\ufffcTheodor W. Adorno: Truth and Dialectical Experience / Verita\u300 ed \ufffcesperienza dialettica

Scopo del presente fascicolo di \u201cDiscipline filosofiche\u201d e\u300 per approfondire l\u2019originale contributo adorniano allo sviluppo del pensiero dialettico mediante la sua proposta di una dialettica negativa, indagando in particolare il ruolo svolto al suo interno dal problema della verita\u300. Un problema, quest\u2019ultimo, analizzato da Adorno soprattutto \u2013 seppur non esclusivamente \u2013 in riferimento alla questione del contenuto di verita\u300 dell\u2019arte (colto nella sua ineliminabile \u201cenigmaticita\u300\u201d, come si legge in vari passaggi fondamentali di "Teoria estetica"), nonche\u301 in riferimento all\u2019ineliminabile componente retorico-linguistica del pensiero filosofico e, dunque, al rapporto tra linguaggio, pensiero e realta\u300. Questi aspetti vengono affrontati in vari modi, cioe\u300 muovendo da background differenti e soffermandosi su aspetti diversi, dagli autori che partecipano al presente numero di \u201cDiscipline filosofiche\u201d. Il percorso di lettura proposto, muovendo da un problema generale e di fondamentale importanza come quello della natura, affronta quindi in vario modo il rapporto tra arte e verita\u300, si sposta da qui (in un modo graduale e continuo, vista l\u2019affinita\u300 tra tali argomenti spesso riscontrabile in Adorno) sul tema del linguaggio e, quindi, della natura del pensare dialettico in quanto tale, sfociando infine in tentativi di interpretazione comparata della filosofia di Adorno, attraverso il confronto con alcuni altri modelli di pensiero contemporaneo (fenomenologia, decostruzione)

Enhanced CXCR4 expression of human CD8Low T lymphocytes is driven by S1P4

Although the human immune response to cancer is naturally potent, it can be severely disrupted as a result of an immunosuppressive tumor microenvironment. Infiltrating regulatory T lymphocytes contribute to this immunosuppression by inhibiting proliferation of cytotoxic CD8+ T lymphocytes, which are key to an effective anti-cancer immune response. Other important contributory factors are thought to include metabolic stress caused by the local nutrient deprivation common to many solid tumors. Interleukin-33 (IL-33), an alarmin released in reaction to cell damage, and sphingosine-1-phosphate (S1P) are known to control cell positioning and differentiation of T lymphocytes. In an in vitro model of nutrient deprivation, we investigated the influence of IL-33 and S1P receptor 4 (S1P4) on the differentiation and migration of human CD8+ T lymphocytes. Serum starvation of CD8+ T lymphocytes induced a subset of CD8Low and IL-33 receptor-positive (ST2L+) cells characterized by enhanced expression of the regulatory T cell markers CD38 and CD39. Both S1P1 and S1P4 were transcriptionally regulated after stimulation with IL-33. Moreover, expression of the chemokine receptor CXCR4 was increased in CD8+ T lymphocytes treated with the selective S1P4 receptor agonist CYM50308. We conclude that nutrient deprivation promotes CD8Low T lymphocytes, contributing to an immunosuppressive microenvironment and a poor anti-cancer immune response by limiting cytotoxic effector functions. Our results suggest that S1P4 signaling modulation may be a promising target for anti-CXCR4 cancer immunotherapy

Abschlussbericht der wissenschaftlichen Begleitung des Modellversuchs 'Ausbildung und Beratung auslaendischer Jugendlicher in Handwerksbetrieben'

UuStB Koeln( 38)-880106569 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Tissue cytokine IL-33 modulates the cytotoxic CD8 t lymphocyte activity during nutrient deprivation by regulation of lineage-specific differentiation programs

IL-1 family member IL-33 exerts a variety of immune activating and regulating properties and has recently been proposed as a prognostic biomarker for cancer diseases, although its precise role in tumor immunity is unclear. Here we analyzed in vitro conditions influencing the function of IL-33 as an alarmin and a co-factor for the activity of cytotoxic CD8+ T cells in order to explain the widely discussed promiscuous behavior of IL-33 in vivo. Circulating IL-33 detected in the serum of healthy human volunteers was biologically inactive. Additionally, bioactivity of exogenous recombinant IL-33 was significantly reduced in plasma, suggesting local effects of IL-33, and inactivation in blood. Limited availability of nutrients in tissue causes necrosis and thus favors release of IL-33, which—as described before—leads to a locally high expression of the cytokine. The harsh conditions however influence T cell fitness and their responsiveness to stimuli. Nutrient deprivation and pharmacological inhibition of mTOR mediated a distinctive phenotype characterized by expression of IL-33 receptor ST2L on isolated CD8+ T cells, downregulation of CD8, a transitional CD45RAlowROlow phenotype and high expression of secondary lymphoid organ chemokine receptor CCR7. Under nutrient deprivation, IL-33 inhibited an IL-12 induced increase in granzyme B protein expression and increased expression of GATA3 and FOXP3 mRNA. IL-33 enhanced the TCR-dependent activation of CD8+ T cells and co-stimulated the IL-12/TCR-dependent expression of IFNγ. Respectively, GATA3 and FOXP3 mRNA were not regulated during TCR-dependent activation. TCR-dependent stimulation of PBMC, but not LPS, initiated mRNA expression of soluble IL-33 decoy receptor sST2, a control mechanism limiting IL-33 bioactivity to avoid uncontrolled inflammation. Our findings contribute to the understanding of the compartment-specific activity of IL-33. Furthermore, we newly describe conditions, which promote an IL-33-dependent induction of pro- or anti-inflammatory activity in CD8+ T cells during nutrient deprivation

Real world application of ocrelizumab in multiple sclerosis: Single-center experience of 128 patients

Background: Pivotal trials showed good clinical efficiency of the monoclonal antibody ocrelizumab while being well tolerated and manageable in multiple sclerosis (MS). However, data on adverse events in everyday practice are scarce. Hence, our study aims at investigating short-term tolerability of ocrelizumab in a "real-world" setting. Methods: In this retrospective cohort study, data of 128 (86 relapsing-remitting, 42 progressive) MS patients at initiation of ocrelizumab were analyzed at the MS center of the University of Erlangen, Germany. Additionally, follow-up data of 68 patients at 6-months retreatment were analyzed. Structured phone interviews were applied after ocrelizumab initiation to report undocumented side effects. Results: Patients predominantly switched from monoclonal antibodies (46%), orals (20%), injectables (10%), steroids or immunosuppressants (each 8%), with a mean interval of 9.0 months after the last application of the previous immunotherapy. Applying a combined premedication with steroids, antihistamines and antipyretics for> 90% of patients, ocrelizumab treatment was well tolerated and mainly comprised mild (n = 59/128 at initiation, n = 5/68 at 6 months retreatment) and rarely moderate (n = 7/128 at initiation, n = 2/68 at 6 months) side effects. Predominantly mild infusion related reactions (IRR) were reported with a declining percentage over the follow-up applications. Infections occurred rarely. No severe side effects were observed. Secondary, treatment appeared efficient when looking at clinical surrogates of stable disease. Discussion: Our study delineates good short-term tolerability of ocrelizumab in a miscellaneous "real-world" MS cohort. Additional studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up

Inflammation-induced mucosal KYNU expression identifies human ileal Crohn’s disease

The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn’s disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD