6 research outputs found
Entzündungsfördernde T-Zellen mit innaten Charakteristika sind im Blut und im entzündeten Darm bei Morbus Crohn vermehrt vorhanden
No full textThe immune system plays a crucial role in maintaining intestinal homeostasis by tolerating environmental antigens and responding to harmful pathogens in the gut. A complex and tissue-specific network of immune cells is responsible for this equilibrium. Altered intestinal immunological homeostasis leads to chronic inflammation in Crohn’s disease (CD). In this study we conducted a multiparametric immunophenotyping of intestinal and peripheral CD3+ T cells from CD patients using a mass cytometry panel that detects 42 T-cell markers. Disease and tissue-specific alterations were identified by comparing inflamed and non-inflamed CD intestinal tissues and CD patients' blood with healthy blood. Chronic inflammation in the intestine was linked to a decrease in major unconventional or tissue-resident T cells, which are important for the first-line mucosal defense. Intestinal inflammation was associated with general hyperactivation and/or exhaustion of conventional T (Tcon) cells, as well as a relative increase in CD4+ regulatory T cells (Tregs) with reduced immunosuppressive effector phenotypes. The CD4+ T-cell compartment showed signs of cross-differentiation of Th17, Tregs or exhausted T cells towards a follicular helper T-cell phenotype, most likely responsible for inducing antibody production. On the other hand, the circulating antigen-experienced CD8+ T cells showed strong migration towards the intestine, where they overpopulated the niche in their most terminally differentiated effector stages. Intestinal inflammatory milieu tended to induce senescence of the late differentiated effector CD8+ T cells, accompanied by their acquisition of NK-like features, such as the expression of CD16. This plasticity of T cells towards innate characteristics within the inflammatory environment, was also demonstrated by the discovery of not well studied CD4+ or CD8+ effector memory CD16+CCR6+CD127+ T cells in the blood of CD patients. This phenotype could be induced in healthy T cells by soluble components of the IBD blood plasma. Furthermore, T cells derived from CD patients could exhibit NK-like effector functions when exposed to CD16-mediated antibody binding, in vitro. Finally, rare Treg subsets with enigmatic properties appeared upon inflammation, such as CD4+HLA-DR+TIGIT–Tregs and CD4+CD56+Tregs, which express pro-inflammatory IFN-γ upon in vitro stimulation. These findings suggest an unusual pro-inflammatory innate-like differentiation of Tregs and Tcon cells, with the acquisition of unspecific cytotoxicity. This differentiation could be both cause and consequence of intestinal inflammation during CD.Das Immunsystem spielt eine entscheidende Rolle bei der Aufrechterhaltung der intestinalen Homöostase. Es toleriert Umweltantigene und reagiert auf schädliche Krankheitserreger im Darm. Ein komplexes und gewebespezifisches Netzwerk von Immunzellen ist für dieses Gleichgewicht verantwortlich. Eine gestörte immunologische Homöostase des Darms führt bei Morbus Crohn (CD) zu chronischen Entzündungen. In dieser Studie wurde eine multiparametrische Immunphänotypisierung von intestinalen und peripheren CD3+ T-Zellen von CD-Patienten durchgeführt. Hierbei wurde ein Massenzytometrie-Panel mit 42 T-Zell-Markern verwendet. Krankheits- und gewebespezifische Veränderungen wurden durch den Vergleich von entzündetem und nicht entzündetem Darmgewebe bei Patienten mit Morbus Crohn sowie von Blut aus Morbus Crohn-Patienten und gesundem Blut ermittelt. Die chronische Entzündung im Darm war mit einem Rückgang der wichtigsten unkonventionellen oder gewebsständigen T-Zellen verbunden, die für die erste Verteidigungslinie der Schleimhäute wichtig sind. Die Darmentzündung war mit einer allgemeinen Hyperaktivierung und/oder Erschöpfung der konventionellen T-Zellen (Tcon) sowie einer relativen Zunahme der CD4+ regulatorische T-Zellen (Tregs) mit reduziertem immunsuppressiven Effektor-Phänotyp verbunden. Das CD4+ T-Zell-Kompartiment zeigt Anzeichen einer Kreuzdifferenzierung von Th17, Tregs oder erschöpften T-Zellen in Richtung eines follikulären Helfer-T-Zell-Phänotyps. Dieser ist höchstwahrscheinlich für die Induktion der Antikörperproduktion verantwortlich. Die zirkulierenden antigenerfahrenen CD8+ T-Zellen zeigten andererseits eine starke Migration in Richtung Darm, wo sie die Nische in ihrem am weitesten ausdifferenzierten Effektorstadium überbevölkerten. Intestinale Entzündungsmilieus führen tendenziell zur Seneszenz der spät differenzierten Effektor-CD8+ T-Zellen, die mit dem Erwerb von NK-ähnlichen Merkmalen wie der Expression von CD16 einhergeht. Die Plastizität von T-Zellen in Richtung innaten Charakteristika innerhalb der entzündlichen Umgebung wurde durch die Entdeckung von bisher nicht gut untersuchten CD4+ oder CD8+ Effektor-Gedächtnis-CD16+CCR6+CD127+ T-Zellen im Blut von CD-Patienten nachgewiesen. Dieser Phänotyp konnte in gesunden T-Zellen durch lösliche Bestandteile des IBD-Blutplasmas induziert werden. Des Weiteren konnten bei CD-Patienten T-Zellen NK-ähnliche Effektor-Funktionen aufweisen, wenn sie in vitro einer CD16-vermittelten Antikörperbindung ausgesetzt waren. Zudem traten bei Entzündungen seltene Treg-
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Untergruppen mit rätselhaften Eigenschaften auf, wie CD4+HLA-DR+TIGIT-Tregs und CD4+CD56+Tregs, die bei In-vitro-Stimulation proinflammatorisches IFN-γ exprimierten. Diese Befunde deuten auf eine ungewöhnliche Differenzierung von Tregs und Tcon-Zellen mit pro-inflammatorischen innaten Eigenschaften hin, die mit dem Erwerb unspezifischer Zytotoxizität einhergeht. Diese Differenzierung könnte sowohl Ursache als auch Folge der Darmentzündung bei CD sein
Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer
No full textM2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC).
Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-beta enhancement, IL-17F secretion, and extracellular vesicle protein content modulation.
We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpblb, SV140, lqcal, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations
A therapeutic approach to treat prostate cancer by targeting Nm23-H1/h-Prune interaction
No full textGenetic Resources, Equity and International Law
No full textThis thesis examines the application of international law to the uses of agricultural crop plants termed plant genetic resources for food and agriculture. In particular, it asks the question, does international law regulate the use of plant genetic resources for food and agriculture so as to enable equity among nations in accessing these resources and sharing the benefits which arise from them?
In answering this question this thesis will also consider several related issues which have arisen in the course of the international debate on this topic. These resources are closely entwined with the lives and livelihoods of certain categories of peoples such as indigenous peoples and farmers and local communities. In addition, they are critical for the economies, agricultural systems and food security of nations. The thesis question will not be considered in the abstract, but will rather be placed against the background of these issues, which will be continuously used to put the legal discourse into perspective.
The legal analysis will focus on five international agreements which directly or indirectly regulate the use of crop plants. These five agreements are placed in two broad categories, i.e. environmental/conservation agreements and trade and property related agreements. The first category includes the Convention on Biological Diversity of 1992 and the International Treaty on Plant Genetic Resources for Food and Agriculture of the Food and Agriculture Organisation of 2001. The second category includes the Convention for the Protection of New Varieties of Plants of 1991, the Agreement on Trade Related Aspects of Intellectual Property Rights of 1994, and several treaties of the World Intellectual Property Organisation. In addition, since the topic raises issues of rights, certain human rights treaties and documents will also be used in the analysis.
The current international conflict over plant genetic resources can be condensed into one of rights, human rights and property rights. The international treaties cited above have all contextualized the issue within a framework of property rights, setting out mechanisms for different forms of legal control of these resources. This thesis will argue that whatever the form and nature of such property rights, they cannot achieve equity in the use of crop plants. Rather the use of such rights results in violations of human rights
