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The role of CD8+ T cells in immune thrombocytopaenia (ITP)

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Title: The role of CD8+ T cells in immune thrombocytopaenia (ITP)
Authors: Sayed, Anwar Abdulfattah A.
Item Type: Thesis or dissertation
Abstract: Immune thrombocytopaenia (ITP) is an autoimmune disorder characterised by isolated low platelet count and a skewed proinflammatory Th1/Th17 profile. However, little is known about the involvement of CD8+ cytotoxic T-cells in ITP pathophysiology in peripheral blood and bone marrow(BM) and how this involvement is regulated. Thrombopoietin-receptor agonists (TPO­RA); eltrombopag(Elt) and romiplostim(Romi), which stimulate the BM to produce more platelets, are increasingly used. However, it is not clear how can these agents induce complete remission in patients. Polychromatic flow cytometric panels were designed to characterize and functionally assess peripheral blood T-cells. Platelet reactivity has been addressed using an IFNγ ELISpot assay. Sixty patients with ITP were included who were on Elt, Romi or on no treatment at the time of analysis. BM trephines were stained for CD4+, CD8+ T cells and CD42b+megakaryocytes(MK), and slides were analysed automatically. MK were generated in vitro to assess their interaction with T-cells. In peripheral blood, CD8+T-cells displayed an effector phenotype characterised by reduced CD4/CD8 T cell ratio and Treg/effector CD8+ T-cell ratio and increased effector CD8+ T-cell, which were associated with disease activity. This polyfunctional population expressed significantly higher intracellular TNFα, IFNγ and Granzyme B compared to HC. Elt seemed to significantly lower effector CD8+T cells and reduced their functionality in vitro in a dose dependent manner. In the BM, MK-T cell interaction and clustering was higher in patients, more prominently in chronic cases. MK demonstrated features of professional antigen-presenting-cells including the surface expression of functional MHC-I, MHC-II, PD-L1 and PD-L2, which controlled MK-T-cell interaction. CD8+ T cells are involved in ITP pathology contributing the inflammatory milieu. These potentially autoreactive cells could target both platelets and MK. MK seems to govern the immune response in the BM; by its direct interaction with either CD4+ or CD8+T-cells, and via its immunomodulation mainly by PD-L1 and PD-L2.
Content Version: Open Access
Issue Date: Oct-2018
Date Awarded: Feb-2019
URI: http://hdl.handle.net/10044/1/86370
DOI: https://doi.org/10.25560/86370
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Cooper, Nichola
Dyson, Julian
Psaila, Bethan
Sponsor/Funder: Taibah University
Funder's Grant Number: P55278
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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