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1
Paun, Andrea. "Regulator T cells in murine AIDS." University of Western Australia. Microbiology and Immunology Discipline Group, 2005. http://theses.library.uwa.edu.au/adt-WU2005.0115.
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[Truncated abstract] In the last ten years regulator T (Tr) cells have re-emerged as an integral part of the immune system. Research in this field has rapidly demonstrated the role of these cells in the maintenance of immune homeostasis and their involvement in disease. Tr cells are generated in the thymus as a normal part of the developing immune system. Furthermore, antigen-specific Tr cells are induced in the periphery by a mechanism which is yet to be completely elucidated, but is likely to involve dendritic cells. Tr cells play an important role in autoimmune disease, transplantation tolerance, cancer. Most recently Tr cell involvement has been demonstrated in a growing number of infectious diseases. Tr cell induction was reported in Friend Virus infection at the commencement of this study, and subsequent to publication of our findings have also been identified in FIV and HIV. Murine AIDS (MAIDS) is a fatal chronic retroviral infection induced in susceptible strains of mice by infection with BM5d, a replication defective virus, in a viral mixture which is designated LP-BM5. The manipulation of Tr cells detailed in this thesis and the related publication represent the first reported therapy utilising targeted removal of Tr cells. Chapter 1 summarises the literature relevant to this study up to November 2004. Chapter 2 details the materials and methodologies used in this work. Chapter 3 investigates whether Tr cells are involved in the development of murine AIDS, particularly in the early stages of infection. The data presented in this chapter provides evidence of a population of CD4+ Tr cells which express CD25 on their cell surface and secrete TGF-β, some IL-10 and low levels of IL-4 are induced following infection with LP-BM5. These cells were found to arise by day 12 post infection (pi) by flow cytometry and immunosuppressive cytokine expression was found to peak at day 16 pi indicating a role in the early stages of disease progression. Chapter 4 investigates the effect of therapeutically targeting these induced Tr cells using the antimitotic agent Vinblastine during their induction period. The efficacy of treatment was found to be time dependent and was shown to abrogate disease progression maximally when given at day 14 pi. Treatment with anti-CD4 monoclonal antibody was also found to be efficacious at day 14 pi and confirmed the identity of the Tr cells as being CD4+ T cells. Adoptive transfer studies demonstrated that the return of these cells to a successfully treated host results in renewed MAIDS progression, confirming their role in disease progression
2
Podrebarac, Theresa A. "CD1 restricted recognition by murine T cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ46602.pdf.
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Hughes, Jane Patricia. "Molecular regulation of apoptosis in immature murine T-cells." Thesis, Keele University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301341.
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Belfrage, Hans. "Activation of murine cytotoxic cells with interleukin-2 and the bacterial superantigen staphylococcal enterotoxin A." Lund : Dept. of Cell & Molecular Biology, Section of Tumor Immunology, the Wallenberg Laboratory, 1996. http://catalog.hathitrust.org/api/volumes/oclc/38037867.html.
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Garefalaki, Anna. "Identification of regulatory regions that determine expression of murine CD8 locus." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250198.
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Chan, Agnes How-Ching. "Purification, biochemical analysis and sequencing of a novel murine T suppressor factor." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/28638.
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The work reported in this thesis involved the purification, biochemical analysis and sequencing of a novel suppressor factor secreted by a T cell hybridoma, A10. The factor, A10F, isolated from spent medium of A10 cells, was found to consist of two forms with molecular weights at 140 - 160 and 80 kD as suggested by NH₂-terminal sequencing, Western blotting and tryptic peptide mapping experiments. Both forms of A10F were found to be capable of suppressing the in vitro generation of cytotoxic T lymphocyte (CTL) specific for P815 cells by syngeneic (DBA/2) splenocytes.
In vitro ³⁵S methionine labeling experiments clearly demonstrated that the 80 kD protein was a secretory product of the A10 cells. The protein, which was specific to the monoclonal antibody (B16G), was absent in the control NS1 and BW5147 cells. Biochemical analysis indicated that the 80 kD molecule, was either a degradation product or a monomer of the 140 - 160 kD molecule. Further degradation products such as the 32 kD molecules were also found. This peptide, however, did not seem to cause substantial suppression in the in vitro CTL assay.
When the 140 - 160, 80 and 32 kD proteins were sequenced at the NH₂ terminus, both 140 - 160 and 80 kD proteins were found to possess the same NH₂ terminus sequence. The 32 kD protein, on the other hand, was found to have an
NH₂-terminus quite different from that of the 80 kD protein. These findings suggested that the 32 kD fragment was probably located at the distal end of the 140 - 160 kD molecule.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
7
Tomkins, Paul Thomas. "Interferon modulation of T-cell responses to Semliki Forest virus infected murine brain cells." Thesis, University of Warwick, 1989. http://wrap.warwick.ac.uk/101165/.
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Cultures of astrocytes prepared from the brains of newborn mice, G26-24 oligodendroglioma cells and C1300 neuroblastoma cells were treated with Interferon (IFN) and the effect on major histocompatibility complex (MHC) antigen expression assessed by indirect immunofluorescence. IFN-αβ increased class I, but not class II, MHC antigen expression on astrocytes, G26-24 cells and C1300 cells. IFN-β1, increased class I, but not class II, MHC antigen expression on astrocytes. IFN-γ increased both class I and class II MHC antigen expression on astrocytes and G26-24 cells. IFN-γ increased class I, but not class II, MHC antigen expression on C1300 cells. IFN-αβ and IFN-β were additive with IFN-γ in the induction of class I MHC antigen expression on astrocytes, but inhibited the ability of IFN-γ to induce class II MHC antigen expression. IFN-αβ and IFN-γ increased the susceptibility of astrocytes, C26-24 cells and C1300 cells to lysis by alloreactive cytotoxic T-lymphocytes (CTL) indicating that IFNs increased the ability of the cells to participate in class I MHC restricted T-cell immune reactions. Astrocytes treated with IFN-αβ or IFN-γ, and G26-24 cells and C1300 cells treated with IFN-γ, prior to infection with Semliki Forest virus (SFV), showed a similar or increased susceptibility to SFV-specific CTL lysis, despite a reduction of SFV antigen display on the cells, as assessed by indirect immunofluorescence and susceptibility to lysis by anti-SFV antibody plus complement. It is concluded that even when SFV antigen expression is reduced by IFN treatment, in the context of enhanced class I MHC antigen expression cells remain susceptible to SFV-specific CTL lysis. IFN-αβ and IFN-γ treatment of astrocytes, and IFN-γ treatment of G26-24 cells, prior to treatment with a β-propiolactone inactivated preparation of SFV, increased the ability of the cells to stimulate SFV-specific T-cell release of IFN-γ. This increased ability correlated with an increase in MHC antigen expression on the cells. IFN-γ released by SFV-specific T-cells increased class I and class II MHC antigen expression on astrocytes and G26-24 cells indicating that a positive feedback mechanism could operate. SFV-infected newborn and adult mice possessed high levels of IFN-αβ in the brain. Brain extracts prepared from SFV-infected newborn and adult mice increased class I, but not class II, MHC antigen expression on astrocytes in vitro. Class I and class II MHC antigen expression was slightly elevated in the brains of SFV-infected newborn mice. To study the role of endogenous IFN-γ, R4-6A2 anti-IFN-γ monoclonal antibody was administered to adult mice, prior to infection with SFV, and the effect on the clinical course of SFV-disease monitored. R4- 6A2 antibody had no effect and preliminary experiments indicated that the antibody may not neutralise all IFN-γ activity in vivo under the conditions used.
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Chan, Po-Ying. "Characterization and cDNA cloning of a novel murine T cell surface antigen YE1/48." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/28640.
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T cell surface antigens are thought to play significant roles in immunological functions. They are involved in cellular interactions and T cell activation and proliferation. Characterization of T cell antigens is important in understanding the molecular machanisms underlying immune responses. The subject of this thesis is to characterize a novel murine T cell surface antigen called YE1/48.
YE1/48, defined by two rat monoclonal antibodies YE1/48.10.6 and YE1/32.8.5, is a dimeric glycoprotein with molecular size and charge resembling the murine T cell antigen receptor α/β. It was initially detected at high levels on two T cell lymphomas, EL-4 and MBL-2. In my thesis studies, the YE1/48 antigen was characterized biochemically, a cDNA clone was isolated, and its expression in lymphoid cell populations was determined. The YE1/48 antigen was found to be distinct from the T cell receptor based on direct comparisons of their primary sequences as well as immunological analyses. It is likely a homodimer with similar or identical subunits. No homology with any known proteins could be detected, including the human T cell activation antigen CD28 (T44) which also has a similar dimeric structure as YE1/48. No function of the YE1/48 antigen could be derived from its primary sequence or with the use of the two monoclonal antibodies because the antibodies do not appear to bind to the surface of intact normal T lymphocytes.
Some intriguing characteristics of the YE1/48 antigen were observed in the current studies. The YE1/48 antigen belongs to a rare group of type II membrane proteins with orientation of the amino-terminus inside the cell and the carboxy-terminus outside. The YE1/48 gene may have two alleles among different mouse strains and may belong to a multigene family. YE1/48 is expressed at low levels on a wide range of T cells with no restriction to their differentiation stages, and on spleen B cells as well as bone marrow cells. Its expression on lymphocytes is not related to activation or proliferation. However, YE1/48 expression appears to be induced at high levels by Abelson Murine Leukemia Virus-transformation of pre-B cells. Moreover, the epitopes defined by the YE1/48.10.6 and YE1.32.8.5 antibodies seem to be exposed only on three T lymphomas but not on normal T cells. It is thus tantalizing to speculate a correlation of the high level expression of YE1/48 antigen and its epitope exposure on transformed lymphocytes with cellular transformation.
In summary, YE1/48 was found to be a novel T cell surface antigen which has similar dimeric structure as the murine T cell receptor α/β and human CD28 (T44). It has now been characterized biochemically, molecularly cloned, and its expression on lymphoid cells has been determined. Although the function of YE1/48 antigen remains unknown, a number of intriguing characteristics observed in the current studies have certainly called for further studies on the antigen and the determination of its function.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
9
Rovis, Flavia. "Functional and molecular characterisation of murine CD4+CD25+ regulatory T cells." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486557.
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CD4+CD2S+ regulatory T cells (Tregs) are naturally occurring lymphocytes that play a central role in tolerance, autoimmune diseases, transplantation, tumour immunology and infectious diseases. Despite the numerous studies carried on this' subpopulation of Tregs, the mechanisms of action of these cells still remain elusive. This project is focused on the functional and molecular characterisation .of murine Tregs with the hypotheses that they mediate suppression by contact-dependent inhibitory signal. A sensitive assay of Treg function in vitro was developed, based on the co-culture of CD2S+ and CD2S- CD4+ T cells with anti-CD3/CD28-coated DynaBeads�®. Potent, titratable suppression of both proliferation and a range of cytokines in culture supernatants - including IL-2, IL-4, IL-S, IFNy and 1NFa. - was demonstrated. This assay has subsequently been used to measure in vitro Treg function using a complex mathematical model - dev~loped in-house - showing that CD4+CD2S+ Tregs restrain the size of a co-cultured CD4+CD2S- T cell population by the simultaneous suppression of cell division and induction of cell death, mediated by both the intrinsic and extrinsic pathways. of apoptosis, using dilution of CFSE as a read-out. These studies have been complemented by the proteomic examination of freshly isolated and anti-CD3/CD28 Dynabead@-activated CD2S+ and CD2S- CD4+ T cells. A number of complex proteomic techniques have been mastered, such as liquid IEF in the first dimension, which were novel in the context of Tregs biology. In addition, new differentially expressed proteins in Tregs were discovered. In particular, a protein, 14.3.3 that may play a hitherto unrecognised role in Treg function, was identified. Overall, these studies suggest several new perspectives on Treg biology and new paths of exploration.
10
Ciurkiewicz, Małgorzata [Verfasser]. "Role of regulatory T cells, cytotoxic T cells and interleukin-10 in Theiler's murine encephalomyelitis virus infection / Małgorzata Ciurkiewicz." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2019. http://d-nb.info/1193489407/34.
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O'Hara, Geraldine. "Characterisation of tissue homing C08+ T cells in a murine cytomegalovirus model." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.600522.
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Stanford, Marianne Michelle. "Immunoregulation in murine experimental autoimmune thyroiditis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0020/MQ54961.pdf.
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Kamal, Mahine. "Parasite-induced changes in murine small intestinal paneth and intermediate cells." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342599.
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Carney, Katharine W. "Expression patterns and functional roles of amphiregulin in murine CD4+ T cells." Thesis, Royal Veterinary College (University of London), 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669191.
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Babichuk, Charolyn Kim. "Transcriptional regulation of the murine granzyme B gene in cytotoxic T cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq22945.pdf.
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Lin, Ya-Ling. "CD4⁺/CD8⁺ T cells and macrophage-derived TNF-α in murine schistosomiasis." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627622.
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Lansdell, Casey. "Characterization of Surgery-Induced Vaccine Dysfunction in a Therapeutic Murine Melanoma Model." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34269.
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Surgical resection is the leading treatment of most solid tumours, however surgical stress creates an immunosuppressive environment that promotes metastases. A global decrease in T cell numbers and function post-surgery has been documented. However, the effect on tumour associated antigen (TAA)-specific T cells remains unclear. The objective is therefore to evaluate the impact of surgical stress on TAA-specific adaptive T cell immunity. Melanoma tumour-bearing C57BL/6 mice were vaccinated using AdhDCT, an adenovirus expressing dopochrome totaumerase (DCT), a melanoma TAA, and underwent abdominal nephrectomies to induce surgical stress. Surgical stress decreased the number of splenic cytotoxic T cells (CTLs) and their capacity to produce immunostimulatory cytokines (IFNγ and TNFα), as determined by flow cytometry. A perioperative accumulation in CTL-suppressive MDSCs was observed and demonstrated a direct suppression of CTL IFNγ and TNFα production and secretion. Understanding the mechanisms of perioperative T cell dysfunction will facilitate the development of targeted immunotherapies.
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Kashyap, Mohit. "Regulation of Murine Mast Cell Homeostasis by TGF-β1 and CD4+CD25+C Regulatory T Cells." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/950.
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Understanding mast cell development is central to allergic disease pathophysiology. Our laboratory has previously shown that cytokines such as IL-4 and IL-10 inhibit mast cell development from bone marrow progenitors. These studies encouraged our interest in other regulatory cytokines, including transforming growth factor β1 (TGF- β1). TGF- β1 has many cellular sources, one of which is CD4+CD25 regulatory T cells (Tregs). We wanted to determine the effects of Transforming Growth Factor (TGF) βl on mast cell development. We find that TGFβl decreased FcεRI, c-Kit, T1/ST2 and FcεR expression, and inhibited granule formation in developing mast cells. Accessory cells were not required for this inhibition. Smad3-deficiency did not alter the response of bone marrow cells to TGFβ1. TGFβl inhibited expression of the FcεRI a subunit protein, without decreasing β or γ proteins. Mast cells derived in the presence of TGFβl were functionally impaired, as IgE-mediated cytokine secretion was greatly reduced. The changes in granule formation and surface antigen expression were long-standing, as they were not reversed by transfer to W/WV mice. The TGF-β1 dependent transcriptional regulation of bone marrow cells from which mast cells develop was examined through DNA microarray analysis. Wild type (WT) bone marrow cells were stimulated with IL-3+SCF+vehicle or IL-3+SCF+TGF-βI for 10 days and their transcriptomes* analyzed. The results identified which components of transcriptional regulation were regulated by TGF- β1. Of particular interest was the upregulation of the β subunit of the FcεRI, inspite of no receptor surface expression and the differential regulation of various mast cell proteases (MCPs). This initial survey provides a potential starting point for further analysis of the role of TGF-β1 -dependent signaling in developing mast cells. Because they produce TGF-β1 and/or IL-10, regulatory T cell-dependent murine mast cell inhibition was examined. Co-culture of mast cells with regulatory T cells for 6 days downregulated mast cell number, high affinity IgE receptor and c-Kit surface expression. This led to a decrease in TNFa release making mast cells functionally impaired. By using Tregs from IL-10 KO mice, this effect was proven to be IL-10 dependent. Mast cells are mediators of inflammatory disease. TGFβl and IL-10 may contribute to mast cell homeostasis by inhibiting maturation from bone marrow precursors. The effects of TGFβ1 and regulatory T cell derived IL-10 result in greatly diminished expression of cell surface markers, reduced granulation, and lack of responsiveness to IgE-mediated activation. Thus TGFβl and/or CD+CD25+ T cells can serve as potent and multifunctional regulators of mast cell maturation and/or function.* A set of genes that are expressed in a cell at any given time.
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Yang, Cuihong. "Regulation of autoimmune responses by dendritic cells and regulatory T cells in murine models of systemic lupus erythematosus." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39573527.
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Pattison, Mari Anne. "The effects of ageing on murine NKT cell and macrophage populations." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/29559.
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The immune system is a complex network of tissues, cells and proteins which protects us against infections and invading pathogens we encounter every day. Immunosenescence refers to age-related impairments in immune function which may contribute to increased prevalence and severity of infectious disease in the elderly. How and why ageing affects the immune system is not fully understood. Using a naturally aged mouse model, work in this thesis shows that the abundance of a rare type of lymphocyte, known as NKT cells, increased across multiple immune organs. Additionally, macrophage abundance was also altered in the lymph nodes of aged mice. Invariant NKT (iNKT) cells express an invariant T cell receptor (TCR) which recognises lipids presented on the CD1d molecule. iNKT cells can be activated and respond to invading pathogens either by recognition of antigens through TCR-CD1d interactions or cytokine-dependent means. Less is known about NKT-like cells, which also express NK cell-associated surface markers, such as CD49b, but lack an invariant TCR. Data within this thesis show that both iNKT and NKT-like cell populations are abundant in the spleen and liver of aged mice. iNKT and NKT-like cells can be divided into subpopulations based on their expression of surface markers or transcription factors, and data suggests that not all subpopulations of these cells are affected by age equally. For instance, flow cytometry showed that while spleen-derived iNKT cells are significantly increased in aged mice, within the iNKT cell population the percentage representation of CD4+ cells are significantly reduced with age. Additionally, data indicates that both iNKT and NKT-like cells from aged mice show compromised responses to in vitro stimulation compared to young controls. Using bone marrow chimeras, where either young cells are reconstituted within an aged mouse or old cells are reconstituted within a young mouse, provided the opportunity to determine whether the aged environment contributes to this diminished response. Data demonstrates that the aged environment plays at least a partial role in these age-related changes to response to stimulation, however the young environment seems unable to reverse these changes. Macrophages are phagocytes which are found within all organs of the body. Studies in this thesis show that CD169+ macrophages have diminished numbers in the lymph nodes of aged mice, but this did not seem to affect the capture of the model antigen, dextran. Further studies revealed ageing affects macrophage populations differently in the different tissues within the body. For example, macrophage numbers remain constant in the spleen with ageing, but appear to increase in density in the lungs. To conclude, ageing can cause dramatic changes to the numbers and function of different cells of the immune system across multiple organs. Furthering our understanding of the ageing immune system and the underlying mechanisms which cause age-related decline in immune function is important to design strategies to improve the quality of the lives of the elderly.
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Zhou, Xinghua. "Immune mechanisms in atherosclerosis : the role of T cells in murine models of atherosclerosis /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4217-X/.
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Whibley, Natasha. "The role of effector and regulatory helper T cells in a murine model of systemic Candida albicans infection." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=192231.
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Diseases caused by fungi are increasing worldwide and are often associated with high mortality rates. In particular, the normally harmless commensal Candida albicans can cause serious disease if immunological and physiological barriers are perturbed, leading to systemic infection, which is fatal in up to 45% of cases. The adaptive immune response is believed to be important in protection against systemic candidiasis, however, the roles of different helper T (Th) cell subsets, particularly Foxp3+ regulatory T (Treg) cells, remain largely unexplored. The aims of this study were to adapt a mouse model of systemic C. albicans infection to test whether the numbers of Th1, Th2, Th17 and Foxp3+ Treg cells increase in mice with systemic C. albicans infection, and determine their contribution to disease. C. albicans drove the expansion of Th1, Th2 and Th17 cells, as well as multiple Foxp3+ populations that displayed characteristics of natural Treg, induced Treg, Th17 and Th1 cells in vitro and in vivo. The expanded Foxp3+ T cells inhibited Th1 and Th2, but promoted Th17, responses to C. albicans antigens in vitro and exacerbated disease, since their depletion in vivo reduced kidney fungal burden and inflammatory lesions. Furthermore, systemic infection with a weakly virulent C. albicans strain was associated with reduced Treg responses compared to those induced during lethal systemic infection. These data lead to a model for systemic candidiasis whereby Treg expansion promotes Th17 responses that drive pathology, and have implications for future immunotherapy.
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Wafula, Paul Ojiambo. "Regulatory T cells, their role and mechanism of fetal protection in a pregnancy murine model /." Berlin : Köster, 2009. http://d-nb.info/996421742/04.
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Yang, Cuihong, and 楊翠紅. "Regulation of autoimmune responses by dendritic cells and regulatory Tcells in murine models of systemic lupus erythematosus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39707362.
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Taylor, Peter Charles. "A study of autoimmune arthritis using xenografts of human immune cells and allografts of murine immune cells into mice with severe combined immunodeficiency." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338516.
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Norrie, Andrew. "Characterization of the Immune Stimulated Release of Extracellular Vesicles from Murine Cells." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41943.
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Introduction: Viruses, extracellular vesicles (EVs) and endogenous retroviruses (ERVs) are types of sub-micron particles which are known to be released from a vast range of cell types, across many species. There are many medically relevant sub-micron particles which can enter healthy cells and enable the intercellular delivery of functional host-derived and foreign products, through their enclosed lipid layers. While multiple particle subsets have been identified, many of the properties, behaviors and biochemical functions have not been fully described and have yet to be characterized.
Materials and Methods: CD4⁺ naïve T-cells were isolated from female C57BL6/N mice and stimulated with varying concentrations of PMA/I. In addition to concentration, the length of PMA/I activation was assessed. Supernatants and cells were harvested, filtered, and stained to be subsequently analyzed by Nanoscale Flow Cytometry, Nanoparticle Tracking Analysis and Flow Cytometry. Particle populations were quantified and sorted by size, by NTA. Labelling dye CFSE was used in conjunction with fluorescently conjugated CD81 and CD9 antibodies to separate EVs, including exosomes, from background signal. Naïve T-cell purity, viability and levels of activation were assessed by flow cytometry using CD3, CD4 and CD62L antibodies and viability staining.
Results: Increasing PMA concentration led to a global increase in particles by T-cells and a specific increase in smaller particle production and were demonstrated to be significant by Welch’s T-test, when compared to non-activated and DMSO controls (p<0.0001). In addition to concentration, activation length also correlated with increases in total particle counts and a specific increase in the secretion of smaller particles in comparison to non-activated and DMSO controls (p<0.0001). Labelling techniques by NFC revealed an increased presence of CFSE-CD81 positive and CFSE-CD9 positive particles secreted by T-cells, treated for 24 hours, compared to the 0- and 12-hour timepoints.
Conclusion: This work demonstrates preliminary steps and outlines methods to begin assessing discrete particle populations and subsets secreted by murine naïve T-cells. Being able to identify patterns of particle secretions by naïve T-cells, especially under immune-stimulated conditions, may be the solution to uncovering the necessary information on EV physiology, that is required to understand the roles EVs play in pathology and how these conserved pathways may lead conditions to become exacerbated. This knowledge is essential to uncovering the roles EVs play in pathophysiology, and in the development of novel rapid diagnostic tests, to screen for cancers, infections, autoimmune disorders, and numerous other pathological conditions.
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Wang, Yang. "Murine adriamycin-induced nephropathy : the roles of cell-mediated immunity and CD4+ T-lymphocytes." Thesis, The University of Sydney, 2000. https://hdl.handle.net/2123/27827.
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Shao, Liang, and 邵亮. "Study on the role of CD4⁺CD25⁺ regulatory T cells in acute and chronicgraft-versus-host disease in murine models." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B50534014.
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To study the pathogenesis and preventive strategies of acute and chronic graft-versus-host disease (aGVHD, cGVHD) after hematopoietic stem cell transplantation (HSCT), murine models of aGVHD and cGVHD were constructed. In addition, the role of CD4+CD25+ regulatory T cells (Tregs) in GVHD was also investigated in these models.
My project consisted of three parts, including MHCI,II mismatched (part 1) and haploidentical BMT(part2) based aGVHD, and MHC matched, minor histocompatibility antigen (miHA)mismatched cGVHD(part 3).
In the first model, aGVHD resulting from an MHC I, II mismatched aGVHD (B6(H-2b)→BALB/c(H-2d)) HSCT was studied, particularly with respect to the role that CD4+CD25+Tregs played. The results showed that CD4+CD25-T-cells induced more severe aGVHD than CD4+ T-cells, resulting in more extensive
target organ lesions, especially in colon. The possible mechanism might be due to the enhanced proliferation and differentiation towards pathogenic Th1 cells.
In the second model, haploidentical (B6(H-2b)→[C57BL/6×CBA/Ca]F1(H-2b×k)) HSCT was used to studied the role of CD4+or CD8+T-cells in aGVHD.Both high dose of donor CD4+-and CD8+-T-cells have the ability to induce lethal aGVHD in the hosts. However, the clinical and histological features of aGVHD induced by CD4+T-cells were significantly different from that induced by CD8+T-cells. Both donor CD4+-and CD8+-T-cells showed marked proliferation and differentiation towards CD4+IFN-γ+Th1and CD8+IFN-γ+cells, respectively. Polyclonalexpanded freshly isolatednTregs (exp-nTregs) showed obvious proliferation, increased apoptosis, and rapid loss of Foxp3 expression with impaired suppressive function. Exp-nTregs were further investigatedfor their preventive function in aGVHD in this haploidentical HSCT model. The results showed that exp-nTregs were capable of attenuating either CD4+-or CD8+-T-cell-induced aGVHD with significantly prolonged survival rate.
In the third model, cGVHD was investigatedin DBA/2 (H-2d)→BALB/c (H-2d) HSCT, where the biologic readout was proteinuria and skin fibrosis. The results showed that donor CD4+T-and B220+B-cells were the main effectors in the pathogenesis of cGVHD. Notably, a more active germinal center (GC) reaction existed in the cGVHD cohorts compared with the control syngeneic cohort. Furthermore, Tfh and GC B-cells were shown to have originated from donor CD4+T-and B220+B-cells, respectively. Importantly, Tfh and GC B cells were mutually stimulatory and inter-dependent.
In conclusion, three murine models were used to investigate aGVHD and cGVHD. The results showed that Tregs played a significant suppressive role in aGVHD complicating haploidentical HSCT. Furthermore, a hyperactive germinal center reaction might be the main cause of cGVHD.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
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Khan, Muhammad Akram [Verfasser]. "Expansion of regulatory T cells in Theiler’s murine encephalomyelitis virusinfected C57BL/6 mice / Muhammad Akram Khan." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2015. http://d-nb.info/1073883086/34.
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Hutchison, Sharon. "Investigation of the role of T cells in airway inflammation using novel murine models of disease." Thesis, University of Glasgow, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443198.
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Abajyan, Anaida. "Characterization of altered cytokine production by memory CD4 T cells in NZBxW murine model of SLE." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20094.
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Der systemische Lupus erythematodes (SLE) ist eine Autoimmunerkrankung, bei der eine Vielzahl an Organen betroffen sein kann. Hierbei spielen T-Zellen mit gestörter Zytokinproduktion, insbesondere von IL-2 und IFN-γ, eine besondere Rolle. Mit Fortschreiten der Krankheit sinkt die Anzahl an IL-2-Produzenten und gleichzeitig steigt die Anzahl an IFN-γ-Produzenten. Während die Rolle von IFN-γ in SLE bisher kontrovers diskutiert wird, wirkt sich die verringerte Produktion von IL-2 beispielsweise negativ auf regulatorische T-Zellen aus, was zur Pathogenese der Krankheit beiträgt.
In dieser Arbeit erfolgte eine Charakterisierung der Zytokinproduzierenden CD4+ Gedächtnis-T-Zellen in erkrankten NZBxW Mäusen, einem Modell für SLE. Anhand der Produktion von IL-2 und/oder IFN-γ wurde dabei in DN (IFN-γ—IL-2— doppelt negative), IL-2 SP (IFN-γ—IL-2+ einzelpositive), DP (IFN-γ+IL-2+ doppelt positive) und IFN-γ SP (IFN-γ+IL-2— einzelpositive) Zellen unterschieden. Ein mehrstufiges Verfahren der Zellsortierung ermöglichte die Isolierung der vier Zellpopulationen. Genexpressionsanalysen legten offen, dass die während der Krankheit vermehrt vorkommende Population der IFN-γ SP Zellen im Vergleich zu DP Zellen deutliche Unterschiede in ihrem Genexpressionsmuster aufweist. IFN-γ SP Zellen exprimieren u.a. verstärkt Chemokinrezeptoren, co-stimulatorische und co-inhibitorische Moleküle, sowie Apoptose-Marker und zeigen eine verminderte Produktion von Effektorzytokinen. Weiterführende funktionelle Analysen untermauerten die Expressionsdaten und zeigten eine verminderte Proliferationsfähigkeit und verstärkte Apoptose der IFN-γ SP Zellen. Die Daten zeigen, dass der Phänotyp der IFN-γ SP Zellen in erkrankten NZBxW Lupus-Mäusen gestört ist, wodurch die IFN-γ SP Zellen zur Erkrankung beitragen könnten.Systemic lupus erythematosus (SLE) is an autoimmune disease, which can affect almost every organ system of the body. Thereby altered cytokine production by T cells plays an important role in the pathogenesis of the disease. With disease progression, production of IL-2 decreases and production of IFN-γ increases. It has been shown that IL-2 deficiency affects Treg homeostasis in SLE and thus contributes to its pathogenesis. The role of IFN-γ in SLE is, however, controversial. In this work, a comprehensive characterization of four subpopulations of memory CD4 T cells of diseased NZBxW lupus-prone mice was performed. These cell subsets are DN (IFN-γ—IL-2— double negative), IL-2 SP (IFN-γ—IL-2+ single positive), DP (IFN-γ+IL-2+ double positive) and IFN-γ SP (IFN-γ+IL-2—single positive) cells. A multi-step cell sorting procedure was used to isolate these cell subsets. The data showed that IFN-γ SP cells were characterized by a different gene expression profile than DP cells. In detail, IFN-γ SP cells revealed an enhanced expression of chemokine receptors, co-stimulatory and co-inhibitory molecules as well as apoptosis markers and decreased production of effector cytokines. In addition, functional analyses showed that IFN-γ SP cells were tended to increased apoptosis and decreased proliferation. These data show an altered phenotype of IFN-γ SP cells of diseased NZBxW lupus-prone mice, which might be important for the disease pathogenesis at least in this animal model of SLE.
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Kaveri, Deepika. "Study of the role of Wnt pathway in a murine model of T-ALL." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00912330.
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We report a murine model, R26-βcat, expressing a stable form of β-catenin in T cells. R26-βcat pre-leukemic mice show a developmental block in T-cell differentiation and exhibit increased resistance to apoptosis. Interestingly, the mice develop T cell lymphomas independent of the Notch pathway. Furthermore, we showed that loss of the tumour suppressor Pten and over-expression of Myc was favoured; and may constitute the secondary events contributing to this leukemogenesis. We also demonstrated that R26-βcat tumours are malignant, heterogeneous and that leukaemia stem cells (LSC) were enriched in DP cells. Furthermore, the self-renewal capapcity of R26-βcat LSCs can to be exhausted.We propose that the R26-βcat model defines a new sub-group of Notch-independent T-ALL and the β-catenin may serve as a potential therapeutic target for these tumours.
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Ananth, Abhirami. "Surgical Stress Attenuates Pre-existing Anti-tumour Immunity Resulting in Postoperative Metastases and local Recurrence in a Murine Model." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31697.
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Solid malignancies in cancer patients require surgical intervention; however, surgery has been shown to promote the metastatic potential of tumour cells. Surgery-induced impairment of adaptive immunity is poorly understood, thus, our aim is to characterize the impact of surgery on tumour antigen-specific cytotoxic T lymphocyte function. To generate anti-tumour immunity, we adopted a C57/B6 model of B16 melanoma immunized with intramuscular (IM) AdhDCT, an adenovirus expressing the melanoma-associated antigen human dopachrome tautomerase (hDCT). Surgical stress was induced by left abdominal nephrectomy. We found that surgery reduces overall survival in AdhDCT-immunized mice, whereas those that did not undergo surgery were cured of their tumours. Surgical stress also decreases both the proportion and absolute spleen numbers of DCT-specific IFN-gamma+ CD8+ T-cells by over 2-fold. We have shown that perioperative suppression of antigen-specific T-cells can lead to increased tumour burden in a murine melanoma model.
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Kusuba, Nobuhiro. "Inhibition of IL-17-committed T cells in a murine psoriasis model by a vitamin D analogue." Kyoto University, 2019. http://hdl.handle.net/2433/243300.
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Berjanskii, Mark. "Structure and dynamics of the N-terminal J-domain of T antigens of murine polyomavirus." MU online access free, to others for fee Free online access, 2002. http://wwwlib.umi.com/cr/mo/preview?3052146.
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Pfeilschifter, Janina Marie. "Targeting B non-Hodgkin lymphoma and tumor-supportive follicular helper T cells with anti-CXCR5 CAR T cells." Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/23169.
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CAR-T-Zell-Therapie ist eine vielversprechende neuartige Behandlungsform für Patienten mit aggressiven B-Zell Non-Hodgkin-Lymphomen (B-NHL). In dieser Arbeit wurde die anti-CXCR5 CAR-T-Zell-Therapie als Alternative zur anti-CD19 CAR-T-Zell-Therapie für die Behandlung von reifen B-NHLs untersucht. CXCR5 ist ein B-Zell-homing Rezeptor, der von reifen B Zellen und follikulären T-Helferzellen (TFH Zellen) exprimiert wird. TFH Zellen wurden als tumor-unterstützend in chronisch lymphatischer Leukämie (CLL) und im follikulären Lymphom (FL) beschrieben. Dieses Expressionsmuster erlaubt es, auf einzigartige Weise zeitgleich die malignen Zellen und die tumorunterstützende Mikroumgebung mithilfe von CAR-T-Zell-Therapie gerichtet gegen einen Chemokinrezeptor anzugreifen. Die wichtigsten Ergebnisse dieser Arbeit waren, dass (1) die anti-CXCR5 CAR T-Zellen zielgerichtet CXCR5 positive reife B-NHL Zelllinien und Patientenproben in vitro eliminierten und eine starke anti-Tumor Reaktivität in einem immundefizienten Xenotransplantationsmausmodell zeigten, (2) die anti-CXCR5 CAR T-Zellen zielgerichtet die tumorunterstützenden TFH Zellen in CLL und FL Patientenproben in vitro erkannten und dass (3) CXCR5 ein sicheres Expressionsprofil zeigte. CXCR5 war stark und häufig auf B-NHL exprimiert und die Expression auf gesundem Gewebe war auf lymphoide Zellen beschränkt. Zusammenfassend lässt sich sagen, dass die anti-CXCR5 CAR-T-Zell-Therapie eine neue Behandlungsmöglichkeit für Patienten mit reifen B-NHL darstellt, indem durch die anti-CXCR5 CAR-T Zellen sowohl der Tumor als auch ein Anteil der tumorunterstützende Mikroumgebung eliminiert werden.
Im zweiten Teil der Arbeit wurde das Eμ-Tcl1 murine CLL Lymphommodell genutzt um die Auswirkung der Lymphomentwicklung auf die CXCR5+ T Zellen zu untersuchen. Mittels RNA-Einzelzell-Sequenzierung konnte ein profunder Einfluss des Lymphomwachstums auf das T Zell-Kompartiment der Mäuse, denen Eμ-Tcl1 Zellen gespritzt wurden, gezeigt werden.CAR T cell therapy is a promising new treatment option for patients suffering from aggressive B non-Hodgkin lymphomas (NHLs). In CAR T cell therapy, patient-derived T cells are genetically modified to express a chimeric receptor commonly directed towards a surface antigen expressed by neoplastic cells. In this thesis, anti-CXCR5 CAR T cell therapy was investigated as an alternative to anti-CD19 CAR T cell therapy for the treatment of mature B-NHLs. CXCR5 is a B cell homing receptor expressed by mature B cells and follicular helper T (TFH) cells. TFH cells were described to support the tumor cells in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This expression pattern allows simultaneous targeting of the malignant cells and the tumor-supporting microenvironment by CAR T cell therapy against a chemokine receptor in an unprecedented manner. Main findings included that (1) anti-CXCR5 CAR T cells targeted specifically CXCR5 expressing mature B-NHL cell lines and patient samples in vitro and showed strong in vivo anti-tumor reactivity in an immunodeficient xenograft mouse model, (2) anti-CXCR5 CAR T cells targeted tumor-supportive TFH cells derived from CLL and FL patient samples in vitro and (3) CXCR5 showed a safe expression profile. CXCR5 was strongly and frequently expressed by B-NHLs and its expression on healthy tissue was restricted to lymphoid cells. In summary, anti-CXCR5 CAR T cell therapy presents a novel treatment option for patients suffering from mature B-NHLs by eliminating the tumor and part of the tumor-supportive microenvironment. The second part of the project, the Eμ-Tcl1 murine lymphoma model, which mimics human CLL, was used to study the impact of lymphomagenesis on CXCR5+ T cells. Using single cell RNA sequencing, a profound influence of lymphoma growth on the T cell compartment in Eμ-Tcl1 tumor-challenged mice could be shown.
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Mays, Jacqueline Wiesehan. "Psychosocial stress modulation of the murine anti-viral immune response during a primary influenza infection and the impact on immunologic memory." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1241712390.
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Kim, Wooki. "Molecular mechanisms of immunosuppressive effects of dietary n-3 pufa, curcumin and limonin on murine cd4+ t cells." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-3212.
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Mora, Ahmed. "Expression and function of the chemokine receptor XCR1 on murine CD8 + DC." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16088.
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In dieser Arbeit wurde die Expression von XCR1 in B6XCR1lacZ+/+ Reporter Mäusen charakterisiert, die β-Galaktosidase unter der Kontrolle des XCR1-Promotors exprimieren. In Gewebeschnitten konnten wir zeigen, dass eine starke XCR1-Expression nur in lymphatischen Organen wie Milz, Lymphknoten und Thymus nachweisbar ist. In der Milz fanden sich XCR1+ Zellen vor allem in der Marginal Zone, aber auch in der roten Pulpa und der T-Zell-Zone. Durchflusszytometrische Analysen zeigten, dass XCR1 in der Milz ausschließlich von dendritischen Zellen DZ exprimiert wird, hauptsächlich von der CD8+DZ Subpopulation aber auch von einer Minderheit der CD4−CD8−DZ. In vivo migrierten diese XCR1+ Zellen nach Applikation von chemotaktischen oder inflammatorischen Substanzen: Die Injektion sowohl einer ATAC-sezernierenden Zelllinie als auch von LPS lösten nach 3-9 h eine Translokation der XCR1+Zellen in die T-Zell-Zone der Milz aus. Untersuchungen der Phagozytose-Aktivität ergaben, dass nur XCR1+CD8+DZ, aber keine anderen DZ Subpopulationen, injizierte allogene Zellen aufnahmen, und dass eine Transfektion dieser Zellen mit ATAC diese Phagozytose signifikant verstärkte. Daher konnten wir allogene Zellen, die intrazellulär Ovalbumin OVA exprimierten, für die selektive Applikation von Antigen auf XCR1+DZ verwenden. Diese selektive Antigen-Applikation induzierte eine starke antigenspezifische zytotoxische Antwort von endogenen T-Zellen, ohne dass es zur Produktion von OVA-spezifischen Antikörpern kam. In Abwesenheit von ATAC war diese endogene zytotoxische Aktivität verringert. Durch adoptivem Transfer und Aktivierung von Wildtyp- oder ATAC-defizienten OVA-spezifischen transgenen CD8+TZellen konnten wir bestätigen, dass ATAC für die Erzeugung einer optimalen zytotoxischen Antwort benötigt wird. Die selektive Applikation von Antigen auf CD8+DZ stellt daher eine vielversprechende Strategie dar, um optimierte Vakzinierungs-Ansätze für die Auslösung einer zytotoxischen Immunantwort zu entwickelnThe G protein-coupled receptor XCR1 has been described as the sole receptor for the chemokine ATAC. As contradictory data were published on the expression pattern of XCR1, its role in the immune system has not yet been defined. In this work, expression of XCR1 was characterized in B6.XCR1 lacZ+/+ reporter mice which express β galactosidase under the control of the XCR1 promoter. In tissue sections, strong expression of XCR1 was only detected in lymphoid organs like spleen, lymph nodes and thymus. In the spleen, XCR1+ cells were mainly found in the marginal zones, but also in the red pulp and the T cell zones. Flow cytometric analysis demonstrated exclusive expression of XCR1 on DC, mainly on the CD8+ DC subset, but also on a minority of CD4− CD8− DC. In vivo, these XCR1+ cells migrated in response to chemotactic or inflammatory stimuli: application of either an ATAC-expressing cell line or LPS induced within 3 9 h the translocation of XCR1+ cells to the T cell area of the spleen. When tested for phagocytic capacity, XCR1+ CD8+ DC, but not other DC subsets, specifically took up injected allogeneic cells, and transfection of these cells with ATAC significantly enhanced their endocytosis by XCR1+ CD8+ DC. Thus, we could employ allogeneic cells expressing OVA intracellularly to target antigen selectively to XCR1+ DC. This antigen targeting induced a strong antigen-specific cytotoxic response by endogenous T cells without a generation of OVA-specific antibodies. In the absence of ATAC, the endogenous cytotoxic activity was markedly diminished. Adoptive transfer and activation of wild type or ATAC-deficient OVA-specific CD8+ transgenic T cells confirmed that ATAC is required for the generation of an optimal cytotoxic response. Targeting of antigen to CD8+ DC via XCR1 may thus be a promising strategy for the development of new vaccination approaches aimed at optimizing the induction of cytotoxic T cells.
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Massey, Robert D. "Peptide expressing phage used as an immunological stimulant for the treatment of murine mammary tumors /." abstract and full text PDF (UNR users only), 2000. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:9997143.
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Ireland, Demelza Jane. "Intra-tumoural regulatory T cells : a potential new target for anti-cancer immunotherapy." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0076.
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[Truncated abstract] Previous studies in the field of tumour immunology had identified regulatory T (Treg) cells as important suppressors of the anti-tumour immune response as the presence of Treg cells in the peripheral blood of cancer patients was correlated with worse disease outcomes. Other studies had identified Treg cells to be active at sites of immune regulation such as the gut of colitis patients. It was therefore hypothesised that Treg cells would be present and active within tumours to suppress the cellular antitumour immune response. ... This treatment targeting multiple pathways of Treg cell mediated immuno-suppression and resulted in tumour regression in 50% of treated animals. Finally, the anti-tumour immune response is complex and a potentially synergistic multi-modality treatment designed to inactivate intra-tumoural Treg cells but to also induce apoptosis in tumour cells themselves was investigated. Alpha-tocopheryl succinate (α-TOS), an analogue of vitamin E, had previously been shown to induce apoptosis in human MM xenografts implanted into immuno-deficient (nude) mice. Administration of α-TOS was therefore examined as a potentially synergistic treatment to be coupled with Treg cell inactivation. At the previously published doses used to treat immuno-deficient mice, α-TOS was found to be toxic to the immuno-competent mice used in this study. A marked depleting effect on total T cells was seen in the treated animals. The results of this thesis demonstrated the high potential for an adjunct immunotherapy of MM. They did however also highlight the importance of future studies into anticancer therapies to be conducted using clinically relevant tumour models and clinically relevant treatment regimes. The need to consider synergistic multi-modal therapies was also emphasised.
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Steer, Henry John. "Combining chemotherapy with immunotherapy to treat mesothelioma : an investigation into the role of CD4+ T cells in a murine model." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/13672/.
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Cytotoxic chemotherapy remains the mainstay of treatment for patients with cancer, however immunotherapy is starting to emerge as an additional modality of treatment. Evidence suggests that chemotherapy can synergise with immunotherapy to improve responses. Although CD8 T cells have been regarded as the main anti-tumour effector cell, the role of CD4 T cells in orchestrating CD8 and other anti-tumour responses is increasingly recognised. However, the CD4 T cell population contains effector and suppressive subsets with diverse and opposing functions. This thesis describes the establishment of a murine mesothelioma model with which to study the effects of different CD4 subsets on anti-tumour immune responses, and investigate their capacity to provide cognate help to tumour antigen specific CD8 T cells. Haemagluttin (HA) specific CD4 T cells from transgenic mice were polarised in vitro into Th1, Th2, Th17 and Treg subsets and adoptively transferred alongside HA specific CD8 T cells into mice bearing HA expressing tumours derived from a mesothelioma cell line. The effects of the different CD4 subtypes on tumour growth and their capacity to provide ‘help’ to CD8 T cells was investigated in a prophylactic treatment model and in the context of treatment with gemcitabine chemotherapy. Results showed that survival and behaviour of in vitro differentiated CD4 subtypes after adoptive transfer was highly variable and that only Th1s displayed anti-tumour activity when injected prophylactically, prior to tumour inoculation. Cytotoxic chemotherapy did not provide a favourable environment for adoptive transfer of in vitro differentiated CD4 cells. No antitumour activity was seen against established tumours, which may have been due to overriding tumour induced immunosuppressive mechanisms. Successful treatment of established tumours that had been treated with chemotherapy required both the provision of HA specific CD8 cells and the prior removal of an established, endogenous regulatory CD4 T cell population.
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Okumura, Kazuhiro. "Expression of a novel isoform of Vav, Vav-T, containing a single Srchomology 3 domain in murine testicular germ cells." Kyoto University, 2000. http://hdl.handle.net/2433/180822.
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Jha, Vibha. "Cellular regulation of mercury-induced autoimmunity." Diss., Temple University Libraries, 2009. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/60597.
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Microbiology and ImmunologyPh.D.
Etiological agents causing autoimmune diseases largely remain unknown. However, several lines of evidence suggest that environmental factors such as heavy metals (arsenic, lead and mercury) play a crucial role in the development of autoimmune disorders. In our model of mercury-induced autoimmunity, administration of subtoxic doses of HgCl2 to genetically susceptible strains of mice result in an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hypergammaglobulinemia and nephritis. However, mice can be tolerized to the disease by a single low dose administration of HgCl2 (tolerogenic dose). Previous studies from our lab had demonstrated that CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) control the induction and maintenance of tolerance to mercury. We investigated the therapeutic role of Tregs in our model by utilizing agents that are known to stimulate in vivo expansion of Tregs. We studied two such agents, CD3-specific non-Fc receptor-binding [(Fab’)2 fragment] monoclonal antibody (Anti-CD3) and immune complexes containing recombinant IL-2 and anti-IL-2 monoclonal antibody (IC). In our model, treatment of mice with Anti-CD3 had no effect on Treg population. Administration of Anti-CD3 with the tolerogenic dose prevented induction of tolerance and failed to improve the maintenance period of tolerance. Anti-CD3 in presence of mercury activated the immune-system causing splenomegaly and expansion of B cell population. Overall, in contrast to its protective role in other experimental autoimmune disease models, Anti-CD3 exacerbated mercury-induced autoimmune syndrome. Treatment of mice with IC resulted in selective expansion of Tregs with a modest decrease in IgE levels and autoantibody production. Administration of IC with the tolerogenic dose led to a reduction in autoantibody response, thus IC was able to extend the maintenance period of tolerance to mercury. Lymphocyte Activation Gene-3 (LAG-3) is an inhibitory molecule that maintains lymphocyte homeostatic balance by controlling effector T cell expansion and contributing to the suppressive functions of Tregs. Thus, with the goal to understand the impact of homeostatic balance on Hg-induced autoimmunity, we investigated the role of LAG-3 in our model. Administration of an anti-LAG-3 monoclonal antibody broke tolerance to Hg resulting in autoantibody production and an increase in levels of serum IgE. Additionally, LAG-3-deficient B6.SJL mice exhibited an increased susceptibility to mercury-induced autoimmunity whereas, wild type controls suffered only from a mild disease. Moreover, adoptive transfer of wild-type CD4+ T cells protected LAG-3-deficient mice from mercury-induced autoimmunity. Therefore, we conclude that LAG-3 exerts an important regulatory effect on autoimmunity elicited by a common environmental pollutant.
Temple University--Theses
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Sanlaville, Amélien. "Rôle de la réponse immunitaire adaptative anti-tumorale dans l’induction de la transition épithélio-mésenchymateuse." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1276.
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Un enjeu majeur en cancérologie est de réduire le risque de développement métastatique et de rechute. La transition épithélio-mésenchymateuse (EMT), processus physiologique au cours de l'embryogenèse, est un mécanisme central de la carcinogenèse, contribuant de façon précoce à la transformation et la dissémination des cellules tumorales via l'inhibition de la surveillance cellulaire (apoptose et senescence) et l'acquisition de capacités migratoires et invasives. Une autre caractéristique des cancers est la capacité d'échapper à la réponse immunitaire, puissante barrière anti-tumorale. Mais les cellules tumorales entretiennent des relations complexes avec le système immunitaire. Alors que la propension de l'inflammation et des cellules immunitaires innées à favoriser le développement tumoral et l'échappement immunitaire, via l'induction de l'EMT et le maintien d'un microenvironnement immuno-suppresseur, a été bien étudiée, le rôle éventuel de la réponse immunitaire adaptative dans la promotion de l'EMT est quant à lui peu connu. Grâce au développement d'un modèle murin de lignée tumorale mammaire plastique surexprimant l'oncogène Her2/Neu, ce travail démontre in vivo la capacité des cellules tumorales à subir l'EMT, induite par la réponse immunitaire médiée par les lymphocytes T. La déplétion spécifique des lymphocytes T (LT) CD4 restaure le phénotype épithélial de la tumeur, indiquant que les LT CD4 médient une réponse immunitaire induisant l'EMT. En retour, l'EMT confère aux cellules tumorales la capacité de modeler l'immunité comme le recrutement de neutrophiles. Ce travail apporte un nouvel éclairage sur les interactions entre cellules tumorales et système immunitaireCurrent clinical challenge in many carcinomas is to reduce the risk of metastasis development and cancer recurrence. Epithelial-mesenchymal transition (EMT), a physiological process during embryogenesis, is a central mechanism in oncogenesis. EMT induction contributes to early transformation and dissemination through inhibition of cellular surveillance (apoptosis and senescence) and increased migrative and invasive behavior. Another necessary hallmark of cancer is the ability of tumor cells to evade immune surveillance, a powerful barrier against tumor progression. But cancer cells enjoy intricate relations with the immune system. Whereas inclination of inflammation and innate immune cells to favor tumor development and immune escape, via EMT induction and immunosuppressive microenvironment maintenance, has been well investigated, the role of adaptive immune response in EMT promotion is understudied. Based on the development of a plastic murine mammary tumor cell line model overexpressing Her2/Neu oncogene, this study demonstrate in vivo that tumor cells keep an epithelial phenotype in adaptive immunodeficient mice but undergo EMT under the pressure of T-cell mediated immune response, characterized by loss of epithelial EpCAM marker and acquisition of mesenchymal features and EMT transcriptomic signature. CD4 T cell depletion but not CD8 restores the epithelial phenotype of tumors, suggesting that CD4 T cells mediate an immune response that could lead ton EMT induction. In return, EMT confers the ability of tumor cells to shape immunity like intra-tumor neutrophil infiltration. This work shed a new light on interactions between tumor cells and immune system
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Chen, S. K. "Induction and maintenance of tolerance generated by temporary blockade of CD4 and CD8 on peripheral T cells in murine allo- and xenografts." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597534.
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Herein, I demonstrate that immunological tolerance can be induced in major histocompatibility complex (MHC) mismatched allogeneic heart and skin graft recipients and in concordant xenogeneic heart and skin graft recipients. Tolerance induction was achieved via temporary blockade of CD4 and CD8 co-signalling pathways mediated by non-depleting monoclonal antibodies. Basically, tolerance was demonstrated with four experimental models: 1) mouse heart allograft; 2) mouse skin allograft; 3) rat-to-mouse heart xenograft; and 4) rat-to-mouse skin xenograft. The tolerance induced to heart allograft was further investigated and was found to be specific, stable and transferable. The induced donor specific suppressive regulatory cells were CD4+: these could drive naive alloreactive cells to become new tolerant cells. Thus the population of tolerant cells can be numerically amplified via serial adoptive transfers. Tolerance may spread to linked antigens co-expressed with the original tolerogen. Tolerance, once established, was self perpetuating. To induce peripheral T cell tolerance, direct control of the pathway of T cell activation itself is more effective than control of the pathway of antigen presentation from antigen presentation from antigen presenting cells (APCs). Inhibition of direct antigen presentation via class II MHC had no effect on prolongation of allograft survival. Inhibition of indirect antigen presentation via class II MHC prolonged allograft survival, but did not lead to tolerance. AT cell may be activated to be aggressive, or suppressive, presumably depending upon their signal transduction at the time of antigen stimulation. Evidence provided here showed that the mature immune system can be reprogrammed to accept non-self organ graft as "self". Importantly the induced tolerance was an actively operational state. This is a demonstration that in principle, natural immune regulatory mechanisms may be exploited to induce permanent tolerance and may be developed for clinical use to avoid the need for prolonged immunosuppressive drug therapy.
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Oyama, Atsushi. "Up-regulated TGF-β mRNA expression in splenic T cells of high IgA-prone mice : a murine model of IgA nephropathy with glomerulosclerosis." Kyoto University, 2001. http://hdl.handle.net/2433/150601.
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Karaki, Soumaya. "Effets immunorégulateurs de la protéine GILZ (Glucocorticoid-induced leucine Zipper) sur la fonction des cellules dendritiques dans la réponse immunitaire allergique : étude Clinique et expérimentale." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00923138.
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Une cellule dendritique (CD) qui exprime le facteur de transcription GILZ durant l'apprêtement de l'antigène et sa présentation aux cellules effectrices, génère des lymphocytes T régulateurs (LTregs) CD25high Foxp3+ sécréteurs d'IL-10. La production de GILZ est dépendante de l'action des glucocorticoïdes, de l'IL-10 et du TGF-.Nous avons mis en évidence chez l'homme qu'une corticothérapie orale de 48h induit l'expression de GILZ dans les cellules présentatrices de l'antigène circulantes (CPAs) de sujets allergiques. Les CPAs isolées après la corticothérapie génèrent des LTregs CD25high Foxp3+ IL-10+ spécifiques de l'allergène.Nous également constaté in vitro que les mastocytes participent à l'activation des CDs au cours des réactions allergiques en régulant l'expression de GILZ. Les médiateurs d'origine mastocytaire, dont l'histamine, diminuent l'expression de GILZ dans les CDs et altèrent ainsi leur capacité à activer des LTregs. Nous avons identifié le mécanisme par lequel l'histamine diminue l'expression de GILZ dans les CDs humaines. L'histamine inhibe l'activité transcriptionnelle de Foxo3, un facteur de transcription régulant l'expression de GILZ. Enfin, nous avons démontré que des souris transgéniques qui surexpriment GILZ constitutivement dans les CDs sont protégées contre le développement de l'asthme allergique. L'ensemble de ces résultats permet d'envisager de nouvelles stratégies d'immunomodulation dans l'allergie, centrée sur la régulation de l'expression de GILZ dans les CDs.
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Keller, Emma Jean. "The Contribution of IFNα-Stimulated Immune Cell Populations to B6.NbA2 Lupus-likeDisease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1625138193480211.
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Abajyan, Anaida [Verfasser], Andreas [Gutachter] Radbruch, Michal [Gutachter] Or-Guil, and Falk [Gutachter] Hiepe. "Characterization of altered cytokine production by memory CD4 T cells in NZBxW murine model of SLE / Anaida Abajyan ; Gutachter: Andreas Radbruch, Michal Or-Guil, Falk Hiepe." Berlin : Humboldt-Universität zu Berlin, 2019. http://d-nb.info/1189214032/34.
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