TY - JOUR AB - The clinical use of cellular immunotherapies is gaining momentum and the number of approved indications is steadily increasing. One class of cellular therapies—chimeric antigen receptor (CAR)-modified T cells—has achieved impressive results in distinct blood cancer indications. These existing cellular therapies treating blood cancers face significant relapse rates, and their application beyond hematology has been underwhelming, especially in solid oncology. Major reasons for resistance source largely in the tumor microenvironment (TME). The TME in fact functionally suppresses, restricts, and excludes adoptive immune cells, which limits the efficacy of cellular immunotherapies from the onset. Many promising efforts are ongoing to adapt cellular immunotherapies to address these obstacles, with the aim of reshaping the tumor microenvironment to ameliorate function and to achieve superior efficacy against both hematological and solid malignancies. AU - Huynh, D.* AU - Winter, P.* AU - Märkl, F.* AU - Endres, S. AU - Kobold, S. C1 - 66320 C2 - 52777 CY - Tiergartenstrasse 17, D-69121 Heidelberg, Germany SP - 215-227 TI - Beyond direct killing—novel cellular immunotherapeutic strategies to reshape the tumor microenvironment. JO - Semin. Immunopathol. VL - 45 IS - 2 PB - Springer Heidelberg PY - 2022 SN - 1863-2297 ER - TY - JOUR AB - Epstein-Barr virus (EBV) is a model of herpesvirus latency and epigenetic changes. The virus preferentially infects human B-lymphocytes (and also other cell types) but does not turn them straight into virus factories. Instead, it establishes a strictly latent infection in them and concomitantly induces the activation and proliferation of infected B cells. How the virus establishes latency in its target cells is only partially understood, but its latent state has been studied intensively by many. During latency, several copies of the viral genome are maintained as minichromosomes in the nucleus. In latently infected cells, most viral genes are epigenetically repressed by cellular chromatin constituents and DNA methylation, but certain EBV genes are spared and remain expressed to support the latent state of the virus in its host cell. Latency is not a dead end, but the virus can escape from this state and reactivate. Reactivation is a coordinated process that requires the removal of repressive chromatin components and a gain in accessibility for viral and cellular factors and machines to support the entire transcriptional program of EBV's ensuing lytic phase. We have a detailed picture of the initiating events of EBV's lytic phase, which are orchestrated by a single viral protein - BZLF1. Its induced expression can lead to the expression of all lytic viral proteins, but initially it fosters the non-licensed amplification of viral DNA that is incorporated into preformed capsids. In the virions, the viral DNA is free of histones and lacks methylated cytosine residues which are lost during lytic DNA amplification. This review provides an overview of EBV's dynamic epigenetic changes, which are an integral part of its ingenious lifestyle in human host cells. AU - Buschle, A. AU - Hammerschmidt, W. C1 - 58847 C2 - 48386 CY - Tiergartenstrasse 17, D-69121 Heidelberg, Germany SP - 131-142 TI - Epigenetic lifestyle of Epstein-Barr virus. JO - Semin. Immunopathol. VL - 42 IS - 2 PB - Springer Heidelberg PY - 2020 SN - 1863-2297 ER - TY - JOUR AB - Obesity and the metabolic syndrome (MS) are two of the pressing healthcare problems of our time. The MS is defined as increased abdominal obesity in concert with elevated fasting glucose levels, insulin resistance, elevated blood pressure, and plasma lipids. It is a key risk factor for type 2 diabetes mellitus (T2DM) and for cardiovascular complications and mortality. Here, we review work demonstrating that various aspects of coagulation and hemostasis, as well as vascular reactivity and function, become impaired progressively during chronic ingestion of a western diet, but also acutely after meals. We outline that both T2DM and cardiovascular disease should be viewed as inflammatory diseases and describe that chronic overload of free fatty acids and glucose can trigger inflammatory pathways directly or via increased production of ROS. We propose that since endothelial stress and increases in platelet activity precede inflammation and overt symptoms of the MS, they are likely the first hit. This suggests that endothelial activation and insulin resistance are probably causative in the observed chronic low-level metabolic inflammation, and thus both metabolic and cardiovascular complications linked to consumption of a western diet. AU - Grandl, G. AU - Wolfrum, C.* C1 - 53020 C2 - 44272 SP - 215-224 TI - Hemostasis, endothelial stress, inflammation, and the metabolic syndrome. JO - Semin. Immunopathol. VL - 40 IS - 2 PY - 2018 SN - 1863-2297 ER - TY - JOUR AB - Neutrophils are among the first cells implicated in acute inflammation. Leaving the blood circulation, they quickly migrate through the interstitial space of tissues and liberate oxidants and other antimicrobial proteins together with serine proteinases. Neutrophil elastase, cathepsin G, proteinase 3 (PR3), and neutrophil serine protease 4 are four hematopoietic serine proteases activated by dipeptidyl peptidase I during neutrophil maturation and are mainly stored in cytoplasmic azurophilic granules. They regulate inflammatory and immune responses after their release from activated neutrophils at inflammatory sites. Membrane-bound PR3 (mbPR3) at the neutrophil surface is the prime antigenic target of antineutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis (GPA), a vasculitis of small blood vessels and granulomatous inflammation of the upper and/or lower respiratory tracts. The interaction of ANCA with mbPR3 results in excessive activation of neutrophils to produce reactive oxygen species and liberation of granular proteinases to the pericellular environment. In this review, we focus on PR3 and dipeptidyl peptidase I as attractive pharmacological targets whose inhibition is expected to attenuate autoimmune activation of neutrophils in GPA. AU - Korkmaz, B.* AU - Lesner, A.* AU - Letast, S.* AU - Mahdi, Y.K.* AU - Jourdan, M.L.* AU - Dallet-Choisy, S.* AU - Marchand-Adam, S.* AU - Kellenberger, C.* AU - Viaud-Massuard, M.C.* AU - Jenne, D. AU - Gauthier, F.* C1 - 26166 C2 - 32102 SP - 411-421 TI - Neutrophil proteinase 3 and dipeptidyl peptidase I (cathepsin C) as pharmacological targets in granulomatosis with polyangiitis (Wegener granulomatosis). JO - Semin. Immunopathol. VL - 35 IS - 4 PB - Springer PY - 2013 SN - 1863-2297 ER -