Comparative expression profiling of distinct T cell subsets undergoing oxidative stress.

The clinical outcome of adoptive T cell transfer-based immunotherapies is often limited due to different escape mechanisms established by tumors in order to evade the hosts' immune system. The establishment of an immunosuppressive micromilieu by tumor cells along with distinct subsets of tumor-infiltrating lymphocytes is often associated with oxidative stress that can affect antigen-specific memory/effector cytotoxic T cells thereby substantially reducing their frequency and functional activation. Therefore, protection of tumor-reactive cytotoxic T lymphocytes from oxidative stress may enhance the anti-tumor-directed immune response.

High expression of GCLC is associated with malignant melanoma of low oxidative phenotype and predicts a better prognosis.

Reactive oxygen species (ROS) are strongly implicated in melanoma development, and treatment with antioxidants has shown efficacy in suppressing malignant transition and progression. Here, we investigated the significance of the glutamate-L: -cysteine ligase catalytic subunit (GCLC) expression, a key regulator of glutathione synthesis, for malignant melanoma. A large set of melanoma cell lines (n = 36) was analyzed, and higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation.

Multipotent mesenchymal stromal cells express FoxP3: a marker for the immunosuppressive capacity?

Multipotent mesenchymal stromal cells (MSCs) have immunosuppressive capacity but the exact mechanism by which they suppress proliferation of T lymphocytes is not fully understood. Recently, the characteristics and function of regulatory T lymphocytes (Tregs) have become better defined. Tregs and MSCs have immunosuppressive features in common.

Nuclear HER3 is associated with favorable overall survival in uveal melanoma.

HER3 is a member of the epidermal growth factor receptor (EGFR) family and is expressed in several types of cancer. Both the cytoplasmic and nuclear appearances of the receptor have been reported. Here, we investigate the expression and subcellular distribution of HER3 in uveal melanoma (UM) cells and tissues and its potential impact on clinical outcome of patients.

The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are characterized by their manifold immunomodulatory and regenerative properties. The stress-responsive, cytoprotective, and immunoregulatory molecule heme oxygenase-1 (HO-1) was recently identified as a key contributor for MSC-mediated suppression of alloactivated T cells. As HO-1 has also been implicated in the induction of regulatory T cells (Tregs), we sought to examine its impact on MSC-driven promotion of Tregs.

Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder.

Background: In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed.

Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress.

Levels of regulatory T cells (Tregs) are increased in different cancer types as well as in inflammatory diseases, such as rheumatoid arthritis. Treg accumulation may result from aberrant proliferation and trafficking as well as greater resilience to oxidative stress compared with conventional T cells. This enhanced antioxidative capacity of Tregs possibly serves as feedback inhibition during inflammation and prevents uncontrolled immune reactions by favoring survival of suppressor rather than effector cells.

T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2.

The HER2 oncogene is frequently over-expressed in human cancers and a promising target for immune therapy. Previous studies have shown that over-expression of mouse or rat HER2 leads to markedly reduced levels of major histocompatibility complex (MHC) class I and molecules of the antigen processing and presentation machinery (APM), thus resulting in a phenotype promoting tumor escape from the immune system. Our study focuses on analyzing the effect of HER2 on MHC class I antigen presentation and sensitivity to tumor-antigen specific cytotoxic T lymphocytes (CTLs) in HLA-A2.

Interaction between lysozyme and colloidal poly(NIPAM-co-acrylic acid) microgels.

The interaction between lysozyme and colloidal poly(NIPAM-co-acrylic acid) microgels is investigated in aqueous solutions at neutral pH. Lysozyme binding isotherms, obtained within the ionic strength range 10-220 mM, indicate that the maximum uptake at 10 mM is 2.4 g lysozyme per gram dry gel, and that the uptake capacity decreases with increasing ionic strength to approximately 0 at 220 mM.

Regulatory T cells in cancer.

At the present time, regulatory T cells (Tregs) are an integral part of immunology but the route from discovery of "suppressive" lymphocytes in the 1980s to the current established concept of Tregs almost 20 years later has been a rollercoaster ride. Tregs are essential for maintaining self-tolerance as defects in their compartment lead to severe autoimmune diseases. This vitally important function exists alongside the detrimental effects on tumor immunosurveillance and antitumor immunity.

Intratumoral forkhead box P3-positive regulatory T cells predict poor survival in cyclooxygenase-2-positive uveal melanoma.

Background: Forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress efficient antitumor responses. Prostaglandin E(2) (PGE(2)) produced by inducible cyclooxygenase-2 (COX-2) can lead to Treg induction. COX-2 expression has been linked to tumorigenesis and growth in various malignancies.

Expression and prognostic significance of iNOS in uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma.

Oxidative stress and lymphocyte persistence: implications in immunotherapy.

CD8(+) T cells respond to antigen stimulation through a process of activation, division, and differentiation generating a large pool of activated effector cytolytic T lymphocytes (CTLs). Many cancer patients harbor the accordant precursor CTLs capable of responding to various tumor-associated antigens (TAA). In selected cases, vaccination with these TAA can elicit detectable antitumor responses.

Electronic structure of water molecules confined in a micelle lattice.

Oxygen K absorption and emission spectra of water molecules confined in dodecyltrimethyl ammonium chloride micelle structures are presented. The local electronic structure of the water molecules is found to be dramatically different from the electronic structure of water molecules in the gas-phase as well as in liquid water. Hybridization with states of the ions in the surrounding ions is directly observed, and evidence for stabilization of the water molecules relative to molecules in bulk water is found.

Antibodies to Staphylococcus aureus bone sialoprotein-binding protein indicate infectious osteomyelitis.

Discrimination of soft tissue infection from osteomyelitis in diabetic foot infections is a common clinical problem. Staphylococcus aureus isolates from patients with osteomyelitis express bone sialoprotein-binding protein (Bbp) that binds the bone matrix protein bone sialoprotein. The serological assay with Bbp discriminated cases of osteomyelitis from soft tissue infections in patients with diabetic foot ulcers.

Mechanism of lysozyme uptake in poly(acrylic acid) microgels.

The uptake of lysozyme by oppositely charged poly(acrylic acid) microgels was investigated by micromanipulator-assisted light microscopy and confocal microscopy. Lysozyme was observed to distribute nonuniformly within the microgels, forming a core-shell structure with considerably higher lysozyme concentration in the shell than in the core. The core-shell formation can be divided into two periods.

Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death.

Although the authors of several studies report elevated numbers of immunosuppressive regulatory T cells (Tregs) in hematologic and solid malignancies, the underlying mechanism is not fully clarified. Cancer is associated with oxidative stress mediated through reactive oxygen species produced by malignant cells, granulocytes, tumor-associated macrophages, and myeloid-derived suppressor cells. Oxidative stress is known to have detrimental effects on natural killer (NK) and T cells during chronic inflammatory conditions and cancer.

Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress.

Patients with diseases characterized by chronic inflammation, caused by infection or cancer, have T cells and NK cells with impaired function. The underlying molecular mechanisms are diverse, but one of the major mediators in this immune suppression is oxidative stress caused by activated monocytes, granulocytes, or myeloid-derived suppressor cells. Reactive oxygen species can seriously hamper the efficacy of active immunotherapy and adoptive transfer of T and NK cells into patients.

Prognostic significance of tumor iNOS and COX-2 in stage III malignant cutaneous melanoma.

Purpose: New prognostic markers are needed for malignant melanoma. Inducible nitric oxide synthase (iNOS) and cyclooxygenase type 2 (COX-2) have been described to correlate with progression of melanoma. Moreover, activating mutations in BRAF/NRAS oncogenes are often detected in melanoma.

The CD16- CD56(bright) NK cell subset is resistant to reactive oxygen species produced by activated granulocytes and has higher antioxidative capacity than the CD16+ CD56(dim) subset.

Human NK cells can be divided into CD56(dim) and CD56(bright) subsets. These two types of NK cells respond to different types of stimuli, with CD56(dim) NK cells having direct cytotoxic ability and CD56(bright) NK cells having mainly an immunoregulatory function. We show that the CD16+ CD56(dim) NK subset is characterized by sensitivity to cell death induced by activated granulocytes.

Interaction between lysozyme and poly(acrylic acid) microgels.

The interaction between lysozyme and oppositely charged poly(acrylic acid) microgels was investigated by micromanipulator-assisted light microscopy, confocal microscopy and circular dichroism. Lysozyme uptake and distribution within the microgel particles, and its effect on microgel deswelling, was studied regarding effects of pH, ionic strength and lysozyme concentration. For a range of conditions, lysozyme distributes nonuniformly within the microgels, forming a lysozyme/microgel shell in the outer parts of the microgel.

Functional gap junctions facilitate melanoma antigen transfer and cross-presentation between human dendritic cells.

Previously, we found that human dendritic cells (hDCs) pulsed with a melanoma cell lysate (MCL) and stimulated with TNF-alpha (MCL/TNF) acquire a mature phenotype in vitro and are able to trigger tumor-specific immune responses when they are used in melanoma immunotherapy in patients. In this study, we describe that MCL/TNF induces gap junction (GJ)-mediated intercellular communications and promotes melanoma Ag transfer between ex vivo produced hDCs from melanoma patients. hDCs also exhibit increased expression of the GJ-related protein connexin 43, which contributes to GJ plaque formation after MCL/TNF stimulation.

FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism.

CD4+CD25+ regulatory T (T(R)) cells suppress effector T cells by partly unknown mechanisms. In this study, we describe a population of human suppressive CD4+CD25+ adaptive T(R) (T(R)(adapt)) cells induced in vitro that express cyclooxygenase 2 (COX-2) and the transcription factor FOXP3. T(R)(adapt) cells produce PGE(2) and suppress effector T cell responses in a manner that is reversed by COX inhibitors and PGE(2) receptor-specific antagonists.

The epidermal growth factor-like growth factor amphiregulin is strongly induced by the adenosine 3',5'-monophosphate pathway in various cell types.

We examined the cAMP-mediated regulation of the epidermal growth factor-like growth factor amphiregulin (AR) in T cells and observed a strong cAMP-induced up-regulation of AR mRNA in a time- and concentration-dependent manner independent of T cell activation. This regulation may be mediated in part through activation of a cAMP-responsive element in the AR promoter, because the cAMP-responsive element conferred cAMP responsiveness to a luciferase reporter in Jurkat TAg cells. Similar effects of AR mRNA induction were seen in T cells treated with cAMP-elevating agents such as prostaglandin E(2) and forskolin as well as with the phosphodiesterase inhibitors rolipram and isobutylmethylxanthine.