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Identifier 000441023
Title Association of T-regulatory cells (Tregs) with the subpopulations of Myeloid-Derived Suppressor Cells (MDSCs) in patients with Chronic Idiopathic Neutropenia (CIN) / Nikoletta Aresti ; supervisor - primary investigator Helen Papadaki, Supervising Nikoleta Bizymi.
Alternative Title Συσχέτιση των Τ ρυθμιστικών κυττάρων (T regulatory cells, Tregs) με τους υποπληθυσμούς των Μυελικών Κατασταλτικών Κυττάρων (Myeloid-Derived Suppressor Cells, MDSCs) σε ασθενείς με Χρόνια Ιδιοπαθή Ουδετεροπενία (Chronic Idiopathic Neutropenia, CIN)
Author Αρέστη, Νικολέττα
Thesis advisor Παπαδάκη, Ελένη
Reviewer Bizimi, Nikoleta
Βεργίνης Παναγιώτης
Χαμηλός, Γεώργιος
Abstract Chronic idiopathic neutropenia (CIN) is a neutrophil disorder characterized by prolonged and unexplained reduction in the number of peripheral blood (PB) neutrophils below the lower limit of the normal range for a prolonged period (more than 3 months). The main pathogenetic mechanism of CIN implicates increased Fas-mediated apoptosis of CD34+CD33+ myeloid progenitor cells. Chronic inflammation driven by an inhibitory bone marrow (BM) microenvironment consisting of activated T-lymphocytes (oligoclonal profile) and proinflammatory mediators (TNF-α, TGF-β1, Fas-ligand, IFN-γ, IL-1b, and IL-6) is also involved. Myeloid Derived Suppressor Cells (MDSCs) are immature cells of myeloid origin, divided into two subpopulations, the polymorphonuclear (PMN)-MDSCs and the monocytic (M)-MDSCs. MDSCs have emerged as important contributors of tumor expansion and chronic inflammation progression by inducing immunosuppressive mechanisms, angiogenesis and drug resistance. Through activation of the enzymes arginase 1 (Arg1) and nitric oxide synthase 2 (NOS2), and production of reactive oxygen species (ROS), they lead to suppression of T-cell proliferation, inhibition of natural killer (NK) cell cytotoxicity, modulation of macrophage polarization and induction of development of regulatory T-cells (Tregs). Tregs have been well described over the past several years as a distinct subset of T cells that are both developmentally and functionally unique and essential to maintaining immune homeostasis and self-tolerance. Tregs suppress the function of other T-cells to limit the immune response. The major subpopulations of Treg cells include natural Treg (nTreg) cells that are produced in the thymus and induced Treg (iTreg) cells that are generated in the periphery from conventional FoxP3-CD4+ T-cells. Alterations in the number and function of Tregs have been implicated in several autoimmune diseases. Also, high levels of Tregs have been found in many malignant disorders. Tregs may also prevent antitumor immune responses, leading to increased mortality. Based on previous studies from our laboratory we already know that CIN patients display low proportion of MDSCs in the PB (peripheral blood) and BM (bone marrow), compared to healthy individuals. Also, CIN patients display higher PMN-MDSC accumulation in BM (vs PB) compared to healthy individuals. Finally, we know that MDSCs in CIN display normal T-cell suppression capacity. So, we assumed that the low proportions of MDSC subsets may have a role in the persistence of the inflammatory processes associated with CIN, and the accumulation of PMN-MDSCs in the BM may represent a compensatory mechanism to suppress the inflammatory processes within patients’ BM. Moreover, we assumed that Tregs may also be altered in number and functionality in patients with CIN, and thus contribute in the sustained inflammatory process in the BM. Finally, we hypothesized that MDSCs may have impaired/altered property of inducing the Treg population in patients with CIN. In order to investigate this, we performed a series of experiments that included 1) the quantification of a) MDSCs in PB of CIN patients vs healthy individuals, b) MDSCs in PB vs BM of CIN patients, c) Tregs in CIN patients vs healthy individuals, by flow cytometry, and 2) the correlation of MDSCs and Tregs. Finally, the immunosuppressive function of MDSCs was studied by T-cell suppression assays in conditions with and without their presence. The study revealed that MDSCs are lower in CIN patients compared to normal, but Tregs are higher in patients compared to normal. Also, CIN MDSCs display normal capacity to suppress Tcell proliferation in vitro. The number of CD25high-high Tregs correlated with the number of PMN-MDSCs. Thus, we concluded that there is no evidence that CIN MDSCs display impaired capacity to induce Tregs. In contrary, a role for PMN-MDSCs in the in vivo expansion of Tregs in our patients may be assumed, as these cells may induce normally Treg proliferation. Obviously, the production of MDSCs is impaired/blocked in CIN in a different manner than the production of Tregs, which is normal. Tregs are induced by several pathways besides MDSCs, and are elevated maybe as a compensatory mechanism to suppress the inflammatory process within patients’ BM and as a compensatory mechanism to their impaired production of MDSCs.
Language English
Subject Μυελικά κατασταλτικά κύτταρα
Τ ρυθμιστικά κύτταρα
Issue date 2021-07-30
Collection   School/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/7/f/c/metadata-dlib-1625647905-241176-16380.tkl Bookmark and Share
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