Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Therefore, new therapeutic options are urgently needed to improve the survival of PDAC patients. Protein kinase G (PKG) conducts the interlude of cGMP signaling which is important for healthy as well as for cancer cells.

Immunological in vivo effects of B7-H1 deficiency.

B7-H1 regulatory protein, a member of the B7-H family, plays a crucial role in the modulation of immune response in healthy steady-state conditions as well as in different pathologies. B7-H1 knockout mice represent an important model to elucidate further molecular and cellular mechanisms involved, among others, in autoimmunity development and cancer progression. However, a deep immunologic characterization of this model is not complete yet.

Gender-specific immunological effects of the phosphodiesterase 5 inhibitor sildenafil in healthy mice.

Phosphodiesterase 5 (PDE5) is a pharmacological target in erectile dysfunction, pulmonary hypertension and in other indications. In tumor-bearing mice an inhibition of PDE5 with sildenafil prolongs survival of the animals through the augmentation of antitumor immunity, indicating the immunomodulatory properties of this drug. Effects of sildenafil on the immune system in healthy organisms are poorly investigated.

Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate. Immunosuppressive cell populations, e.g.

In vivo immunoregulatory properties of the novel mitochondria-targeted antioxidant SkQ1.

Reactive oxygen species (ROS) is a group of highly reactive oxygen-containing chemicals. ROS are essential for various biological functions, including cell survival and growth, proliferation and differentiation. At the same time ROS production is connected to a number of disorders, such as chronic inflammation, age-related diseases and cancers.

Screening of human tumor antigens for CD4 T cell epitopes by combination of HLA-transgenic mice, recombinant adenovirus and antigen peptide libraries.

Background: As tumor antigen-specific CD4+ T cells can mediate strong therapeutic anti-tumor responses in melanoma patients we set out to establish a comprehensive screening strategy for the identification of tumor-specific CD4+ T cell epitopes suitable for detection, isolation and expansion of tumor-reactive T cells from patients.

Methods And Findings: To scan the human melanoma differentiation antigens TRP-1 and TRP-2 for HLA-DRB1*0301-restricted CD4+ T cell epitopes we applied the following methodology: Splenocytes of HLA-DRB1*0301-transgenic mice immunized with recombinant adenovirus encoding TRP-1 (Ad5.TRP-1) or TRP-2 (Ad5.

Both TLR2 and TLR4 are required for the effective immune response in Staphylococcus aureus-induced experimental murine brain abscess.

Toll-like receptors (TLRs) play central roles in the innate reaction to bacterial products and transmit specific immune responses against these pathogens. TLRs are expressed on numerous cell types, including innate immune cells, and on astrocytes, neurons, and microglial cells of the central nervous system (CNS). Lipoproteins and lipopolysaccharides are specifically recognized by TLR2 and TLR4, respectively.

Interleukin-1 receptor type 1 is essential for control of cerebral but not systemic listeriosis.

Listeria monocytogenes may infect the central nervous system and several peripheral organs. To explore the function of IL-1 receptor type 1 (IL-1R1) in cerebral versus systemic listeriosis, IL-1R1(-/-) and wild-type mice were infected either intracerebrally or intraperitoneally with L. monocytogenes.

Organ- and disease-stage-specific regulation of Toxoplasma gondii-specific CD8-T-cell responses by CD4 T cells.

Toxoplasma gondii induces a persistent central nervous system infection, which may be lethally reactivated in AIDS patients with low CD4 T-cell numbers. To analyze the role of CD4 T cells for the regulation of parasite-specific CD8 T cells, mice were infected with transgenic T. gondii expressing the CD8 T-cell antigen beta-galactosidase (beta-Gal).

TNF is important for pathogen control and limits brain damage in murine cerebral listeriosis.

Cerebral listeriosis is a life-threatening disease. However, little is known about the bacterial virulence factors responsible for the severe course of disease and the factors of the immune system contributing to the control of Listeria monocytogenes (LM) or even to the damage of the brain. To analyze the importance of the actA gene of LM, which mediates cell-to-cell spread of intracellular LM, the function of TNF in murine cerebral listeriosis was studied.

An essential role for tumor necrosis factor in the formation of experimental murine Staphylococcus aureus-induced brain abscess and clearance.

Tumor necrosis factor-alpha (TNF-alpha) is a central mediator of the immune response to pathogens, but may also exert neurotoxic effects, thereby contributing to immunopathology. To define the role of TNF during the course of brain abscess, TNF-deficient (TNF(0/0) mice were stereotaxically infected with Staphylococcus (S.) aureus-laden agarose beads.

The intermediate filament GFAP is important for the control of experimental murine Staphylococcus aureus-induced brain abscess and Toxoplasma encephalitis.

The functional role of astrocytes exerted via their intermediate protein glial fibrillary acidic protein (GFAP) in CNS infections was studied in Staphylococcus aureus-induced brain abscess. Compared to wild type (WT) mice, GFAP(0/0) mice developed larger and more poorly demarcated inflammatory lesions paralleled by a significantly increased intracerebral bacterial load, a diffuse leukocytic infiltration of the contralateral hemisphere, purulent ventriculitis, vasculitis, and severe brain edema. These observations were correlated with the lack of a bordering function of activated astrocytes that strongly upregulated their GFAP expression in the abscess surrounding of WT mice.

Both lymphotoxin-alpha and TNF are crucial for control of Toxoplasma gondii in the central nervous system.

Immunity to Toxoplasma gondii critically depends on TNFR type I-mediated immune reactions, but the precise role of the individual ligands of TNFR1, TNF and lymphotoxin-alpha (LTalpha), is still unknown. Upon oral infection with T. gondii, TNF(-/-), LTalpha(-/-), and TNF/LTalpha(-/-) mice failed to control intracerebral T.

The induction and kinetics of antigen-specific CD8 T cells are defined by the stage specificity and compartmentalization of the antigen in murine toxoplasmosis.

Toxoplasma gondii forms different life stages, fast-replicating tachyzoites and slow-growing bradyzoites, in mammalian hosts. CD8 T cells are of crucial importance in toxoplasmosis, but it is unknown which parasite stage is recognized by CD8 T cells. To analyze stage-specific CD8 T cell responses, we generated various recombinant Toxoplasma gondii expressing the heterologous Ag beta-galactosidase (beta-gal) and studied whether 1) secreted or cytoplasmic Ags and 2) tachyzoites or bradyzoites, which persist intracerebrally, induce CD8 T cells.

Protective immunosurveillance of the central nervous system by Listeria-specific CD4 and CD8 T cells in systemic listeriosis in the absence of intracerebral Listeria.

The invasion of the CNS by pathogens poses a major risk for damage of the highly vulnerable brain. The aim of the present study was to analyze immunological mechanisms that may prevent spread of infections to the CNS. Intraperitoneal application of Listeria monocytogenes to mice induced infection of the spleen, whereas pathogens remained absent from the brain.