouse model whether the lectin pathway of complement activation is involved in anaphylaxis.

Localization of the mouse defense lectin ficolin B in lysosomes of activated macrophages.

Ficolins are pattern-recognition molecules of the innate immune system able to trigger the lectin pathway of the complement activation upon binding to microbial surfaces. In humans, two plasma ficolins have been identified and characterized, whereas a third cell-associated ficolin (M-ficolin) was found on monocyte surfaces. The mouse homologue of M-ficolin is called ficolin B.

Improved resistance to bacterial superinfection in mice by treatment with macrophage migration inhibitory factor.

Nosocomial infections in immune-suppressed patients are a widespread problem in intensive care medicine. Such patients are highly susceptible to infections because their immune defenses are impaired and, therefore, unable to adequately combat invading microorganisms. To investigate the problem of sepsis-induced immune suppression, we used a model in which mice developed sublethal peritonitis induced by cecal ligation and puncture (CLP).

Failure of interferon-gamma and tumor necrosis factor in mediating anemia of chronic disease in a mouse model of protracted septic peritonitis.

Interferon-gamma (IFN-gamma) is considered one of the main inflammatory cytokines contributing to the generation of anemia of chronic disease (ACD). In this study, we used a previously described murine model for ACD based on sublethal cecal ligation and puncture (CLP) with ensuing protracted peritonitis. Within 2 weeks after CLP, a moderate normochromic anemia with low serum iron concentration and preserved iron stores develops, which is consistent with ACD.

Divergence of protection induced by bacterial products and sepsis-induced immune suppression.

Susceptibility to bacterial infections after a primary immune stimulation differs drastically depending on the presensitization of the innate immune system. To determine the conditions that either induce protection or enhanced susceptibility to infection with Salmonella enterica serovar Typhimurium, we pretreated mice either with tumor necrosis factor (TNF), whole killed bacteria, or sublethal cecal ligation and puncture (CLP) as a mouse model for septic peritonitis. Impaired production of the cytokines TNF, interleukin-6 (IL-6), and IL-10 was induced by these pretreatment schedules, with TNF-signaling not being essential for this effect.

Involvement of the lectin pathway of complement activation in antimicrobial immune defense during experimental septic peritonitis.

A critical first line of defense against infection is constituted by the binding of natural antibodies to microbial surfaces, activating the complement system via the classical complement activation pathway. In this function, the classical activation pathway is supported and amplified by two antibody-independent complement activation routes, i.e.

Treatment of experimental sepsis-induced immunoparalysis with TNF.

Following a severe septic abdominal infection induced by sublethal cecal ligation and puncture (CLP) in mice, a phase of depressed immune reactivity occurred two days after CLP characterized by a reduced capacity to produce TNF. To determine whether this reduced TNF production causes immunoparalysis as determined by increased susceptibility to bacterial infection and whether therapeutic TNF substitution can be beneficial during this phase, a super-infection with Salmonella enterica Serovar typhimurium or Listeria monocytogenes was induced two days after sublethal CLP. After CLP a state of true immunoparalysis developed during which Salmonella or Listeria super-infection led to increased lethality paralleled by increased bacterial numbers in spleens and livers.

TNF-independent development of transient anemia of chronic disease in a mouse model of protracted septic peritonitis.

TNF is considered one of the inflammatory cytokines and contributes mainly to the generation of anemia of chronic disease (ACD). In nude mice TNF has been reported to impair iron metabolism and erythropoiesis, leading to anemia with a low serum iron and preserved iron stores. In this work, we established a murine model for ACD based on sublethal cecal ligation and puncture (CLP) with ensuing protracted peritonitis.