Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of biomarkers in vivo, it lacks resolving morphology. MRI has lower sensitivity, but produces high soft-tissue contrast and provides spectroscopic information and functional MRI (fMRI). We have developed a three-dimensional animal PET scanner that is built into a 7-T MRI. Our evaluations show that both modalities preserve their functionality, even when operated isochronously. With this combined imaging system, we simultaneously acquired functional and morphological PET-MRI data from living mice. PET-MRI provides a powerful tool for studying biology and pathology in preclinical research and has great potential for clinical applications. Combining fMRI and spectroscopy with PET paves the way for a new perspective in molecular imaging.
Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
Polymorphonuclear leukocytes (PMNs) characterize the pathology of T cell–mediated autoimmune diseases and delayed-type hypersensitivity reactions (DTHRs) in the skin, joints, and gut, but are absent in T cell–mediated autoimmune diseases of the brain or pancreas. All of these reactions are mediated by interferon γ–producing type 1 T cells and produce a similar pattern of cytokines. Thus, the cells and mediators responsible for the PMN recruitment into skin, joints, or gut during DTHRs remain unknown. Analyzing hapten-induced DTHRs of the skin, we found that mast cells determine the T cell–dependent PMN recruitment through two mediators, tumor necrosis factor (TNF) and the CXC chemokine macrophage inflammatory protein 2 (MIP-2), the functional analogue of human interleukin 8. Extractable MIP-2 protein was abundant during DTHRs in and around mast cells of wild-type (WT) mice but absent in mast cell–deficient WBB6F1-KitW/KitW- v (KitW/KitW -v) mice. T cell–dependent PMN recruitment was reduced >60% by anti–MIP-2 antibodies and >80% in mast cell–deficient KitW/KitW -v mice. Mast cells from WT mice efficiently restored DTHRs and MIP-2–dependent PMN recruitment in KitW/KitW-v mice, whereas mast cells from TNF−/− mice did not. Thus, mast cell–derived TNF and MIP-2 ultimately determine the pattern of infiltrating cells during T cell–mediated DTHRs.
High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies.
No therapeutic cancer vaccine has yet shown sufficient efficacy to be approved in the U.S., in part because of the complex immune response to vaccination. A study in Cancer Cell helps refine the tactics for developing pancreatic cancer vaccines, showing that local activity by tumor-seeking helper T cells can retard-or promote-tumor development. 1 The study, conducted by a team led by Martin Röcken, professor of dermatology at Eberhard Karls University, could help cancer vaccine makers design therapies that direct T cells to the right place and elicit the right kind of immune response. The group used an established mouse model in which overexpression of a viral oncoprotein called T antigen (TAG) promotes islet cell adeno-mas and, eventually, carcinomas in the pancreas. 2 Such tumors develop extensive vascular structures that facilitate tumor growth. The researchers raised helper T cells that recognized a TAG fragment in cell culture. The T cells were labeled with a fluorescent dye and injected into mice. Within days, the TAG-seeking T cells migrated to pancreatic lymph nodes in TAG-expressing mice but not in wild-type controls. Once on the scene, the T cells prevented both the appearance of new tumors and the expansion of existing ones beyond the adenoma stage. Compared with mock-treated controls, mice that received TAG-specific T cell transfusions had fewer and smaller pancreatic tumors with less extensive vascularization. T cell-treated mice, including those treated after tumors started to form, lived longer than mock-treated controls. "We show that T cells can induce tumor dormancy, " Röcken told SciBX. Playing TAG with tumors According to conventional wisdom, helper T cells act indirectly in cancer vaccines by secreting cytokines that prompt cytotoxic T cells to attack tumors. This principle is the basis of several therapeutic cancer vaccines. 3 However, Röcken's team found that mice lacking most of their cytotoxic T cells still could benefit from TAG-specific helper T cells. Although the pancreatic tumors of these T cell-treated mice showed no signs of apoptosis, which would be indicative of cytotoxic T cell attack, the researchers did see a decrease in the pancreatic incorporation of bro-modeoxyuridine (BrdU) compared with that seen in wild-type controls. BrdU labels newly replicated DNA in proliferating tumors.
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