The Association Between Dimethylacetamide Exposure and Liver Toxicity: A Large Retrospective Analysis in Workers From Four European Factories.

Objective: This study examines the association between 8-h time weighted N, N-dimethylacetamide (DMAc) air exposure and potential hepatocellular injury in a retrospective study among fibre-production workers in four European factories.

Methods And Results: Twenty-nine (1.5%) of 1844 alanine aminotransferase (ALT) observations had liver values two times above normal; 0.

Further experience with the local lymph node assay using standard radioactive and nonradioactive cell count measurements.

In a previous study, the predictive capacity of a modified local lymph node assay (LLNA) based on cell counts, the LNCC, was demonstrated to be closely similar to that of the original assay. In addition, a range of substances, including some technical/commercial materials and a range of agrochemical formulations (n = 180) have also been assessed in both methods in parallel. The results in the LNCC and LLNA were generally consistent, with 86% yielding an identical classification outcome.

Refinement and reduction of acute oral toxicity testing: a critical review of the use of cytotoxicity data.

Acute oral toxicity testing is still required for the classification and labelling of chemicals, agrochemicals and related formulations. There have been increasing efforts over the last two decades to reduce the number of animals needed for this testing, according to the Three Rs concept. To evaluate the utility of an in vitro cytotoxicity test in our routine testing for acute oral toxicity, we have implemented in our laboratory the neutral red uptake (NRU) method, with Balb/c 3T3 fibroblasts after a 48-hour exposure, which was recommended in ICCVAM Report 07-4519, 2006.

Experience with local lymph node assay performance standards using standard radioactivity and nonradioactive cell count measurements.

The local lymph node assay (LLNA) is the preferred test for identification of skin-sensitizing substances by measuring radioactive thymidine incorporation into the lymph node. To facilitate acceptance of nonradioactive variants, validation authorities have published harmonized minimum performance standards (PS) that the alternative endpoint assay must meet. In the present work, these standards were applied to a variant of the LLNA based on lymph node cell counts (LNCC) run in parallel as a control with the standard LLNA with radioactivity measurements, with threshold concentrations (EC3) being determined for the sensitizers.

The bovine corneal opacity and permeability test in routine ocular irritation testing and its improvement within the limits of OECD test guideline 437.

Data on eye irritation are generally needed for the hazard identification of chemicals. As the Bovine Corneal Opacity and Permeability (BCOP) test has been accepted by many regulatory agencies for the identification of corrosive and severe ocular irritants since September 2009 (OECD Test Guideline 437, TG 437), we evaluated this alternative method for routine testing at BASF. We demonstrated our technical proficiency by testing the reference standards recommended in TG 437, and 21 additional materials with published BCOP and in vivo data.

Experience with the HET-CAM method in the routine testing of a broad variety of chemicals and formulations.

Data on eye irritation are generally needed for the hazard identification of chemicals. For the routine testing of a broad variety of chemicals and formulations, we have used the Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) method. In the course of a tiered-testing strategy, and due to the lack of global regulatory acceptance of the HET-CAM method, we have also performed the Rabbit Eye Irritation test according to OECD Test Guideline 405.

Priming of CD4+ T cells by liver sinusoidal endothelial cells induces CD25low forkhead box protein 3- regulatory T cells suppressing autoimmune hepatitis.

Unlabelled: Elucidating cellular mechanisms that maintain the intrahepatic immune balance is crucial to our understanding of viral or autoimmune liver diseases and allograft acceptance. Liver sinusoidal endothelial cells (LSECs) play an important role in modifying local immune responses to tolerance in major histocompatibility complex (MHC) I-restricted models, whereas their contribution in the MHCII context is still controversial. In an MHCII chimeric mouse model that excludes MHCII-mediated antigen presentation by professional antigen-presenting cells, we demonstrated that LSECs prime CD4(+) T cells to a CD45RB(low) memory phenotype lacking marker cytokine production for effector cells that was stable in vivo following immunogenic antigen re-encounter.

CD152 (CTLA-4) determines CD4 T cell migration in vitro and in vivo.

Background: Migration of antigen-experienced T cells to secondary lymphoid organs and the site of antigenic-challenge is a mandatory prerequisite for the precise functioning of adaptive immune responses. The surface molecule CD152 (CTLA-4) is mostly considered as a negative regulator of T cell activation during immune responses. It is currently unknown whether CD152 can also influence chemokine-driven T cell migration.

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines.

Unlabelled: Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4(+) T cells, indicating a mechanism of hepatic immunoregulation.

Sustained delayed-type hypersensitivity reaction after in vivo priming but successful induction of unresponsiveness after adoptive transfer of CD4+ effector T cells.

Potential reasons for weak effects of oral tolerance in the primed immune system are still under discussion. In the present study, impacts of oral antigen uptake were studied in adoptive transfer models using T cell receptor transgenic CD4(+) T cells allowing analysis of antigen-specific donor cells on single cell level. After in vivo priming and subsequent feeding, an antigen-specific delayed-type hypersensitivity reaction was sustained.

In vivo modulation of antigen-experienced cells in response to high-dose oral antigen: deletion but no evidence for alterations in the cytokine phenotype.

Whether also antigen-experienced CD4(+) T cell populations undergo modulations upon oral antigen uptake supporting systemic unresponsiveness is still not fully understood. Using an adoptive transfer model with chicken ovalbumin (OVA)-specific T cells, we demonstrated that absolute numbers of transferred ex vivo-isolated CD4(+) memory T cells and in vitro-polarized T(h)1 cells considerably decrease within spleen and liver upon repetitive OVA feeding. As a consequence, these mice did not mount a delayed-type hypersensitivity reaction after OVA challenge.

Murine CD146 is widely expressed on endothelial cells and is recognized by the monoclonal antibody ME-9F1.

The endothelium plays an important role in the exchange of molecules, but also of immune cells between blood and the underlying tissue. The endothelial molecule S-Endo 1 antigen (CD146) is preferentially located at endothelial junctions and has been claimed to support endothelial integrity. In this study we show that the monoclonal antibody ME-9F1 recognizes the extracellular portion of murine CD146.

Early intrahepatic antigen-specific retention of naïve CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice.

We have previously shown that naïve CD8+ T cells recognizing their cognate antigen within the liver are retained and undergo activation in situ, independent from lymphoid tissues. Intrahepatic primary T cell activation results in apoptosis and may play a crucial role in the ability of the liver to induce tolerance. Although adhesion molecules required for intrahepatic retention of T cells that have undergone previous extra-hepatic activation have been characterized, adhesive interactions involved in selective antigen-dependent intrahepatic retention of naïve CD8+ T cells have not been investigated.

Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization.

The liver is tolerogenic in many situations, including as an allograft and during the response to allogeneic MHC expressed on hepatocytes. The majority of data that address this issue focus on endogenous Ags. Little is known about CD4(+) T cells and their fate under tolerizing conditions, especially with respect to fully differentiated CD4(+) effector T cells.