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Divekar, Rohit Dilip Zaghouani Habib. "Two aspects of peripheral immune tolerance systemic and mucosal tolerance mechanisms /." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6868.
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The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on April 1, 2010). Vita. Thesis advisor: Habib Zaghouani. "May 2008" Includes bibliographical references.
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Chen, Tse-Ching. "Dominant tolerance to a minor histocompatibility antigen." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400052.
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Whitley, Nathaniel T. "Mechanisms in antigen-specific tolerance induction therapy." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411069.
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Matriano, James Abcede. "Peripheral tolerance to an organ-specific antigen." Case Western Reserve University School of Graduate Studies / OhioLINK, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=case1059484721.
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Ferry, Helen. "B cell tolerance to systemic, intracellular self-antigen." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442947.
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Marshall, Naomi Jane. "Antigen presentation in autoimmune disease." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4212.
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The aim of my project was to examine the extent to which endogenous expression of a largely renal-specific antigen influences the repertoire in adulthood of autoreactive T cells specific to that antigen. The renal-specific antigen, human α3(IV)NC1, is the target of autoimmune attack in Goodpasture’s disease. This protein was expressed and purified in recombinant (using bacterial and mammalian cell expression systems) and purified in native (extracted from human tissue) forms. Transgenic mice were generated that express HLA-DR15 (associated with Goodpasture’s disease) as their sole MHC class II molecule, and for which α3(IV)NC1 can be endogenous or exogenous. The CD4 T cell responses of these mice were then tested following immunisation with α3(IV)NC1. In mice with endogenous expression of α3(IV)NC1 there were no consistent detectable proliferative T cell responses to any α3(IV)NC1 peptides in a set of overlapping peptides representative of the entire sequence. In the mice lacking endogenous α3(IV)NC1 there were consistent responses to the peptide α3(IV)NC1 136-150. This contains part of the peptide recognised by the most abundant autoreactive T cells in patients with acute Goodpasture’s disease. Therefore, the T cell responses seen in man to an endogenous (auto)antigen have similar fine specificity to those seen in mice responding to the same protein as a foreign antigen. This is surprising as one might expect self-tolerance in man to be most secure to such dominantly presented and immunogenic (in HLA DR15 mice) self peptides. However, recent work suggests that the peptide most commonly presented in humans is normally destroyed during antigen processing, giving a possible explanation for the lack of tolerance. Future work should study why tolerance is ineffective to this particular peptide, whether tolerance can be reinforced, these questions could be addressed using a transgenic mouse model that develops Goodpasture-like pathology. In addition, how processing is defective in Goodpasture’s disease could be explored by making antigen presenting hybridomas from patient samples or from the transgenic mouse line described within this thesis.
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Wheeler, Paul Richard. "Characterisation of T cell anergy in allo-antigen specific CD4⺠cells." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288516.
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Konkel, Joanne Elizabeth. "Signals required for the induction of antigen-based therapeutic tolerance." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3942.
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Despite the actions of central tolerance during thymic selection, it is clear that the peripheral T cell repertoire contains significant numbers of self-reactive T cells. The immune system needs to curtail the risk of autoimmune disease by controlling the activity of these self-reactive T cells. Various mechanisms are in place to achieve this control (peripheral tolerance). Activation of CD4+ T cells requires two signals; engagement of the T cell receptor (TCR) with an appropriate peptide:MHC complex (signal 1), and the aggregate effect of multiple signals generated following ligation of costimulatory and coinhibitory molecules (signal 2). Both signals are required for the generation of a productive T cell response and both are provided by the professional antigen presenting cell, the dendritic cell (DC). T cells are fully activated upon receiving both signal 1 and 2, but are rendered tolerant when they receive only signal 1. This can be exploited therapeutically through the administration of peptides to induce tolerance in peptidereactive T cells. Administration of peptide with an adjuvant provides both signal 1 and 2, and leads to a sustained T cell response against the administered peptide (immunity). However, if the same peptide is administered in soluble form, only signal 1 is provided, leading to the establishment of T cell tolerance. The studies in this thesis explore the role of both signal 1 and signal 2 in peptide-induced T cell tolerance. Previous data from our laboratory have highlighted PD-1 and RANKL as costimulatory molecules which could play a role in peptide-induced T cell tolerance. Here we show that PD-1, an important coinhibitory molecule, plays a vital role in restraining peripheral T cell expansion under conditions leading to T cell immunity. However, in contrast to data from other studies, we demonstrate that PD-1 plays no role in the induction, establishment or maintenance of peptide-induced T cell tolerance. We show that the costimulatory receptor ligand pair RANK:RANKL plays a role in the balance between T cell tolerance and immunity; as administration of anti-RANKL was seen to potentiate both tolerance and immunity. We also explored the effect of altering the affinity of a peptide for MHC on the induction of peptide tolerance. We demonstrate that use of a peptide with a high-affinity for MHC induces tolerance via a novel, non-deletional mechanism of peptide-tolerance induction. Importantly, we show that the high-affinity peptide can form peptide- MHC complexes which persist in a biologically relevant form for fourteen days following peptide administration. We suggest that this leads to chronic stimulation of peptide-reactive T cells which promotes acquisition of a novel tolerant phenotype. Collectively the work described in this thesis demonstrates the important roles both signal 1 and 2 play in therapeutic-tolerance induction and how the qualitative and quantitative alteration of these signals can alter T cell fate and/or responsiveness.
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Yuschenkoff, Victoria Nicole. "Tolerance Induction to a Foreign Protein Antigen: Analysing the Role of B Cells in Establishing Peripheral Tolerance." eScholarship@UMMS, 1995. http://escholarship.umassmed.edu/gsbs_diss/298.
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Tolerance to self proteins is largely dependent upon the deletion of immature, self-specific T and B cells in the thymus and bone marrow. Although highly efficient, the elimination of these self-reactive lymphocytes is dependent on the expression of their target antigen in these primary lymphoid organs. Many proteins, however, such as hormones, are developmentally regulated and expressed at different stages of life, while other proteins are expressed outside the thymus and marrow. To ensure self-tolerance, other mechanisms must exist to inactivate or prevent the activation of mature, potentially self-reactive lymphocytes and maintain peripheral tolerance.
T cell activation requires direct recognition of a specific protein fragment, presented on the surface of an antigen presenting cell (APC), as well as the interaction between various T cell and APC surface molecules. In the absence of the costimulatory signals provided by these ligand-pair interactions and lymphokines, antigen recognition leads to T cell inactivation and tolerance to the protein. Since many autoimmune disorders appear to be based upon the aberrant activation of mature T lymphocytes, it is important to identify and understand the mechanisms of peripheral tolerance.
The obvious importance of the APC in initiating the T cell immune response has led our lab to examine one of the many antigen-processing cells, the B lymphocyte. Our studies have shown that B cells are highly efficient APC and can present antigen at very low doses to cultured T cell lines. In addition, we have found that we can induce tolerance, as measured by a reduced antibody response to an immunogenic form of the protein, in naive, normal mice by targeting a foreign protein to their B cells for antigen processing and presentation. Tolerance in the treated mice can be traced to a lesion in the T cell compartment of the animals, thus suggesting that B cells can act as tolerizing APC for peripherally expressed antigens. To further explore this idea and find more direct evidence for the role of B cells in establishing peripheral tolerance, we developed a model system that would more closely resemble in vivo conditions.
This thesis tests and provides additional evidence for the hypothesis that B cells are tolerizing antigen presenting cells for peripherally expressed protein antigens. Tolerance to the foreign protein human μ chain, is induced in normal recipient mice by the transfusion of splenocytes from transgenic mice that express the membrane-bound form of μ on their B cells. Tolerance is antigen-specific since the transfused recipients' antibody production to the irrelevant protein chicken IgG is not compromised. Only viable transgenic spleen cells are tolerogenic and even when human μ chain is accessible to other APCs for presentation, tolerance can be induced by the transfusion of live μ transgenic splenoctyes. These data suggested that the transfused μ chain-expressing B cells are the tolerizing APCs which was confirmed by experiments that compared the tolerizing abilities of purified B and T cells from the transgenic mice. Adoptive transfer experiments showed that the recipients' T cell response to human μ was impaired but an analysis of the isotypes produced by tolerized mice did not indicate that either helper T cell subset was specifically compromised. Splenocytes from human μ chain-secreting transgenic B cells also induce tolerance to human μ in nontransgenic mice. Although human μ chain-expressing B cells were not detected in transfused mice, the presence of measurable levels of human IgM in the sera of mice transfused with μ chain-secreting spleen cells suggests that the transfused transgenic B cells persist in their new host. In addition, the tolerizing ability of both resting and activated membrane-bound μ chain B cells was compared. Lipopolysaccharide (LPS)-activated transgenic spleen cells do not tolerize, nor do they prime for antibody to human μ, thus suggesting that the induction of costimulatory molecules on the transgenic B cells inhibits tolerance induction. To more specifically address this, human μ chain-expressing mice were bred to transgenic mice that express the costimulatory molecule, B7-1 (CD80), on their B cells. Double transgenic splenocytes, in which the B cells bear both human μ and B7-1, did not induce tolerance to human μ chain, a result that supports the idea that activated B cells are not tolerogenic. Together the data in this thesis show that resting B cells can process and present a foreign endogenous antigen in a tolerogenic manner to the immune system and suggest a role for the B cell in the maintenance of peripheral tolerance.
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Sefia, Eseberuo. "Mechanism of immune tolerance induction in antigen-specific human autoimmune disease." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8982.
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Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system and is considered to be a T-cell mediated autoimmune disease. The “ideal” method in treating MS would be an antigen-specific therapy that does not require generalized immunosuppression. To date there are no definitive treatments for MS but there are several licensed therapies such as -interferon. Unfortunately the effect of interferon (IFN) is reduced by the development of neutralizing antibodies (NAbs) in up to 35% of MS patients within two years of starting treatment. An immunization schedule was developed in the BALB/c mice by subcutaneous administration of recombinant human IFN, and this resulted in development of high incidence of NAbs to the protein in the BALB/c model termed “NAbs model”. The mechanism of NAbs formation in this model is believed to be similar to that observed in IFN-treated MS patients with NAbs, which is as a result of an immune response to the protein. We elected to study NAbs in the context of IFN rather than MS directly to investigate the effects of antigen-specific tolerization strategies on the outcome of NAbs and indirectly on the outcome of IFN treatment in MS disease. The depletion of the immune cells triggers a reconstitution program that leads to renewal of the immune cell repertoire. Tolerance can be induced by intravenous administration of a protein. Within this window of reconstitution following depletion, it is hoped that the immune system can be manipulated to tolerate an otherwise foreign protein (human recombinant IFN). The tolerance strategy employed in this project was immune cell depletion using antibodies and mitoxantrone, followed by intravenous re-introduction of rhIFN. Tolerance was successfully induced in the NAbs model by intravenous administration of rhIFN, and further enhanced by immune cell depletion prior to intravenous administration of rhIFN. The BALB/c “NAbs model” offers a suitable model for use in investigating induction of tolerance to rhIFN following the formation of NAbs to the protein. The antigen of interest is known and the time to NAbs formation is also known. Tolerance induction can be monitored and investigated in this model.
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Lau, Annie Wai-Ting. "The role of antigen presentation in the induction of immune tolerance." Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485395.
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Experimental Autoimmune Dveoretinitis (EAD), a CD4+ T cell-mediated retinaspecific disease, is a model for the sight-threatening human posterior uveitis. Dendritic cells (DC) are key regulators of immune responses. Mature DC are traditionally considered to be immunogenic due to their ability to directly activate naIve T cells, though there is accumulating evidence that mature DC can also be tolerogenic and induce antigen-specific regulatory T cells (Treg). Although many studies have demonstrated that systemic administration of DC can suppress the induction ofautoimmune disease, the mechanism ofthis disease suppression in vivo is largely undefined. Here in this thesis, we have examined the mechanism of disease suppression by the subcutaneous (s.c.) transfer oftolerogenic DCs. Tolerogenic DC were prepared by altemative activation of bone marrow derived DC using LPS. In Chapter 3 we have characterised the phenotype and function of differential LPS-activated mature DCs that secrete either the immunoregulatory cytokine 11-10 (ILIO-DC) or the pro-inflammatory cytokine IL-12 (1112-DC). In addition, we have identified their differential expression of TLR4/CDI4 and phosphorylation of the MAPkinase ERKI. The'in vivo tolerogenicity of IRBPpeptide- pulsed ILIO-DC (ILIO-DC+IRBP ) was examined in Chapter 4, where it was evident that the s.c. administration of 1110-DC+IRBP at the nape can significantly suppress the induction of IRBP-peptide-induced EAD at the inguinal, and this effect correlates strongly with an increase in the absolute number of CD4+CD25+Poxp3+ regulatory T cells as well as the cellularity ofthe DC-dLNs.
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Eynon, Elizabeth E. "Small B Cells as Antigen Presenting Cells in the Induction of Tolerance to Soluble Protein Antigens: A Dissertation." eScholarship@UMMS, 1991. https://escholarship.umassmed.edu/gsbs_diss/185.
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This thesis proposes a mechanism for the induction of peripheral tolerance to protein antigens. I have investigated the mechanism of tolerance induction to soluble protein antigens by targeting an antigen to small, resting B cells. For this purpose I have used a rabbit antibody directed at the IgD molecule found on the surface of most small, resting B cells but missing or lowered on activated B cells. Intravenous injection of normal mice with 100 μg of an ultracentrifuged Fab fragment of rabbit anti-mouse IgD (Fab anti-δ) makes these mice profoundly tolerant to challenge with nonimmune rabbit Fab (Fab NRG) fragments. This tolerance is antigen specific since treated mice make normal responses to an irrelevant antigen, chicken immunoglobulin (Ig). Fab fragments of rabbit Ig (rabbit Fab) not targeted to B cells do not induce tolerance as well as Fab anti-δ. Evidence suggests that the B cells must remain in a resting state for tolerance to be induced, since injection of F(ab)'2 anti-δ does not induce tolerance. Investigation of the mechanisms of the tolerance, by adoptive transfer, have shown that rabbit Fab specific B cell function has been impaired. The major effect however is in helper T cell function, as shown by adoptive transfer and lack of help for a hapten response. In vitro proliferation experiments show that the T cell response has not been shifted toward activation of different T cell subsets which do not help Ig production, nor is there any change in the Ig isotypes produced. Suppression does not appear to be the major cause of the helper T cell defect as shown by cell mixing experiments. This work shows that an antigen targeted to small B cells can induce tolerance to a soluble protein antigen, and suggests a role for small B cells in tolerance to self-proteins not presented in the thymus.
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Harper, Helen Margaret. "The induction of immune responses in the murine small intestine." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389589.
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McPherson, Rhoanne Catherine. "Effect of tolerogenic peptide administration on pathogenic antigen-experienced T cells." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/8199.
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The administration of soluble antigenic peptides is known to be effective at inducing tolerance in naïve antigen-reactive CD4+ T cells. This observation forms the basis of antigen-based therapy, which offers the potential to specifically target the auto-reactive CD4+ T cells involved in driving autoimmune disease pathogenesis, whilst leaving the rest of the immune system intact. The prophylactic administration of soluble autoantigen-derived peptides has proven to be effective at inhibiting disease induction in various experimental models of autoimmune disease. However, the clinical requirement is to switch off the activated antigen-experienced CD4+ T cells that are present during an ongoing immune response. The effect of soluble peptide administration of antigenexperienced CD4+ T cells is poorly understood, and several clinical trials using peptides in multiple sclerosis patients had to be halted due to the exacerbation of disease. This thesis characterises the effect of soluble peptide administration on pathogenic antigen-experienced CD4+ T cells, using experimental autoimmune encephalomyelitis (EAE) as a model of autoimmune disease of the central nervous system. Using traceable myelin-reactive T cells from Tg4 mice, it was determined that soluble peptide administration induces substantial expansion of antigen-experienced CD4+ T cells. Despite the increase in number, these cells were no longer able to induce EAE. Production of effector cytokine was significantly decreased in peptide treated antigen-reactive CD4+ T cells, and this correlated with high level expression of the co-inhibitory molecule PD-1. The induction of tolerance in both naïve and antigen-experienced CD4+ T cells was found to be dependent upon PD-1 expression, whereby peptide treatment of naïve and antigen-experienced CD4+ T cells that were deficient in PD-1, did not inhibit disease induction. This thesis identifies a novel mechanism of peptide-induced tolerance in CD4+ T cells, and demonstrates that soluble peptide administration can induce tolerance in antigen-experienced T cells.
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Verbeke, Catia Stéphanie. "Antigen-specific immune modulation using an injectable biomaterial." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11456.
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The field of immunology has advanced tremendously over the last 40 years, with seminal findings that have guided the development of powerful new therapies. However, the ability to induce safe and long-lasting antigen-specific tolerance has remained elusive. A therapy that could prevent the immune system from aberrantly destroying self-tissues, without impairing its capacity to eliminate dangerous pathogens, would be transformative for the treatment of autoimmune diseases. In addition, such a therapy could also greatly advance the field of organ transplantation by inducing antigen-specific tolerance to prevent graft rejection.<br>Engineering and Applied Sciences
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Winnewisser, Julia [Verfasser], and Ludger [Akademischer Betreuer] Klein. "Central tolerance induction to the self-antigen PLP / Julia Winnewisser ; Betreuer: Ludger Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/112092362X/34.
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Dieti, Anastasia. "Influence of guar galactomannan on antigen absorption and induction of immunological oral tolerance." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433117.
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Walker, Kenneth G. "Intrathymic injection of donor antigen as a technique for prolonging cardiac allograft survival in the rat." Thesis, University of Aberdeen, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265536.
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In this study we have reproduced the prolongation of graft survival by ITI in a rat heart transplant model in which an ITI of an optimal number of donor bone-marrow cells (BMC) was given together with 1ml ALS IP 14 days before transplant. The efficacy of this protocol was critically dependent on the donor-recipient haplotype and influenced by antigenic strength and MHC disparity but not by non-MHC background genes. In strain disparities where ITI was unsuccessful, this was caused by alloreactive recent thymic emigrant cells. In a high responder strain combination the effect was highly dependent on the dose of BMC in the intrathymic injection. Moreover it was readily reproduced with injection of antigen by the intravenous route, even at a lower dose than that required via the intrathymic route. This was in contrast to the other strain combinations tested in which the beneficial effect of donor antigen injection was specific to the intrathymic route, and it suggested that the effect in this group might be at least partly dependent on peripheral mechanisms. The polyclonal ALS can easily be demonstrated to be non-specific in its depletion of peripheral lymphocytes at the dose used in these studies, and we have shown that it also penetrates the thymus. Therefore treatment with ALS may have more effects that mere disablement of peripheral alloreactive T cells, thus complicating the interpretation of the experiments. We have therefore refined our model by recruiting in place of ALS a more specific agent, the partially depleting anti-CD4 monoclonal antibody MRC-OX38, which is equally effective as an adjunct to ITI. We have shown using flow cytometry and immunohistochemistry, that this and certain other monoclonal antibodies, at a therapeutic dose, do not cross the "blood-thymus barrier", and therefore do not complicate the model as ALS potentially does. We would recommend this approach in further studies.
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Bushell, Andrew Richard. "Transplantation tolerance in the mouse induced by antigen and anti-CD4 antibody : mechanisms and strategies." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335772.
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Rovere, Querini Patrizia. "Clearance of dying cells by antigen presenting and scavenger phagocytes : implications for autoimmunity and tolerance." Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323272.
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Dresch, Christiane. "Antigen-specific tolerance induction by transcriptional targeting of dendritic cells with a novel lentiviral vector." Diss., kostenfrei, 2008. http://edoc.ub.uni-muenchen.de/9310/.
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Nishimura, Eiji. "Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3[+]CD25[+]CD4[+] regulatory T cells." Kyoto University, 2004. http://hdl.handle.net/2433/145292.
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Carl, Joseph William Jr. "ON THE ROLE OF CD24 IN THE PATHOGENICITY OF MYELIN ANTIGEN SPECIFIC T CELLS." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1210699484.
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Seamons, Audrey. "Implications of myelin basic protein processing and presentation on T cell activation and tolerance /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/10851.
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Teng, Yen-Tung Andy. "Analysis of the mechanism(s) of immunological tolerance to a physiological soluble antigen in transgenic mice." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/Nq27740.pdf.
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Marelli-Berg, Frederica Maria. "Antigen presentation by parenchymal cells as a mechanism for the induction and maintenance of peripheral tolerance." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266255.
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Berbudi, Afiat [Verfasser]. "Filarial infection and filarial antigen administration promotes glucose tolerance in diet-induced obese mice / Afiat Berbudi." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1080561366/34.
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Henry, Emmanuelle. "Dendritic cells genetically engineered to express IL-10 induce long-lasting antigen-specific tolerance in experimental asthma." Doctoral thesis, Universite Libre de Bruxelles, 2007. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210584.
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Dendritic cells (DCs) are professional APCs that have a unique capacity to initiate primary immune responses, including tolerogenic responses. We have genetically engineered bone marrow-derived DCs to express the immunosuppressive cytokine IL-10 and tested the ability of these cells to control experimental asthma. A single intratracheal injection of OVA-pulsed IL-10-transduced DCs (OVA-IL-10-DCs) to naive mice prior to OVA sensitization and challenge prevented all the cardinal features of airway allergy, namely eosinophilic airway inflammation, airway hyperreactivity, and production of mucus, Ag-specific Igs and IL-4. OVA-IL-10-DCs also reversed established experimental asthma and had long-lasting and Ag-specific effects. We furthermore showed, by using IL-10-deficient mice, that host IL-10 is required for mediating the immunomodulatory effects of OVA-IL-10-DCs and demonstrated a significant increase in the percentage of OVA-specific CD4+CD25+Foxp3+IL-10+ regulatory T cells in the mediastinal lymph nodes (MLNs) of OVA-IL-10-DC-injected mice. Finally, adoptive transfer of CD4+ MLN T cells from mice injected with OVA-IL-10-DCs protected OVA-sensitized recipients from airway eosinophilia upon OVA provocation. Our study describes a promising strategy to induce long-lasting Ag-specific tolerance in airway allergy./L’asthme atteint des proportions épidémiques dans les pays développés et a un impact négatif sur la qualité de vie. De plus les coûts des soins de santé relatifs à cette maladie ne cessent d’augmenter. La nette augmentation de l’incidence durant ces dernières décennies reste une énigme, les facteurs environnementaux ayant probablement contribués pour une large part dans ce processus.<p>Bien que le traitement actuel de l’asthme avec des corticostéroïdes inhalés et des agonistes β2 à longue durée d’action est satisfaisant et sans danger, des inquiétudes restent sur les effets à long terme des corticostéroïdes, en particulier lorsqu’on voit que les traitements commencent parfois très tôt dans l’enfance. De plus, la thérapie actuelle ne semble pas inhiber le TGF-β ni les dépôts de collagène, importants dans le remodelage des voies aériennes qui, au final, contribue à augmenter l’HRB des voies respiratoires.<p>La prévalence et la sévérité de l’asthme atopique augmentent de façon alarmante partout dans le monde depuis ces vingt dernières années {Eder, 2006 2}. Les traits pathophysiologiques de l’asthme allergique, à savoir l’éosinophilie pulmonaire chronique, l’hyperréactivité bronchique des voies aériennes (HRB) à une variété de stimuli non spécifiques, la production excessive de mucus dans les voies aériennes et les niveaux élevés d’IgE dans le sérum, sont tous étroitement liés à une réponse immune de type Th2 aberrante envers des antigènes habituellement inhalés (Ag) {Busse, 2001 466; Larche, 2003 467; Ray, 1999 465; Wills-Karp, 1999 464}. Les lymphocytes Th2 spécifiques de l’antigène exercent des fonctions effectrices cruciales en produisant un répertoire propre de cytokines, les plus importantes d’entre-elles étant l’IL-4, l’IL-5 et l’IL-13 {Busse, 2001 466; Larche, 2003 467; Ray, 1999 465; Wills-Karp, 1999<br>Doctorat en Sciences<br>info:eu-repo/semantics/nonPublished
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Rizzuto, Gabrielle Ann. "Self-antigen specific CD8+ T cell precursor : frequency determines the quality of the anti-tumor immune response /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1621818951&sid=3&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Kaye, P. M. J. "Particle mediated co-delivery of IL-10 and antigen inhibits T cell activation but fails to induce tolerance." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1302067/.
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Immune disorders such as allergy and autoimmunity are becoming increasingly common in developed countries. Self-reactive T cells exist in both healthy and autoimmune individuals. It is generally understood that hyperimmune disorders are caused by insufficient regulation, namely loss of activity of regulatory T cells. Whilst regulatory T cells exist naturally it is also possible to induce them both in vitro and in vivo. Immunotherapeutic techniques aim to provide noninflammatory exposure of antigen to the immune system with the aim of inducing antigen-specific regulatory T cells. Interleukin-10 (IL-10) is a cytokine with well known immunosuppressive qualities. It inhibits both the migration and the antigen-presenting ability of dendritic cells. It also has direct effects on T cells. Indeed, IL-10-secreting TR1 regulatory T cells were identified almost 15 years ago; their in vitro generation being dependent on exposure to IL-10. Particle-mediated DNA delivery (PMDD) is a promising method of immunisation and is especially suited to vaccines intended to have greater control over the response they induce. One of the main reasons for this is the possibility of including genes encoding immunomodulatory molecules alongside the antigen gene. This study utilises a mouse model involving the adoptive transfer of TCR-transgenic CD4+ T cells and establishes the response of these cells to PMDD immunisation. The model was then used to examine the effect of coadministration of the IL-10 gene. Its inclusion in the vaccine suppressed the response to antigen. This effect was maximal when the IL-10 gene was expressed in the same cell as the antigen gene. Using sequential immunisations the model was extended in order to study long-term effects, namely tolerance and the induction of regulatory T cells. Finally a mouse model of allergic asthma was used to examine any tolerogenic/therapeutic effects of the antigen-IL-10 vaccine. No significant longterm tolerance to antigen was identified. These results demonstrate that whilst the presence of IL-10 clearly inhibits the T cell response to antigen it does not necessarily confer tolerogenic properties on these cells. This brings into question whether IL-10 in the periphery, supplied, for example, by TR1 cells, generates fresh regulatory T cells or merely inhibits the response to a particular antigenic challenge.
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Ha, Hong Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "Role of T cells and cytokines in the induction of tolerance to renal tubular antigen in active Heymann nephritis." Awarded by:University of New South Wales. Clinical School - St Vincent's Hospital, 2007. http://handle.unsw.edu.au/1959.4/40871.
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Idiopathic Membranous nephropathy (MN) is a common cause of nephrotic syndrome in humans, and many patients progress to end-stage kidney disease. The best available animal model of MN is active Heymann nephritis (HN) in which rats are immunized with renal tubular antigen (RTA) in complete Freund's adjuvant (CFA). Rats develop heavy proteinuria, a key measure of glomerular damage, and the disease is histologically identical to human MN. It has been thought that HN is mediated by antibody-based mechanisms. More recent evidence demonstrates a critical role for cytotoxic T cells. This thesis aims to further examine the role of T cell responses in active HN. First, the effect of the anti-CD3 monocIonal antibody (mAb) G4.18 was investigated. Anti-CD3 given 4 weeks after immunization prevented the development of proteinuria, delayed anti-RTA antibody responses, and reduced glomerular infiltration of CD8+ T cells and macrophages, but did not affect glomerular deposition of IgG or complement. Increased mRNA expression of the Th2 cytokines IL-4 and IL-5 was detected in draining lymph nodes. These findings suggest that immune deviation to a Th2 response reduces glomerular injury in HN. Second, the role of CD4+ T cells in immune tolerance was examined. Rats were given RTA in incomplete Freund's adjnvant (lFA) to induce tolerance to RTA, and three weeks later were immunized with RTA in CFA. Anti-CD4 mAb therapy at the time of RTA1IFA treatment had no effect on subsequent proteinuria or anti-RTA autibodies. Third, the role of IL-4 in this model of immune tolerance was examined. Anti-IL-4 mAb therapy blocked the induction of tolerance, and led to the development of proteinuria. Finally, the effect of treatment with IL-4 and IL-5 was examined. Treatment with these cytokines separately or together after immunization blocked the development of proteinuria, without a consistent effect on anti-RTA antibodies. These results demonstrate a central role for T cell regulation in HN, and show that immune deviation to a Th2 response is protective against glomerular injury. The findings may have implications in the future for focused therapeutic intervention in human idiopathic MN.
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Boardman, Dominic Anthony. "Generation of MHC class I allospecific regulatory T cells using chimeric antigen receptors, tools for eliciting targeted transplant tolerance." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/generation-of-mhc-class-i-allospecific-regulatory-t-cells-using-chimeric-antigen-receptors-tools-for-eliciting-targeted-transplant-tolerance(64bd3dfe-1285-4b28-a4f2-39b31fd70bc3).html.
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Regulatory T cells (Treg) therapy using autologous Tregs expanded ex vivo is currently being assessed clinically as a means of limiting graft rejection. However, pre-clinical data has demonstrated that graft-specific Tregs protect from graft rejection more effectively than polyclonal Tregs. Chimeric antigen receptor (CAR) technology is currently being investigated clinically as a means of conferring tumour antigen-specificity onto T cells in cancer research. CARs are synthetic fusion proteins which translate the engagement of extracellular target antigens into the activation of intracellular T cell signalling cascades. The hypothesis tested in this thesis was that the efficacy of polyclonal Treg therapy to inhibit transplant rejection could be enhanced by using CARs to confer specificity for donor MHC class I, alloantigens which are ubiquitously expressed in allografts. A human CAR was constructed to incorporate a patient-derived HLA-A2-targeting moiety and a CD28-CD3ζ signalling domain. Delivery of this CAR into human Tregs which were isolated using GMP-compatible protocols did not influence the phenotype or suppressive capacity of these cells. Compared to polyclonal Tregs, A2 CAR Tregs exhibited a greater suppressive function in the presence of HLA-A2+ antigen presenting cells, without eliciting cytotoxic activity. Furthermore, these cells preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers, suggesting a favoured migration in to HLA-A2+ target tissues. In a human skin xenograft transplant model, A2 CAR Tregs alleviated alloimmune-mediated damage of HLA-A2+ skin more effectively than polyclonal Tregs. A second CAR was designed to redirect mouse Tregs towards BALB/c MHC class I (Kd) with the rationale of comparing the efficacy of CAR Tregs and Tregs with different allospecificities at reducing graft rejection. Murine CAR Tregs maintained their phenotype and suppressive ability and appeared to proliferate in the presence of Kd in vivo although conclusive evidence for the functionality of this CAR remained to be acquired. The results obtained demonstrated that CARs can be used to generate MHC class I-allospecific Tregs which are functionally superior to polyclonal Tregs at protecting from alloimmune-mediated transplant rejection, suggesting that CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation.
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Kodituwakku, Aruna Poojitha. "Antigen specific B cells in the immune response to Haemophilus influenzae type b PRP conjugate vaccine /." Title page, table of contents and summary only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09phk769.pdf.
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Lute, Kenneth D. "Costimulation and tolerance in T cell immunotherapy." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1141850521.
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Loschko, Jakob [Verfasser], Anne [Akademischer Betreuer] Krug, Dirk [Akademischer Betreuer] Haller, and Diana [Akademischer Betreuer] Dudziak. "Antigen targeting to plasmacytoid dendritic cells - induction of tolerance or immunity / Jakob Loschko. Gutachter: Dirk Haller ; Diana Dudziak. Betreuer: Anne Krug." München : Universitätsbibliothek der TU München, 2011. http://d-nb.info/101958839X/34.
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Wang, Lei [Verfasser], and Ludger [Akademischer Betreuer] Klein. "Mechanisms of central and peripheral T cell tolerance to an antigen of the central nervous system / Lei Wang ; Betreuer: Ludger Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1128074060/34.
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Saitovitch, David. "Transplantation tolerance : an experimental model exploring mechanisms of its induction and maintenance after pretreatment with donor antigen and anti-CD4 antibodies." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308688.
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Baird, Allison Michelle. "Analysis of Low Zone Tolerance in Normal and B Cell-Deficient Mice." eScholarship@UMMS, 1996. https://escholarship.umassmed.edu/gsbs_diss/142.
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This thesis investigates the role of B cells as antigen-specific antigen-presenting cells (APC) in self tolerance to low concentrations of soluble self proteins and in acquired tolerance to low doses of soluble foreign protein antigens. Experiments were performed in normal and B cell-deficient animals, and tolerance induction was measured by T cell proliferation assays. T cell proliferation was reduced in B cell-deficient mice, indicating that B cells may be involved in efficient activation of naive T cells in response to protein antigen both in vivo and in vitro. To study acquired tolerance induced by low doses of soluble foreign protein antigen, normal and B cell-deficient adult mice were injected intravenously with repeated low doses (10 μg) of deaggregated ovalbumin (OVA), and then challenged with OVA in complete Freund's adjuvant. In animals treated with deaggregated OVA, the in vitro proliferative responses of LN T cells to OVA were significantly reduced, and production of the Th1 cytokine, IFN-γ, in response to OVA was lost. This occurred in both normal and B cell-deficient treated animals, indicating that B cell antigen presentation was not required for this phenomenon. B cells were also unnecessary for self tolerance of T cells to the transgenic self antigen, hen egg lysozyme (HEL), in a transgenic mouse strain with very low serum lysozyme concentration. Partial low zone tolerance induced by deaggregated, low-dose OVA was selective for the Th1 response, as measured by in vitro proliferation and IL-2 and IFN-γ production, because antibody responses of normal mice to this T cell-dependent antigen were largely unaffected. Both treated and untreated animals produced equivalent titers of anti-OVA antibodies, predominantly of the IgG1 and IgG2b isotypes, following challenge with OVA in complete Freund's adjuvant. Tolerance to low levels of the transgenic HEL self protein in mice expressing different MHC molecules was also addressed. Transgenic mice that were H-2b/b in the class II region were not tolerant to the transgenic self protein, whereas transgenic mice of the H-2b/k were tolerant.
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Blish, Catherine Anne. "Modulation of T cell function and T cell receptor repertoire during the induction of peripheral tolerance /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/8323.
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Shakhawat, Ayesha. "Function and regulation of human leukocyte antigen G in trophoblast derived cells : A model for the study of human feto-maternal tolerance." Thesis, University of Essex, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520116.
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Casacuberta, Serra Sílvia. "Antigen-specific mdscs induce immunological tolerance in an experimental model of multiple sclerosis. generation of human mdscs from hematopoietic progenitors as a therapeutic tooll." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/384609.
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En estudis previs realitzats en el nostre laboratori vam demostrar que la infusió de cèl·lules de medul·la òssia (MO) transduïdes amb un autoantigen (MOG40-55), dirigit a la via de presentació d'antígens per MHC de classe II, induïen tolerància immunològica en un model experimental d'esclerosi múltiple, la encefalomielitis autoimmune experimental (EAE), tant en un abordatge preventiu com terapèutic (Eixarch et al. 2009). Per altra banda, l'absència d'empelt de les cèl·lules que expressaven la MOG va permetre eliminar la mieloablació i ens va conduir a la hipòtesis de que l'efecte terapèutic observat no estava mediat per cèl·lules amb capacitat d'empeltar sinó més aviat per unes cèl·lules més madures que presentaven l'autoantigen de forma tolerogènica. Estudis posteriors van revelar que la majoria de les cèl·lules que es generaven en els cultius de transducció amb retrovirus de cèl·lules de MO eren d'origen mieloide i que, de fet, eren cèl·lules mieloide supressores (MDSCs, sigles en anglès) (Gomez et al.2014). Per tant, la primera part d'aquesta tesi es va iniciar amb el propòsit de caracteritzar millor aquestes MDSCs i de determinar si eren elles les responsables de la inducció de tolerància immunològica observada en la EAE a més d'estudiar els possibles mecanismes d'acció implicats. Amb aquesta finalitat es van transduïr cèl·lules de MO amb un vector retroviral que codificava per l'autoantigen (MOG40-55) o amb un vector control. Es van aïllar les MDSCs i es van administrar als ratolins set dies abans (braç preventiu) o 13-14 dies després (braç terapèutic) de la inducció de la EAE. Els resultats mostren que una única administració de MDSCs antigen-específiques va induir tolerància immunològica in vivo i que va prevenir i millorar els signes clínics de la EAE de manera antigen-específica. A més a més, els animals toleritzats presentaven una neuropatologia reduïda, proporcions de limfòcits activats reduïdes i proporcions de limfòcits B amb un fenotip regulador augmentades. D'altra banda, aquestes MDSCs generades ex vivo expressaven la molècula inhibitòria programmed death ligand 1 (PD-L1) i produïen espècies reactives d'oxigen, mecanismes associats amb la inhibició dels limfòcits T autoreactius i amb la inducció de tolerància immunològica.
Després d'obtenir resultats prometedors amb les MDSCs antigen-específiques de ratolí, vam decidir donar un pas més i la segona part d'aquesta tesi està enfocada a desenvolupar mètodes eficients per generar MDSCs humanes a partir de progenitors hemopoètics per la seva potencial aplicació clínica. Es van cultivar progenitors CD34+ obtinguts de productes d'afèresis de donants sans durant 9, 14 i 20 dies en presència de diferents combinacions de citoquines bàsicament formades per SCF, TPO, FLT3-L, IL-3, GM-CSF i IL-6. Els resultats mostren que les MDSCs es poden generar de manera eficient a partir de progenitors hemopoètics i que les seves proporcions augmentaven amb els dies de cultiu. A més, aquestes cèl·lules expressaven la molècula immunosupressora PD-L1, eren molt poc al·loreactives, suprimien la proliferació de cèl·lules T induïda per un estímul policlonal i reduïen els nivells de les citoquines proinflamatòries mentre que augmentaven el nivell de la citoquina immunomoduladora IL-10.
Per aquests motius creiem que les MDSCs generades in vitro són una eina potencial pel tractament de malalties autoimmunes i per evitar la malaltia de l'empelt contra l'hoste després del trasplantament.<br>In previous studies conducted at our laboratory we demonstrated that infusion of bone marrow (BM) cells transduced with a self-antigen (MOG40-55), targeted to the MHC class II antigen presentation pathway, induced immunological tolerance in an experimental model of multiple sclerosis, the experimental autoimmune encephalomyelitis (EAE), both preventively and therapeutically (Eixarch et al. 2009). Moreover, the absence of engraftment of the MOG-expressing cells allowed to eliminate myeloablation and hypothesize that the therapeutic effect observed was not mediated by cells with engrafting potential but rather by a more mature cell type that expressed the self-antigen in a tolerogenic manner. Subsequent studies revealed that the majority of cells generated in standard retroviral transduction cultures of BM cells were of myeloid origin and that, indeed, were myeloid-derived suppressor cells (MDSCs) (Gomez et al. 2014). Therefore, the first part of this thesis was initiated with the purpose of better characterizing these MDSCs generated in BM retroviral transduction cultures and determining whether these cells were responsible for the induction of the immunological tolerance observed in the EAE model as well as studying the potential mechanisms of action involved. To this end, BM cells were transduced either with a retroviral vector encoding for the self-antigen or with a control vector. Both BM cells and isolated MDSCs were infused to the animals seven days before (preventive arm) or 13-14 days after (therapeutic arm) EAE induction. Results showed that a single infusion of antigen-specific MDSCs induced immunological tolerance in vivo and was able to prevent and ameliorate established EAE in an antigen-specific manner. In addition, tolerized animals presented a decreased neuropathology, reduced proportions of activated T cells and increased proportions of B cells with a regulatory phenotype. Moreover, the ex vivo generated MDSCs expressed the inhibitory molecule programmed death ligand 1 (PD-L1) and produced reactive oxygen species, mechanisms associated with the inhibition of autoreactive T cells and with the induction of immunological tolerance.
After obtaining these promising results with the murine antigen-specific MDSCs, we decided to move one step further and, therefore, the second part of this thesis was aimed at developing efficient methods to generate human MDSCs from hematopoietic progenitor cells for its potential clinical application. To this end, CD34+ progenitor cells from apheresis products of healthy donors were cultured for 9, 14 and 20 days in the presence of different cytokine combinations mainly consisting of SCF, TPO, FLT3-L, IL-3, GM-CSF and IL-6. Results showed that MDSCs can be efficiently generated from hematopoietic progenitor cells and that their proportions significantly increased along with the days of the culture. Moreover, these cells expressed the immunosuppressive molecule PD-L1, had very little alloreactivity, suppressed polyclonal-induced T-cell proliferation and decreased the levels of proinflammatory cytokines while increasing the levels of the immunomodulatory cytokine IL-10.
For these reasons, we believe that in vitro generated MDSCs constitute a potential tool for the treatment of autoimmune diseases and to prevent graft-versus-host disease (GVHD) in transplantation settings.
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Zheng, Xincheng. "Two-signal requirement for the development of T lymphocytes." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1109258062.
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Thesis (Ph. D.)--Ohio State University, 2005.<br>Title from first page of PDF file. Document formatted into pages; contains xvi, 156 p.; also includes graphics (some col.) Includes bibliographical references (p. 127-156). Available online via OhioLINK's ETD Center
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Haßler, Tobias Johannes [Verfasser], and Ludger [Akademischer Betreuer] Klein. "How central tolerance shapes the polyclonal CD4 T cell repertoire specific for the central nervous system antigen myelin proteolipid protein 1 / Tobias Johannes Haßler ; Betreuer: Ludger Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1233200860/34.
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Cabbage, Sarah E. "Reversible regulatory T cell-mediated suppression of myelin basic protein-specific T cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5034.
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Hässler, Signe. "Autoimmune Regulator Deficient Mice, an Animal Model of Autoimmune Polyendocrine Syndrome Type I." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7218.
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<p>Autoimmune diseases develop when the immune system fails to distinguish self from non-self or when the immune system is hypersensitive to endogenous or exogenous danger signals, or when a tissue erroneously sends a danger signal to the immune system. The education of the immune system to distinguish self from non-self is mainly carried out in the thymus and gives rise to central tolerance, whereas the ability to sense a danger or a healthy tissue constitutes peripheral tolerance. In these studies we have investigated the peripheral tolerance mechanisms controlled by the autoimmune regulator <i>(Aire)</i> gene in Aire deficient mice, an animal model of the monogenic disease autoimmune polyendocrine syndrome type I (APS I).</p><p>Aire-/- mice displayed increased numbers of myeloid-derived antigen-presenting cells (APCs) in the spleen, lymph nodes and peritoneum as well as more blood monocytes and metallophilic macrophages in the spleen. Monocytes were also increased in the blood of APS I patients. Monocyte precursors displayed an accelerated development in the bone marrow of Aire-/- mice, and Aire-/- APCs had an altered phenotype that caused an increased immune response in several different contexts. Aire-/- splenic and lymph node dendritic cells had an increased ability to activate naive T cells, partly as a result of an upregulated expression of the costimulatory molecule VCAM-1. In Aire-/- mice increased activity of the metallophilic macrophages in the splenic marginal zone seems to be responsible both for the activated phenotype of marginal zone B cells and for the frequent development of marginal zone lymphoma with aging. In a TCR transgenic model Aire deficiency caused an increased superantigen-mediated TCR revision in the spleen, perhaps as a result of the altered phenotype of APCs in the spleen. Finally, Aire was shown to influence autoimmune disease development by a macrophage-dependent mechanism in diabetes induced with multiple low dose streptozotocin injections.</p><p>These results indicate that Aire has an important function in peripheral tolerance by controlling the phenotype of myeloid-derived APCs and thereby regulating the activation of T and B lymphocytes.</p><br><p>Autoimmune diseases develop when the immune system fails to distinguish self from non-self or when the immune system is hypersensitive to endogenous or exogenous danger signals, or when a tissue erroneously sends a danger signal to the immune system. The education of the immune system to distinguish self from non-self is mainly carried out in the thymus and gives rise to central tolerance, whereas the ability to sense a danger or a healthy tissue constitutes peripheral tolerance. In these studies we have investigated the peripheral tolerance mechanisms controlled by the autoimmune regulator <i>(Aire)</i> gene in Aire deficient mice, an animal model of the monogenic disease autoimmune polyendocrine syndrome type I (APS I).</p><p>Aire-/- mice displayed increased numbers of myeloid-derived antigen-presenting cells (APCs) in the spleen, lymph nodes and peritoneum as well as more blood monocytes and metallophilic macrophages in the spleen. Monocytes were also increased in the blood of APS I patients. Monocyte precursors displayed an accelerated development in the bone marrow of Aire-/- mice, and Aire-/- APCs had an altered phenotype that caused an increased immune response in several different contexts. Aire-/- splenic and lymph node dendritic cells had an increased ability to activate naive T cells, partly as a result of an upregulated expression of the costimulatory molecule VCAM-1. In Aire-/- mice increased activity of the metallophilic macrophages in the splenic marginal zone seems to be responsible both for the activated phenotype of marginal zone B cells and for the frequent development of marginal zone lymphoma with aging. In a TCR transgenic model Aire deficiency caused an increased superantigen-mediated TCR revision in the spleen, perhaps as a result of the altered phenotype of APCs in the spleen. Finally, Aire was shown to influence autoimmune disease development by a macrophage-dependent mechanism in diabetes induced with multiple low dose streptozotocin injections.</p><p>These results indicate that Aire has an important function in peripheral tolerance by controlling the phenotype of myeloid-derived APCs and thereby regulating the activation of T and B lymphocytes.</p>
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Marguti, Ivo. "Efeito das células dendríticas na geração de células T CD4+CD25+Foxp3+." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-18102007-154828/.
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As células dendríticas (DCs) são as principais células apresentadoras de antígeno do sistema imune. No entanto, trabalhos têm demonstrado seu envolvimento na manutenção da tolerância imunológica. As células T CD4+CD25+Foxp3+ possuem a capacidade de suprimir respostas imunes. Neste estudo avaliamos as alterações ocorridas na população de células T CD4+CD25+Foxp3+ após co-cultura de células de linfonodo com DCs. Nossos resultados demonstram que após a co-cultura há um aumento da população de células CD4+CD25+Foxp3+ de maneira independente do estado de ativação das DCs ou da presença de antígenos exógenos. No entanto, o aumento observado é maior quando DCs imaturas são incubadas com antígenos exógenos. Notamos ainda que há presença de TGF-ß em todas as condições experimentais em que observamos aumento da população de células CD4+CD25+Foxp3+. Nossos dados sugerem ainda que este aumento se deve à proliferação das células T CD4+CD25+Foxp3+.<br>Dendritic cells (DCs) are the most important antigen-presenting cells of the immune system. However, DCs have also been implicated in maintaining immunologic tolerance. CD4+CD25+Foxp3+ T lymphocytes are known as cells with regulatory properties. In this study we evaluated the changes in the CD4+CD25+Foxp3+ T cell population after co-culture of lymph-node cells with DCs. Our results show an increase in the CD4+CD25+Foxp3+ T cell population after co-culture and occurs regardless of the activation state of DCs and the presence of exogenous antigens; however it is greater when immature DCs are previously pulsed with exogenous antigen. We also noticed that TGF-? is present in all cultures conditions in which the CD4+CD25+Foxp3+ T cell population increases. Our data also suggests that the increase of the CD4+CD25+Foxp3+ T cell population may be due to the proliferation of these cells.
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Gallegos, Alena M. "Central tolerance to tissue-specific antigens /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/8353.
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Steinhoff, Ulrich Johannes. "Von Toleranz zur Autoimmunität." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2002. http://dx.doi.org/10.18452/13835.
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Immunologische Toleranz ist eine elementare Eigenschaft des Immunsystems, die primär durch die klonale Deletion autoreaktiver T-Zellen im Thymus gewährleistet wird. Neben diesem als zentrale Toleranz bezeichneten Mechanismus, verfügt ein Organismus gleichzeitig über periphere Toleranzmechanismen wie Ignoranz, Anergie und regulatorische T-Zellen. Trotz dieser Kontrollmechanismen können in bestimmten Situationen autoreaktive CD4+ und CD8+ T-Zellen aktiviert werden und meistens zu örtlich und zeitlich begrenzten Autoimmunreaktionen führen. Ursache hierfür kann die hormonelle Regulation oder das gewebespezifische Vorkommen eines Selbsttantigens sein. Am Beispiel von HSP60-kreuzreaktiven CD8+ T-Zellen konnte gezeigt werden, dass der Transfer dieser T-Zellen in Tiere zu einer Entzündung des Dünndarms aber nicht des Dickdarms führt, obwohl das Selbstantigen im letzteren wesentlich stärker exprimiert wird. Die Gewebespezifität der Autoimmunpathologie konnte durch die in den Organen unterschiedliche, proteasomale Antigenprozessierung, erklärt werden. Proteinbiochemische und immunologische Analysen ergaben, dass sich die 20S Proteasomen verschiedener Organe strukturell und funktionell deutlich unterscheiden und somit jedes Gewebe ein individuelles Repertoire von MHC-Klasse I restringierten Peptiden präsentiert. Damit wurde ein weiterer Mechanismus entdeckt, durch den Reaktivität von protektiven und pathologischen CD8+ T-Zellen kontrolliert wird.<br>Immunological tolerance which is primarily mediated by the clonal deletion of autoreactive T cells in the thymus is a key feature of the immune system. Besides this central tolerance, several mechanisms act also in the periphery including ignorance, anergy and regulatory T cells. Despite all these checkpoints, autoreactive CD4+ and CD8+ T cells may still be activated causing local and time restricted autoimmune-reactions. This may refer primarily to self-antigens which are hormonally regulated or tissue-specifically expressed. Adoptive transfer of crossreactive, hsp60-specific CD8+ T cells into mice induced an local inflammation of the small intestine but not the colon despite elevated expression of hsp60 in the latter organ. The pathology could be explained by the finding that the proteasomal antigen processing varies between different organs. Biochemical and immunological analyses revealed that 20S proteasomes of different organs vary in their structural and functional properties indicating that every tissue displays an individual and distinct repertoire of MHC class I peptides. This represents a new mechanism by which the activity of protective and pathological CD8+ T cell responses may be controlled.
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Honey, Karen J. "Mechanisms of transplantation tolerance." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301519.
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Sadissou, Ibrahim Abiodoun. "Influence de l’antigène leucocytaire humain (HLA-G) sur la sensibilité au paludisme chez la femme enceinte et le nouveau-né." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P628.
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L’objectif général de cette thèse était d’étudier le rôle de la protéine soluble HLA-G (sHLA- G) dans la variabilité des réponses à l’infection par P. falciparum chez la femme enceinte et son nouveau-né pendant ses deux premières années de vie. Précisément, nous avons étudié, chez les mères pendant la grossesse et leurs nourrissons de la naissance à 2 ans, les relations entre les niveaux de sHLA-G et l’infection palustre au niveau périphérique et placentaire. Nous avons également étudié les polymorphismes génétiques situés dans la région 3’UTR du gène HLA- G chez les mères et leurs nourrissons par la détermination des fréquences alléliques, génotypiques et haplotypiques afin évaluer l’impact de ces polymorphismes sur la cinétique d’expression de sHLA-G dans un contexte d’infection palustre. Nos résultats ont montré une association entre le niveau élevé de sHLA-G chez les nourrissons et l’augmentation du risque d’infection palustre au cours du trimestre suivant. Ces niveaux élevés de sHLA-G dans le sang de cordon ont été également associés au faible poids de naissance du nouveau-né. De même, nous avons trouvé une forte corrélation entre les niveaux de sHLA-G maternels dans le sang périphérique à l’accouchement et ceux de l’enfant dans le sang du cordon à la naissance. Nous avons aussi montré l’existence de trois profils d’expression de sHLA-G chez les individus inclus dans l'étude. Certains individus expriment la protéine à chaque prélèvement (HLA-G ++) alors que d’autres l’expriment par intermittence (HLA-G +-) ou ne l’expriment pas (HLA-G --). Le risque de développer un accès palustre chez les mères était respectivement trois fois plus élevé (p=0,001, OR=3,47;p=0,008, OR=3,14) chez celles appartenant au groupe HLA-G (++) et HLA-G (+-) que le groupe HLA-G (--). L’analyse génétique de la région 3’UTR du gène nous a permis de mettre en évidence huit sites polymorphes dans cette région et de construire six haplotypes correspondant (UTR 1, 2, 3, 4, 5, 6). Nous avons aussi montré chez les mères une association entre l’allèle T en position +3001 (C/T) et une expression plus fréquente de sHLA-G tandis que l’allèle C en position +3003 (T/C) et l’haplotype UTR-4 ont été associés à une expression moins fréquente de la protéine. Ces associations n’ont pas été mises en évidence chez les enfants. L’ensemble de ces résultats suggère l'implication de sHLA-G dans la sensibilité à l'infection palustre. Cette sensibilité serait, en partie, corrélée à l’inhibition des réponses anticorps spécifiquement dirigées contre P. falciparum. sHLA-G pourrait donc à terme devenir un bio-marqueur de susceptibilité au paludisme chez la femme enceinte et chez le nouveau-né au cours des premières années de vie<br>The general objective of this thesis was to study the role of soluble HLA-G protein (sHLA-G) in the variability of individual response to malaria during pregnancy and during the first 2 years of infant life. Actually, we assessed the relationships between sHLA-G and malaria infection in peripheral and placental blood. We also investigated the effect of polymorphisms in the 3’UTR region of HLA-G gene in 400 mothers and their infants on the kinetic of sHLA-G expression three times during pregnancy and at 6, 9, 12, 18, 24 months of life in a context of malaria infection. Our results showed that high levels of sHLA-G increased the risk of malaria at the subsequent trimester in infants and were associated with low birth weight. We also showed a strong correlation between the plasmatic sHLA-G level of the mothers at delivery and those of newborns in cord blood. We found that the risk of developing malaria in mothers was respectively three fold higher in the HLA-G (++) (OR=3.47; p=0.001) and HLA-G(+-)(OR=3.14, p=0.008) groups compared to HLA-G (--) group. Besides, we described eight polymorphic sites in the 3’UTR corresponding to six haplotypes (UTR 1, 2, 3, 4, 5, 6) and showed in mothers, an association between the allele T at position +3001 (C/T) and a higher frequency of sHLA-G expression. However, the allele C at position +3003 (T/C) and UTR-4 were associated to a lower frequency of sHLA-G expression. In infants, no association was observed between alleles or haplotypes and expression of the soluble protein. Overall, these results suggest that sHLA-G is implicated in malaria susceptibility. This could be partly, related to the inhibition of P. falciparum-specific antibody responses. Therefore, sHLA-G might be useful as a bio- marker of malaria susceptibility during pregnancy and during the first years of infancy