CD8+ T cell responses can be generated against antigens that are not expressed directly within antigen-presenting cells (APCs), through a process known as cross-priming. To initiate cross-priming, APCs must both capture extracellular antigen and receive specific activation signals. We have investigated the nature of APC activation signals associated with virus infection that stimulate cross-priming. We show that infection with lymphocytic choriomeningitis virus induces cross-priming by a mechanism dependent on type I interferon (IFN-alpha/beta). Activation of cross-priming by IFN-alpha/beta was independent of CD4+ T cell help or interaction of CD40 and CD40 ligand, and involved direct stimulation of dendritic cells. These data identify expression of IFN-alpha/beta as a mechanism for the induction of cross-priming during virus infections.

Human coinfection with the helminth parasite Schistosoma mansoni and hepatitis B and hepatitis C viruses is associated with increased hepatic viral burdens and severe liver pathology. In this study we developed a murine S. mansoni/lymphocytic choriomeningitis virus (LCMV) coinfection model that reproduces the enhanced viral replication and liver pathology observed in human coinfections, and used this model to explore the mechanisms involved. Viral coinfection during the Th2-dominated granulomatous phase of the schistosome infection resulted in induction of a strong LCMV-specific T cell response, with infiltration of high numbers of LCMV-specific IFN-γ-producing CD8+ cells into the liver. This was associated with suppression of production of the Th2 cytokines dominant during S. mansoni infection and a rapid increase in morbidity, linked to hepatotoxicity. Interestingly, the liver of coinfected mice was extremely susceptible to viral replication. This correlated with a reduced intrahepatic type I IFN response following virus infection. Schistosome egg Ags were found to suppress the type I IFN response induced in murine bone marrow-derived dendritic cells by polyinosinic-polycytidylic acid. These results suggest that suppression of the antiviral type I IFN response by schistosome egg Ags in vivo predisposes the liver to enhanced viral replication with ensuing immunopathological consequences, findings that may be paralleled in human schistosome/hepatotropic virus coinfections.

1 Non-steroidal anti-in¯ammatory drugs (NSAIDs) induce apoptosis in gastrointestinal cancer cell lines. Similar actions on normal gastric epithelial cells could contribute to NSAID gastropathy. The present work therefore compared the actions of diclofenac, ibuprofen, indomethacin, and the cyclooxygenase-2 selective inhibitor, NS-398, on a primary culture of guinea-pig gastric mucous epithelial cells. 2 Cell number was assessed by staining with crystal violet. Apoptotic activity was determined by condensation and fragmentation of nuclei and by assay of caspase-3-like activity. Necrosis was evaluated from release of cellular enzymes. 3 Ibuprofen (250 mM for 24 h) promoted cell loss, and apoptosis, under both basal conditions and when apoptosis was increased by 25 mM N-Hexanoyl-D-sphingosine (C 6 -ceramide). 4 Diclofenac (250 mM for 24 h) reduced the proportion of apoptotic nuclei from 5.2 to 2.1%, and caused inhibition of caspase-3-like activity, without causing necrosis under basal conditions. No such reduction in apoptotic activity was evident in the presence of 25 mM C 6 -ceramide. 5 The inhibitory eect of diclofenac on basal caspase-3-like activity was also exhibited by the structurally similar mefenamic and¯ufenamic acids (1 ± 250 mM), but not by ni¯umic acid. 6 Inhibition of superoxide production by the cells increased caspase-3-like activity, but the inhibitory action of diclofenac on caspase activity remained. Diclofenac did not aect superoxide production. 7 Diclofenac inhibited caspase-3-like activity in cell homogenates and also inhibited human recombinant caspase-3. 8 In conclusion, NSAIDs vary in their eect on apoptotic activity in a primary culture of guineapig gastric mucous epithelial cells, and the inhibitory eect of diclofenac on basal apoptosis could involve an action on caspase activity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a considerable symptom burden and poor prognosis. Focus on maintaining patients’ quality of life and pain control is therefore paramount. Pain management in MPM is complex due to its multifactorial etiology resulting from direct tumor infiltration of the surrounding soft tissue, bone, and encasement of the intercostal nerves. A variety of treatment modalities, including pharmacological and non-pharmacological options, are often required to achieve adequate pain control in this challenging disease. This review article examines the current challenges and solutions available for pain management in MPM.