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Kaiser, Tina Katarina [Verfasser]. "Treatment of acute Graft-versus-Host Disease using inorganic-organic hybrid nanoparticles / Tina Katarina Kaiser." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2019. http://d-nb.info/1222265001/34.
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Lopez, Rodriguez Yelica Virginia. "Immunosuppressive properties of Wharton's jelly derived mesenchymal stromal cells in the treatment of graft versus host disease in rat model." Diss., Kansas State University, 2013. http://hdl.handle.net/2097/16331.
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Doctor of Philosophy<br>Department of Anatomy and Physiology<br>Mark L. Weiss<br>Graft Versus Host Disease (GVHD) is the major complication following hematopoietic stem cell transplantation. GVHD is activated by immunocompetent T cells presented in the donor grafted tissue. Due to the increased use of bone marrow transplantation to treat diverse malignancies, the incidence of GVHD has shown a notable increase. Depending of the degree of immunological mismatch between donor and host, 50-70% of patients develop GVHD after allogeneic Bone Marrow Transplantation (BMT). Once GVHD develops, mortality reaches up to 50% in humans. Several studies using Mesenchymal Stromal Cells (MSCs) to prevent and treat GVHD have produced controversial results. It is thought that distinct MSCs sources used in those studies might be an important factor that produces different outcomes. For cellular therapy, the most attractive characteristics of MSCs are their reduced immunogenic potential, and their abilities to modulate immune responses. This dissertation addressed the hypothesis that Wharton’s jelly cells (WJCs) would prevent the pathology and death associated with GVHD after BMT. To accomplish this, I created a clinically relevant model of GVHD by transplanting allogeneic bone marrow across minor histocompatibility antigen (HA) barriers in the rat. To enhance alloreactive T-cell stimulation, bone marrow (BM) was co-administered with a fraction of CD8[superscript]+ cells magnetically selected from spleen to induce GVHD. Bone marrow tissue was isolated from a donor rat Fischer 344 (F344, RT1lv) and transplanted into lethally irradiated (10 Gray) Lewis rat (LEW, RT1l). Once GVHD was induced, MSCs derived from umbilical cord WJCs were either co-transplanted at day 0 with bone marrow, or given on day 2 post-BMT intravenously. The prophylactic potential of WJCs in an in vivo GVHD model was assessed as survival time, clinical symptomatology occurrence, and histopathology injuries in target tissues. Results indicate that while co-administration of WJCs with hematopoietic cells on day 0 failed to alleviate GVHD associated symptomatology and mortality. WJCs administered on day 2 post-induction ameliorated GVHD-associated symptomatology, improved engraftment and survival.
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Papert, Susanne [Verfasser], Holger [Akademischer Betreuer] Budde, Holger [Gutachter] Reichardt, and Hubertus [Gutachter] Jarry. "New approaches to improve Extracorporeal Photopheresis for the treatment of Graft-versus-Host Disease / Susanne Papert. Betreuer: Holger Budde. Gutachter: Holger Reichardt ; Hubertus Jarry." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://d-nb.info/1102536156/34.
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Theiss-Sünnemann, Jennifer [Verfasser], Holger [Akademischer Betreuer] Reichardt, Steven [Akademischer Betreuer] Johnsen, and Tobias [Akademischer Betreuer] Pukrop. "Molecular and cellular mechanisms of glucocorticoids in the treatment of acute graft-versus-host disease / Jennifer Theiss-Sünnemann. Gutachter: Holger Reichardt ; Steven Johnsen ; Tobias Pukrop. Betreuer: Holger Reichardt." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2012. http://d-nb.info/1042305749/34.
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Tomlins, Paul John. "Ocular graft-versus-host disease." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8114/.
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Haemopoietic Stem Cell Transplant (HSCT) is used as a treatment for a number of conditions particularly leukaemias. Following conditioning and HSCT, there is a ‘resetting’ of the immune system, which reconstitutes over a number of months. Graft-versus-Host Disease (GvHD) is a life-threatening complication of HSCT that includes severe, sight-threatening dry eye disease. In GvHD transplanted immune cells mount an immune response against the host. This thesis investigated how the immune cells of the conjunctiva are affected by HSCT and how the ocular surface leukocytes reconstitute. A non-invasive technique, ocular surface impression cytology (OSIC), was used to demonstrate that whilst there was no apparent depletion of innate immune cells in the conjunctiva, there was a marked reduction in the lymphocytes, which gradually reconstituted, returning to normal levels at the 6 months timepoint. Secondly OSIC was used to profile the leukocyte population in a cohort of patients post-HSCT with and without eye disease. In patients with dry eye disease following HSCT, the conjunctiva contained increased CD8+ lymphocytes, macrophages and neutrophils; a pattern that was distinct to that found in patients with dry eye disease following HSCT.
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Loschi, Michael. "CD19SFv-CAR regulatory T-cell prevent acute graft versus host disease and improve chronic graft versus host disease." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC265.
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La greffe de cellules souches hématopoïétiques est une option curative pour de nombreuses maladies hématologiques malignes et bénignes. Cependant, son effet bénéfique est contrebalancé par le développement de la maladie du greffon contre l'hôte (GVHD) aiguë et chronique. Les options thérapeutiques permettant de réduire l'incidence et la gravité de la GVH reposent principalement sur des médicaments pan-immunosuppresseurs qui exposent le destinataire à des infections opportunistes et à une rechute de la maladie d'origine. Les immunothérapies à base de cellules T régulatrices (Treg) se sont révélées efficaces, mais sont limitées par les capacités de suppression variables entre les produits et le nombre de Treg. L’ingénierie des récepteur antigénique chimérique (CAR) donne maintenant la possibilité de rediriger les cellules T et d’augmenter leur fonction. Ici, nous avons testé le Treg CAR 4-1BB ciblant le CD19 humain (hCD19) pour supprimer la GVHD. Nous avons constaté que le CD19SFv-CAR Treg est spécifiquement activé via leur CAR. Cette hyperactivation confère des capacités métaboliques et suppressives plus élevées. Après l’activation du CAR, le CD19SFv-CAR Treg affiche des capacités de migration accrues vers l’intestin, principal organe cible de la GVHD. Les CD19SFv-CAR Treg préservent la réponse du greffon contre la leucémie (GvL) et présente une activité anti-tumorale. Dans un modele de cGVHD les CD19SFv-CAR Treg éliminent les cellules B du centre germinatif (cellules B de GC) et améliore la fonction pulmonaire des receveurs. Cette étude identifie les CAR-hCD19 Treg comme un moyen d’améliorer l’efficacité de l’immunothérapie par Treg en augmentant les capacités de suppression du Treg, leur migration et leur métabolisme sans modifier la réponse GvL du greffon<br>Allo-hematopoietic stem cell transplantation is a curative option for many malignant and benign hematologic disorders. However, its beneficial effect is counterbalanced by the development of acute and chronic graft versus host disease (GVHD). The therapeutic options to reduce GVHD incidence and severity mostly rely on pan immunosuppressive drugs that expose the recipient to opportunistic infections and relapse of the original disease. Regulatory T cell (Treg) therapies have proven efficient but are limited by inter product variable suppressive capacities and number of Treg. The chimeric antigen receptor (CAR) engineering now give the opportunity to redirect Tcell and increase their function. Here, we tested CAR 4-1BB Treg targeting the human CD19 (hCD19) to suppress GVHD. In aGVHD we found that CD19SFv-CAR Treg are specifically activated through their CAR. This hyperactivation confers higher metabolic and suppressive capacities. After CAR activation, CD19SFv-CAR Treg display increased homing abilities to the gut which is the main target organ in aGVHD. CD19SFv-CAR Treg preserve the Graft versus leukemia (GvL) response and display anti-tumor activity. In cGVHD CD19SFv-CAR Treg eliminate Germinal center B-cells (GC B-cells) and improve the pulmonary function of the recipients. This study identifies the CAR-hCD19 Treg as a way to improve Treg immunotherapy efficiency by increasing Treg suppressive capacities, homing, and metabolism without altering the GvL response of the graft
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Cavet, James. "Risk factors for graft-versus-host-disease." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250123.
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Mertlitz, Sarah [Verfasser]. "Angiogenesis in Graft-versus-Host Disease / Sarah Mertlitz." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1217657312/34.
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Dignan, F. L. "Novel strategies for managing graft-versus-host disease." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1368222/.
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Graft-versus-host disease (GvHD) is a major barrier to the successful outcome of allogeneic haematopoietic stem cell transplantation. This thesis investigates four novel strategies for managing GvHD: the role of extracorporeal photopheresis (ECP), the use of economic data to allow for funding of new treatments, the impact of a new dedicated GvHD clinic and the writing of national guidelines. The main hypothesis is that fortnightly ECP would improve signs and symptoms of chronic GvHD. A single centre retrospective analysis of 82 patients showed that this ECP schedule was effective with 94% of patients who completed 6 months of treatment achieving a complete or partial response. The information derived from this study was subsequently used to design a study to test this hypothesis in a prospective cohort of patients. 70% of patients who completed 6 months of ECP had a complete or partial response. Analysis of quality of life in a subset of patients showed a significant improvement in chronic GvHD symptom score (22 v 36, p=0.012) and dermatology quality of life index (3.4 v 6.9, p=0.009). A second hypothesis is that patients with GvHD have a higher readmission rate and economic burden than patients without GvHD. A retrospective review of 187 consecutive patients was undertaken which showed that the overall readmission rate was higher in patients with GvHD (86% (101/118) v 59% (41/69), p<0.001). The mean cost of readmission was higher in GvHD patients (£28860) than in non-GvHD patients (£13405; p=0.002) and in patients with grade III/IV GvHD (£40012) compared to those patients with grade I /II GvHD (£24560; p=0.038). This information was used to obtain funding for on-site ECP for acute GvHD. In addition, an exploratory evaluation of a new dedicated GvHD clinic is reported demonstrating the impact on referral patterns, quality of life and morbidity and mortality and the process of writing three national clinical practice guidelines is described.
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Nestel, Frederick P. (Frederick Peter). "Macrophage effector mechanisms mediating acute graft-versus-host disease." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41302.
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The study presented in this thesis is an investigation of M$ phi$ effector mechanisms that mediate the pathogenesis of acute graft-versus-host disease (GVHD). Since the time that the GVH reaction was first described the mechanisms underlying the development of the disease have not been characterized. We have examined the state of M$ phi$ activation in nonirradiated B6AF1 mice injected with either 60 $ times$ 10$ sp6$ (acute GVHD) or 30 $ times$ 10$ sp6$ (nonlethal GVHD) parental B6 lymphoid cells. TNF-$ alpha$ and nitric oxide (NO) generation by M$ phi$ occurs following priming by IFN-$ gamma$ and triggering by LPS. During the early phase of acute GVHD, administration of normally sublethal amounts of LPS triggered release of significant amounts of TNF-$ alpha$ into the serum resulting in death of the animals within 36 hours. The amount of serum TNF-$ alpha$ produced following LPS injection increased during the course of GVHD and was significantly greater in acute GVH reactive mice. Normal animals treated with the same dose of LPS neither died nor produced detectable amounts of serum TNF-$ alpha$. In vitro studies demonstrated that M$ phi$ undergo priming for both TNF-$ alpha$ and NO production during the developing GVH reaction and that priming was greater during acute GVHD than nonlethal GVHD. As a result of M$ phi$ priming during acute GVHD, M$ phi$ mediated the selective release of iron from $ sp{59}$Fe,$ sp{51}$Cr dual-labelled target cells and expressed cytostatic activity when triggered by LPS. NO generation and cytostasis mediated by M$ phi$ from acute GVH-reactive animals were inhibited by NMMA. Endogenous bacterial-derived LPS was detected in the livers and spleens of acute GVH reactive animals and appeared subsequently the serum coincident with the onset of mortality. Immunohistochemical staining for TNF-$ alpha$ during acute GVHD demonstrated TNF-$ alpha$ in the splenic red pulp and liver, however, the hepatic portal infiltrates that characterize acute<br>Our results demonstrate the entry of bacterial-derived LPS during the acute GVH reaction and that as a result of M$ phi$ priming, LPS in the transplant recipient acts as a trigger for TNF-$ alpha$ and NO production by M$ phi$. The presence of enteric Gram-negative bacteria is a risk factor for development of acute GVHD due to the triggering effect of LPS on M$ phi$ that are primed following bone marrow transplantation. The development of acute GVHD therefore involves the excessive priming of M$ phi$ followed by contact with LPS leading to the activation of NO and TNF-$ alpha$-mediated mechanisms of tissue injury, weight loss, septic shock and death of the transplant recipient.
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Cordes, Steffen [Verfasser]. "Endothelial dysfunction during Graft-versus-Host Disease / Steffen Cordes." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1155420799/34.
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De, Ascensao Santos E. Sousa P. M. "A systems immunology approach to graft-versus-host disease." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1536088/.
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It is not known why only certain tissues are prone to graft-versus-host disease (GVHD) injury following allogeneic hematopoietic stem cell transplantation despite widespread antigen expression. Although it is known that T cell effector pathways can have distinct effects upon individual GVHD organs, there has been no unbiased or systems-wide approach to defining the mechanisms underlying tissue-specific pathology. This thesis reports the results from a systems immunology approach to address the hypothesis that GVHD target tissues exert dominant, idiosyncratic roles in regulating effector T cell functions. To test this concept, gene expression profiles of effector CD8+ T cells infiltrating lymphoid and GVHD target organs were compared in two clinically relevant murine GVHD models. Using Weighted Gene Network Correlation Analysis, a dichotomy between the transcriptomes of T cells in peripheral tissues and lymphoid organs was identified. These profiles diverged sharply between the different GVHD target organs, and between individual sub-compartments of single organs, independently of the TCR repertoire and antigen distribution. In the skin, expression of a broad effector program was determined by the transition of T cells from the dermis to the epidermis, in a process regulated by Langerhans cells (LC). In the absence of LC, T cells were rendered incapable of up-regulating the full panoply of effector genes, showed impaired differentiation into resident memory cells and failed to induce cutaneous GVHD. By performing localized LC depletion, it was demonstrated that LC regulated T cell effector programs in situ within the epidermis by providing signals to enhance local cytokine production, promote resistance to apoptosis and enhance local survival. Collectively, these data demonstrate that GVHD is defined by tissue-autonomous regulation of effector T cells; in the skin, this is dictated by interaction with epidermal LC in situ. This work provides a rationale for precision therapies directed at blocking GVHD in individual tissues.
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Jardine, Laura Elizabeth. "The mononuclear phagocyte system in Graft-versus-Host-Disease." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3305.
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The human mononuclear phagocyte system of monocytes, macrophages and dendritic cells participates in both innate and adaptive immune responses. However, the accurate identities, functions and inter-relationships of these crucial immune cells during inflammation are poorly defined. Two inflammatory settings were examined in this work: the skin in acute Graft-versus-Host Disease and the lung during experimental inflammation induced by LPS inhalation. The purpose of this enquiry was to characterize inflammatory mononuclear phagocytes in tissue, investigate their origins and explore their contribution to disease pathogenesis. In the skin GvHD study, shave biopsies were obtained from 73 individuals on presentation with acute rash following bone marrow transplantation (BMT). Controls were obtained from 19 BMT recipients at matched time points without rash and 26 healthy individuals undergoing plastic surgery. Tissue was digested and the leukocyte composition analysed by flow cytometry/sorting. Sorted populations were used in functional assays or in gene expression experiments performed using NanoString technology. An in vitro equivalent of CD14-expressing mononuclear phagocytes (MPs) was developed using HLA-matched mixed leukocyte reactions. Gene expression was measured and the function of these equivalents in a skin explant model of GvHD was tested. GvHD lesional skin was characterized by expansion of CD14-expressing MPs (GVH14) and a reduction in CD1c-expressing MPs. GVH14 were identified as donor monocyte-derived macrophages. Functionally, GVH14 could produce chemokines to recruit T lymphocytes to lesions. They were capable of activating and expanding T lymphocytes in vitro. GVH14 equivalents could damage basal keratinocytes of the epidermis without the presence of T cells. This characterization has identified a novel pathogeneic role for macrophages in acute GvHD. In the LPS inhalation study, 13 healthy individuals received saline (0.9% sodium chloride) and 13 received LPS (0.9% sodium chloride with 2mg LPS from E.coli 026:B6) by dosimeter nebulizer. Blood samples were obtained at 2, 4, 6 and 24 hours following inhalation. Between 7 and 8 hours post-inhalation, bronchoalveolar lavage (BAL) of a sub-segment of the right middle lobe was performed. BAL fluid supernatant chemokines and cytokines were analysed by multiplexed ELISA. The cellular component of BAL was analysed by flow cytometry/sorting. Sorted populations were used in functional assays or in gene expression experiments performed using NanoString technology. Seven distinct MPs were identified in steady state (i.e. following saline inhalation). Following LPS inhalation, neutrophils, CD14-expressing MPs and CD1c-expressing MPs were expanded. Phenotypically, CD1c expressing MPs resembled blood cDC2. Both subsets of blood cDC2 were recruited to the airspace but their distinct functions and gene expression profiles converged upon recruitment. This analysis provides the first detailed characterization of BAL fluid MPs. As such it provides a foundation for studying MPs in human lung diseases, including the Idiopathic Pneumonia Syndrome occurring after BMT. It detailed the surprising observation that blood cDC2 can be recruited to tissue in inflammation, challenging the dogma that inflammatory MPs must be monocyte-derived.
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You-ten, Fung Voon Kong Eric. "Role of endogenous glucocorticoids during murine graft-versus-host disease." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40291.
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The studies presented in this thesis investigated the mechanism responsible for glucococorticoid secretion during graft-versus-host disease (GVHD), and the role of endogenous glucocorticoids on the outcome of the disease. GVHD was induced in unirradiated F1 hybrid mice by an intravenous injection of parental lymphoid cells. Our results demonstrated that the secretion of glucocorticoids during GVHD was independent of pituitary adrenocorticotropin hormone (ACTH). However, adrenal hyperactivity was associated with increased expression of proopiomelanocortin (POMC) mRNA in the adrenal glands of GVHD mice. Expression of adrenal POMC transcripts was not due to mononuclear infiltrates. The transcripts for interleukin-12, a cytokine produced by activated macrophages, were also upregulated in GVHD adrenals. Since macrophages have been shown to reside in the adrenal glands and produce ACTH, it appeared that resident adrenal macrophages were activated during GVHD to produce local ACTH that stimulated the secretion of glucocorticoids, independent of pituitary ACTH.<br>We next investigated the role of endogenous glucocorticoids on the outcome of GVHD by adrenalectomizing the F1 recipient mice before GVHD induction in order to deplete the source of glucocorticoids. Our results showed that adrenalectomized (ADX), but not non-ADX, F1 recipients injected with parental lymphoid cells recovered rapidly from symptoms characteristic of GVHD, after a two week manifestation of the disease. Recovery from GVHD was attributed to the induction of a glucocorticoid sensitive, asialoGM1$ sp+$ and/or CD8$ sp+$, but not NK1.1$ sp+$, F1-anti-parental effector cell that rejected or eliminated the parental graft, after an initial period of engraftment. In addition, the effector was not dependent on a mature thymus and was not renewed after anti-asialoGM1 treatment, but was renewed after glucocorticoid treatment.<br>We further demonstrated that high levels of glucocorticoids during GVHD caused severe deficiency of host T cell populations in the lymph nodes and contributed to the suppression of lymph nodes T cells. Taken together these studies suggest that endogenous glucocorticoids play a central role in the pathogenesis of GVHD.
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Price, Kursteen S. (Kursteen Salter). "The role of lipopolysaccharides during acute graft-versus-host Disease /." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=68245.
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In this study we have shown that translocation of intestinal LPS into the portal and systemic circulatory systems during graft-versus-host disease (GVHD) is predictive of morbidity and mortality. Randomized C57BL/6 x AF1 (B6AF$ sb1$) mice were injected with C57BL/6 (B6) lymphoid cells and sacrificed at predetermined times after transplantation for bacterial lipopolysaccharide (LPS) tissue analysis. The liver, the spleen and the sera from some acute GVH reactive mice first tested positive for LPS from day 2, 4 and 16 post transplant, respectively. Total hepatic and splenic LPS in acute GVH reactive mice peaked, and LPS was first detected in the sera of these same animals, at a time coincident with the onset of mortality. These results show that LPS is present to initiate tumour necrosis factor alpha (TNF-$ alpha$) release from interferon gamma (IFN-$ gamma$) primed macrophages, resulting in the manifestations of acute GVHD.
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Kichian, Krikor. "Interferon gamma regulatory mechanisms during acute graft-versus-host disease." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23280.
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The onset of acute graft-versus host disease (aGVHD) is accompanied by macrophage priming and the presence of bacteria derived lipopolysaccharide (LPS) in the sera and organs of transplanted animals. Priming of macrophages occurs despite suppression of T cell function. We have investigated whether interleukin 12 (IL-12) mediates the continued production of interferon gamma (IFN-$ gamma$) during the state of T cell immunosuppression accompanying aGVHD. AGVHD was induced in non-irradiated AxC57BL/6 mice by an injection of C57BL/6 lymphoid cells. Despite T cell immunosuppression, macrophages remained primed as shown by their expression of inducible nitric oxide synthase (iNOS) mRNA and production of nitric oxide (NO) in response to exogenous LPS. Continued exposure to IFN-$ gamma$ was found to be required in order to maintain the primed state of macrophages during aGVHD; IFN-$ gamma$ mRNA within target organs of aGVHD including thymus, salivary gland, and lung was increased between day 7 and 14 after transplantation and was accompanied by the induction of the p40 peptide of IL-12 and iNOS mRNA. p40 peptide mRNA was also increased in macrophages purified on day 14 of aGVHD. These results provide evidence for localized production of IFN-$ gamma$ in aGVHD target organs and suggest that it is mediated by LPS induced IL-12 production by macrophages.
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Williamson, Eilidh. "Cytokines in the immunopathogenesis of murine graft-versus-host disease." Thesis, University of Glasgow, 1997. http://theses.gla.ac.uk/40906/.
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Murine models of graft-versus-host disease (GvHD) provide important information relevant to clinical bone marrow transplantation (BMT), as well as to other types of T cell-mediated pathology. The nature of the GvHD which develops in (C57BL/6 X DBA/2)F1 (BDF1) mice injected with parental lymphocytes is dependent on whether C57B1/6 (B6) or DBA/2 parental donor cells are used. BDF1 mice injected with B6 donor cells (B6 => BDF1) develop an acute GvHD with early lymphoid hyperplasia and NK cell activation, followed by immunosuppression, activation of anti-host cytotoxic T lymphocytes (CTL), weight loss and early death. In contrast, BDF1 mice given DBA/2 donor cells (DBA/2 => BDF1) exhibit a chronic, stimulatory GvHD, characterised by B cell hyperreactivity, autoantibody production and immune complex-mediated glomerulonephritis (ICGN). Previous studies have shown that the distinct forms of GvHD in BDF1 recipient mice are associated with different patterns of cytokine production. Whereas acute GvHD is characterised by production of high levels of Th1 cytokines, chronic GvHD is associated with a preferential Th2 response. Therefore, it was suggested that the two forms of GvHD may reflect differential activation of distinct subsets of CD4+ T helper (Th) cells. However, when and why such T cell polarisation should occur has remained unclear. A number of recent studies have demonstrated that cytokines produced by cells of the non-specific immune system during the early phase of an immune response can strongly influence the type of specific response which develops subsequently. The main aim of this thesis was to explore the role of these early immune mediators in determining the outcome of the GvHD in BDF1 mice. These studies of the cellular and molecular interactions involved in murine GvHD have implications for understanding the pathogenesis of clinical GvHD and the development of specific therapy following BMT. In addition, they provide an important insight into the regulation of immune responses during other immunologically-mediated diseases.
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Zitzer, Nina Celia. "Immunobiology and Novel Therapeutics in Acute Graft-versus-Host Disease." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1532003009790858.
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Stokes, Jessica Lynnette. "Activated MHC-Mismatched T Helper-1 Lymphocyte Infusion Enhances Graft-Versus-Leukemia with Limited Graft-Versus-Host Disease." Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/311807.
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Riesner, Katarina [Verfasser]. "Initiation of Acute Graft-versus-Host Disease by Angiogenesis / Katarina Riesner." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1137867833/34.
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Svahn, Britt-Marie. "Stem cell transplantation: home care, graft-versus-host disease and costs /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-611-5/.
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Bachstein, Elke [Verfasser]. "Immunhistologische Diagnostik der akuten Graft-versus-Host Disease (aGvHD) / Elke Bachstein." Ulm : Universität Ulm. Medizinische Fakultät, 2003. http://d-nb.info/1015354386/34.
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Li, Hu [Verfasser]. "Mechanisms of Glucocorticoids in the modulation of Graft-versus-Host Disease and the Graft-versus-Leukemia Reaction / Hu Li." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1215338570/34.
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Weber, Michael [Verfasser]. "Immunregulatorische Mechanismen bei einer experimentellen akuten Graft-versus-Host-Disease / Michael Weber." Mainz : Universitätsbibliothek Mainz, 2013. http://d-nb.info/1045260681/34.
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Keenan, Russell David. "The investigation of the cellular mechanisms of autologous graft versus host disease." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274419.
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Marshall, Scott. "The mechanism and potential of extracorporeal photochemotherapy in graft versus host disease." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446191.
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Anthony, Bryan Alan. "THE ROLE OF CD103 EXPRESSION IN PROMOTING INTESTINAL GRAFT VERSUS HOST DISEASE." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1324750762.
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Stark, Lisa Gail. "An investigation of potential novel predictive factors for graft-versus-host disease." Thesis, University of Newcastle upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401301.
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Jaksch, Marie. "Molecular monitoring of acute graft-versus-host disease after allogeneic stem cell transplantation /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-987-0/.
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Lucas, Svenja [Verfasser]. "CXCR3 Liganden vermittelte Hautentzündung bei kutaner lichenoider Graft-versus-Host Disease / Svenja Lucas." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1077271077/34.
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Klangsinsirikul, Phennapha. "The role of dendritic cells in the development of graft versus host disease." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394917.
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Appleton, Anne Laura. "An investigation into the relationship between herpes viruses and graft-versus-host disease." Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295538.
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Carlens, Stefan. "Leukaemic relapse after allogeneic haematopoietic stem cell transplantation and the use of the graft-versus-leukaemia effect /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4310-9/.
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Sviland, Lisbet. "Histology and immunopathology of skin and rectum following bone marrow transplantation." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235533.
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Bos, Gerardus Marinus Josef. "Chronic graft-versus-host disease, autoimmunity and microvascular pathology an experimental approach to scleroderma /." Amsterdam [etc.] : Maastricht : Thesis ; University Library, Maastricht University [Host], 1989. http://arno.unimaas.nl/show.cgi?fid=5449.
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Leonhardt, Franziska [Verfasser], and Gunther [Akademischer Betreuer] Neuhaus. "Pathophysiologische Komponenten der akuten graft-versus-host disease: T-Zellen, dendritische Zellen und Endothelzellen." Freiburg : Universität, 2013. http://d-nb.info/1123476764/34.
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Latis, Eleonora M. T. "Exploring immunological mechanisms of human graft-versus-host disease after hematopoietic stem cell transplantation." Thesis, Sorbonne Paris Cité, 2018. https://theses.md.univ-paris-diderot.fr/LATIS_Eleonora_va.pdf.
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L’allogreffe de cellules souches hématopoïétiques est un traitement curatif pour de nombreuses maladies hématologiques. Cependant, le succès de cette procédure est entravé par la maladie du Greffon-contre-l’Hôte (GVH), une complication potentiellement fatale induite par l’attaque des tissues de l’hôte par les cellules T alloreactives du donneur. La GVH a une prévalence de 40 à 80%, selon les caractéristiques de la transplantation. La GVH est la cause principale de mortalité post-greffe en dehors des rechutes et, en dépit des nombreuses avancées dans le domaine de l’allogreffe, la physiopathologie de cette maladie est encore mal comprise à ce jour, en particulier chez l’homme. Dans cette étude, nous nous sommes concentrés sur la caractérisation phénotypique et moléculaire du système immunitaire des patients greffés et de leurs donneurs. L’objectif de l’étude est de déterminer les facteurs liés à la reconstitution du système immunitaire et au développement de la GVH aigüe. Nous avons collecté le sang de 101 couples donneur /receveur apparentés HLA-identique provenant de trois cohortes indépendantes : avant transplantation pour les donneurs, à l’apparition des premiers symptômes chez les patients atteint de la GVH aigüe et 30 ou 90 jours post-greffe pour les patients non atteints. Nous avons caractérisé le profil cellulaire de ces échantillons par cytométrie spectrale et analysé leur profil transcriptomique.L’immunophenotypage des patients nous a permis de montrer que la reconstitution du compartiment des cellules T est incomplète, avec une inversion du rapport CD4/CD8 après la greffe. De plus, le compartiment cellulaire T est enrichi en cellules possédant un phénotype effecteur/mémoire tandis que le réservoir des cellules T naïves est appauvri. La reconstitution des cellules NK est caractérisée par un enrichissement du sous-type CD56bright et celle des monocytes par l’enrichissement des cellules CD16+. A l’apparition de la GVH, une augmentation de la fréquence des cellules possédant un phénotype semblable aux cellules souches mémoire est observée, par rapport aux patients non-atteints. Ces cellules pourraient représenter un réservoir cellulaire de la maladie, maintenant la production de cellules T alloréactives. Le profilage transcriptomique montre que les cellules T du donneur réagissent à l'environnement de l’hôte en acquérant un phénotype activé, avec une surexpression des gènes associés à l’activation, l’adhésion, la migration et les fonctions effectrices. Au commencement de la maladie, on observe que les cellules T surexpriment des gènes médiateurs de l’inflammation ainsi que des gènes impliqués dans la transduction du signal cytokinique et la migration cellulaire. Nos données démontrent que l’analyse de la distribution des sous-types cellulaires par cytométrie associée au profilage transcriptomique peut contribuer à élucider les mécanismes impliqués dans la reconstitution immunitaire et dans le développement de la GVH humaine<br>Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematologic malignancies. However, its success is hindered by graft-versus-host disease (GVHD), a potentially fatal complication deriving from alloreactive donor T cells attacking recipient tissues. Acute GVHD (aGVHD) prevalence lies between 40 and 80% depending on transplant characteristics. GVHD is the main cause of non-relapse morbidity and mortality after HSCT and despite the advances in the field, disease processes in humans remain poorly understood.In this study we investigated the phenotypic and molecular characteristics of immune cells in patients after HSCT and in their HLA-identical sibling donors, with the goal of defining immune parameters associated with the recovery of donor-derived immunity and with the development of acute GVHD. We analysed 101 donor-recipient pairs in three independent cohorts for which blood was collected from the donors before transplantation and for the recipients either at aGVHD onset, before any treatment, or at day 30 or 90 post-HSCT for recipients that did not develop GVHD. On the donors’ and recipients’ samples we performed cellular profiling using spectral flow cytometry as well as gene expression analysis.Immunophenotyping reveals an incomplete reconstitution of the T cell compartment in the recipients, with an inversion of the CD4/CD8 ratio, both at one and three months after HSCT. Moreover, the reconstituting T cell compartment is characterized by a shift in the effector/memory phenotype of these cells, with a parallel depletion of the naïve T cell pool. NK cell reconstitution is characterized by an expansion of the CD56bright subset, while monocytes undergo an expansion of CD16+ cells. At aGVHD onset recipients have an increase of cells with a T stem cell memory-like (TSCM-like) phenotype compared to recipients without aGVHD. These cells may represent a cellular reservoir for GVHD, maintaining the production of alloreactive T cells in the presence of host persistent antigens. Molecular profiling shows that donor T cells react to the environment of the host by acquiring an activated phenotype, with upregulation of genes associated with T cell activation, adhesion, migration and effector functions. T cell transcriptome profiling at aGVHD onset shows upregulation of inflammatory mediators as well as genes involved in cytokine signal transduction, cell migration and cell trafficking.Our data demonstrate that comprehensive analysis of the distribution of different immune cell subsets with flow cytometry together with gene expression profiling can contribute to elucidate the processes involved in immune reconstitution and acute GVHD development in humans. In the future, studies with new technologies will hopefully bring insights into the mechanisms underlying GVHD development that will help design new preventive and therapeutic strategies to be applied in the clinics
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Khoder, Ahmad. "The role of B cells in the pathogenesis of chronic graft-versus-host disease." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29854.
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Chronic graft-versus-host disease (cGVHD) remains a major complication of allogeneic haematopoietic stem cell transplantation. Traditionally, GVHD has been approached as a T-cell-mediated process and current therapies reflect this understanding. The successful treatment of a proportion of refractory cGVHD patients with a CD20-depleting-agent supports a pathological role for B cells. To study the role of B cells in cGVHD, I designed a comprehensive multi-parameter panel of surface antibodies to distinguish different B cell subsets. The panel was validated on a number of healthy volunteers and applied to peripheral blood samples from cGVHD patients. I showed that patients with active chronic GVHD have an expanded population of CD21- with an 'exhausted' phenotype, based on upregulation of inhibitory receptors, altered expression of chemokine receptors and poor proliferative capacity. A similar subset of CD21- exhausted B cells was described in patients with chronic HIV viraemia. Interestingly, there was a significant correlation between frequencies of CD21- B cells and the severity of cGVHD. Further work to identify the potential antigens that drive the expansion of these cells is currently underway. I also explored the role of IL10 producing regulatory B cells (Breg); powerful regulators of immune responses. A number of B cell subsets have been described in murine models of autoimmunity and some human autoimmune diseases. I investigated the presence of IL10 producing B cells in the peripheral blood of healthy donors. Using intracellular cytokine staining for IL10 and surface phenotyping, I showed that IL10 producing B cells are enriched within the CD27+ IgMhi (IgM memory) B-cell subset. The purified populations of IgM memory B cells had regulatory properties and are capable of suppressing CD4+ T cell proliferation and IFNγ in vitro. Finally, I showed that B cells from cGVHD patients produce significantly less IL10 compared with both HC and 'no-GVHD' patients. I thereby propose that B cells play a significant role in the pathogenesis of cGVHD. Ex vivo expanded and adoptively transferred IgM memory B-cells may offer a potentially effective immunomodulatory therapy for the treatment of refractory cGVHD.
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Berrie, Jennifer. "DISTINCT T CELL CLONES ARE ASSOCIATED WITH GRAFT-VERSUS-HOST DISEASE (GVHD), AND POTENTIALLY GRAFT-VERSUS-TUMOR (GVT), RESPONSES FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2450.
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In patients undergoing hematopoietic stem cell transplantation (HSCT) with HLA-identical donors, genetic polymorphisms result in a mismatch between donors and recipients in their minor histocompatibility antigens (mHAgs), and tumors may also express tumor-associated antigens (TAA) that may not be abundantly present in the donors. Donor T cells can recognize such mHAgs and TAAs as foreign antigens and generate an objective response against hematologic malignancies in a graft-versus-tumor (GVT) effect. However, a major side effect of HSCT occurs when donor T cells are alloreactive against the recipients’ normal cells, leading to graft-versus-host disease (GVHD). The ability to identify T cell clones that are exclusively involved in the GVT or GVHD responses remains elusive. In this study, we looked at clonally-driven CD3+ T cells in patients with hematologic malignancies prior to and after transplantation. We identified Vbeta families of increased expression involved in GVHD or GVT responses, with Vbetas 4, 11, and 23 being associated with GVHD, Vbetas 9, 16, and 20 being associated with GVT, and Vbetas 2, 3, 7, 8, 12, 15, and 17 being involved in GVHD and/or GVT. We were also able to identify some of the Vbeta families that were increased in the peripheral blood at the site of GVHD. Furthermore, one of our twelve patients had donor lymphocyte infusions (DLIs) for treatment of relapse, from which we were able to observe oligoclonal T cells that emerged at the time of post-DLI remission and re-establishment of GVHD.
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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.<br>published_or_final_version<br>Medicine<br>Doctoral<br>Doctor of Philosophy
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Wells, Janet Catherine. "The influence of regulatory T cells and mobilisation regimens on graft versus malignancy, graft versus host disease and relapse in haematopoietic progenitor cell transplantation." Thesis, University of the West of England, Bristol, 2015. http://eprints.uwe.ac.uk/24703/.
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Regulatory T cells (Tregs) are key players in controlling immune responses, limiting autoimmune disease and allergies, and attenuating immune responses to tumours and pathogens. Understanding and harnessing the suppressive effects of Tregs in autologous and allogeneic haematopoietic progenitor cell (HPC) transplantation presents a significant challenge due to lack of consensus over optimal markers to uniquely identify Tregs and variation in centre-specific factors including disease mix, conditioning regimens, graft origin and manipulation and prophylaxis and treatment of graft versus host disease (GVHD). This study aimed to determine if CD3+CD4+CD125highCD127lowFoxP3+ Treg quantification, assessed flow cytometrically, in grafts or in the post-transplant peripheral blood of patients who received transplants for malignant disease, could provide a useful predictor for disease relapse in autologous (n=85) and allogeneic patients (n=75) and falling chimerism and/or incidence of GVHD in the latter group. The impact of Treg numbers were quantified in HPC harvests, in transplant grafts and in recipients’ peripheral blood during immune reconstitution. Additionally, a simplified Treg assessment protocol using the marker tumour necrosis factor receptor-2 (TNFR2) with CD3, CD4 and CD25 was assessed. In autologous donors, significantly higher Tregs relative to CD34 HPCs were noted in harvests mobilised with the more novel regimen, granulocyte-colony stimulating factor (G-CSF) plus Plerixafor than with G-CSF alone or used in combination with cyclophosphamide. In allogeneic harvests Treg numbers following G-CSF mobilisation were significantly lower than in non-mobilised harvests. Lower absolute Treg numbers in donor lymphocyte infusion (DLI) doses were significantly associated with successful outcome in terms of restoration of donor chimerism and resolution of relapse. Cryopreservation of mobilised cells at the time of initial transplant for later use for DLI has thus been incorporated into practice at this Trust as this is expedient in terms of clinical result, convenience and cost. Interestingly although mobilisation regimens influenced Treg levels in harvests, no correlation was apparent between Treg doses transplanted or peripheral blood levels during immune reconstitution post autologous or allogeneic transplantation or with falling chimerism and/or incidence and severity of GVHD in allogeneic patients during the first year post transplant. Extending this follow-up time would be an interesting area of further study as the majority of patients who relapse do so beyond one year.
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Häntzschel, Ingmar. "Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogenic blood stem cell transplantation." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-64815.
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Fritsch, Susanne. "Extrakorporale Photopherese als Therapie der akuten steroidrefraktären Graft-versus-Host Disease nach allogener hämatopoetischer Zelltransplantation." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-125357.
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Zerdzitzki, Matthäus R. [Verfasser], and Ernst [Akademischer Betreuer] Holler. "Risikofaktoren für die Graft-versus Host Disease der Leber / Matthäus R. Zerdzitzki. Betreuer: Ernst Holler." Regensburg : Universitätsbibliothek Regensburg, 2015. http://d-nb.info/1080954465/34.
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Cullup, Hannah. "An investigation of interleukin-1 in graft versus host disease following allogeneic bone marrow transplantation." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247827.
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Conlan, T. J. "Mechanisms of graft-versus-host-disease : a role for Langerhans cells in regulating skin GVHD." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1462578/.
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Allogeneic bone marrow transplantation (BMT) is an important and commonly used treatment for a variety of haematological malignancies. Central to the therapeutic benefits of allogeneic BMT is the role of donor T cells, which mediate a potent anti-neoplastic effect against tumours in the recipient. However, the presence of donor T cells is also tightly associated with the development of the life-threatening condition graft-versus-host-disease (GVHD), a disorder where alloreactive donor T cells recognise the recipient as ‘non-self’ and elicit a potent anti-host immune response. Antigen presenting cells (APC) are critical to the induction of acute GVHD. However, recent studies have questioned whether any particular subset of APC has a non-redundant role in the priming of an alloreactive donor T cell response. One of the most commonly affected organs in acute GVHD is the skin, which contains a diverse array of professional APC subsets capable of initiating potent immune responses. One such subset is Langerhans cells (LC), a population of radioresistant dendritic cells (DC) that form a dense interlacing network within the epidermis. Using an in vivo mouse model of acute GVHD where host LC can be conditionally depleted, LC were found to play an important role in the development of acute GVHD in the skin. The depletion of host LC significantly reduced the severity of cutaneous GVHD that developed following allogeneic BMT. Host LC were required in situ in the epidermis for both the accumulation and function of alloreactive donor CD8 T cells in the skin. A role for host Langerin+ dDC, a population shown to be critical for CD8-mediated T cell responses in the skin, was also ruled out. These findings describe a novel role for host LC in the regulation of cutaneous GVHD in situ, which could identify a novel target for organ specific immunosuppression following allogeneic BMT.
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Scroggins, Sabrina Marie. "Generation and characteriztion of regulatory dendritic cells for the amelioration of acute graft versus host disease." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/2011.
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Despite Human Leukocyte Antigen (HLA) matching and use of immunosuppressive drugs, graft-versus-host disease (GVHD) following hematopoietic stem cell transplant (HSCT) is prevalent and often fatal. Additionally, older HSCT recipients experience increased morbidity and mortality. Prophylactic treatment with age-matched syngeneic (recipient strain-derived) cultured regulatory DC (DCreg) has been shown to decrease GVHD-associated mortality in young bone marrow transplanted (BMT) mice. The purpose of this study was to investigate: 1) the potential to generate DCreg from older mice and their subsequent ability to ameliorate GVHD in older BMT mice, 2) the mechanism(s) by which DCreg mitigate GVHD in vivo, 3) the ability of DCreg-treated BMT mice to respond to infectious pathogens, and 4) whether DCreg can be generated under clinically relevant conditions from healthy donor and HSCT recipient PBMCs.
To evaluate the efficacy of DCreg treatment in older mice, complete MHC-mismatched BMT mice were treated with DCreg (hereafter referred to as DCreg-treated BMT mice). Although DCreg treatment ameliorated GVHD in older BMT mice, these mice had increased morbidity and decreased survival compared to their young counterparts.
Following transfer into BMT mice, older DCreg failed to increase inhibitory molecule (PD-L1 and PIR B) expression while significantly upregulating co-stimulatory molecule (CD40 and CD80) expression, conversely young DCreg upregulated inhibitory molecules as well as co-stimulatory molecules. These phenotypic differences between young and older DCreg in vivo provide a potential mechanism for modestly increased morbidity and mortality in older DCreg-treated BMT mice relative to their young counterparts. Indeed, BMT mice treated with DCreg deficient in PD-L1 or PIR B had significantly reduced overall survival, thus both molecules are required for optimal GVHD mitigation.
A murine H1N1 influenza (IAV) infection model was used to assess the donor immune system's capacity to respond to relevant antigens other than those responsible for GVHD. Surprisingly, sub-lethally IAV-infected DCreg-treated BMT mice began to die after d. +21 and all were deceased by d. +25. Virus-specific CD8+ T cell and antibody (Ab) responses were undetectable following primary infection. Interestingly, following a prime-boost infection strategy, DCreg-treated BMT mice survived lethal IAV challenge with no signs of morbidity and had demonstrable IAV-specific Ab and CD8+ T cell responses. Thus a prime-boost IAV infection strategy establishes a protective immune response in the DCreg-treated BMT mice and underscores the potential role vaccination may play in establishing immune competence in DCreg-treated BMT mice.
We investigated whether human DCreg can be generated under clinically relevant conditions: 1) following peripheral blood mononuclear cell (PBMC) cryopreservation, 2) in bovine serum-free media, and 3) from older individuals and HSCT recipients. DCreg were generated from healthy donor and HSCT patient PBMCs isolated from young (old) and older (> 50 years old) individuals by culturing cells in X-vivo serum-free.
Human DCreg generated from both young and older healthy donor PBMCs had comparable numbers, surface molecule phenotype, cytokine production, and able to induce Treg. Cryopreserved and fresh PBMCs generated DCreg with similar phenotypes and cytokine production. DCreg generated from HSCT recipients maintained low co-stimulatory molecule and high inhibitory molecule expression as well as immunosuppressive cytokine production. These studies confirm DCreg can be generated under clinically relevant conditions.
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Uttenthal, B. J. "T cell receptor-transduced regulatory T cells : functional studies in models of graft-versus-host disease." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1379030/.
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Alloreactive immune responses directed against malignant cells in recipients of allogeneic haematopoietic stem cell transplants are able to cure patients with haematological cancers. However, such immune responses may cause severe morbidity when directed against healthy recipient tissue, resulting in graft-versus-host disease (GvHD). Naturally occurring regulatory T cells (Tregs) are CD4+ T cells characterized by their expression of the transcription factor Foxp3. Whilst adoptively transferred polyclonal Tregs suppress GvHD in several murine models, their lack of specificity may compromise beneficial immunity against malignancy or infection. The generation of MHC class I-restricted, alloantigen-specific Tregs would allow them to recognize antigen presented directly on GvHD target tissues, concentrating their sites of activation at these tissues and potentially reducing non-specific immune suppression. I have generated ‘converted’ Tregs through retroviral transfer of genes encoding Foxp3 and specific MHC class I-restricted T cell receptors (TCRs) into conventional CD4+ T cells. I used the 2C-TCR, which recognizes the MHC class I molecule H-2Ld, expressed in Balb/c and other H-2d mice, in complex with the ubiquitously expressed peptide p2Ca; and the MH TCR, which recognizes the MHC class I molecule H-2Db, expressed in B6 and other H-2b mice, in complex with the male peptide WMHHNMDLI. In vitro, Foxp3 2C-TCR-transduced B6 CD4+ T cells are hyporesponsive to stimulation and are able to suppress the alloreactive proliferative response of B6 CD4+ and CD8+ T cells to Balb/c splenocytes, consistent with the acquisition of regulatory function. When adoptively transferred to lethally irradiated Balb/c recipients of MHC-mismatched B6 bone marrow and conventional T cells, Foxp3 2C-TCR-transduced B6 CD4+ T cells reduce early proliferation of donor T cells, weight loss and GvHD score in the recipients. Similarly, CD4+ T cells transduced with Foxp3 and the MH-TCR are able to suppress allogeneic responses both in vitro and in vivo. However, while both the 2C-TCR and the MH TCR confer specificity to their cognate antigens in vitro, antigen specificity of suppression is not evident in these in vivo models. In this thesis I show that the endogenous TCR of transduced CD4+ T cells contributes to this lack of specificity, a finding that has important implications for the use of class I-restricted TCRs alongside Foxp3 in CD4+ T cells to direct regulatory activity.
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Jarvis, Mark. "An investigation into the mechanisms of graft-versus-host disease involving apoptosis and heat shock proteins." Thesis, University of Newcastle Upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405344.
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Stokes, Jessica, Emely A. Hoffman, Yi Zeng, Nicolas Larmonier, and Emmanuel Katsanis. "Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation." WILEY-BLACKWELL, 2016. http://hdl.handle.net/10150/621784.
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Advances in haploidentical bone marrow transplantation (h-BMT) have drastically broadened the treatment options for patients requiring BMT. The possibility of significantly reducing the complications resulting from graft-versus-host disease (GvHD) with the administration of post-transplant cyclophosphamide (PT-CY) has substantially improved the efficacy and applicability of T cell-replete h-BMT. However, higher frequency of disease recurrence remains a major challenge in h-BMT with PT-CY. There is a critical need to identify novel strategies to prevent GvHD while sparing the graft-versus-leukaemia (GvL) effect in h-BMT. To this end, we evaluated the impact of bendamustine (BEN), given post-transplant, on GvHD and GvL using clinically relevant murine h-BMT models. We provide results indicating that post-transplant bendamustine (PT-BEN) alleviates GvHD, significantly improving survival, while preserving engraftment and GvL effects. We further document that PT-BEN can mitigate GvHD even in the absence of Treg. Our results also indicate that PT-BEN is less myelo-suppressive than PT-CY, significantly increasing the number and proportion of CD11b(+)Gr-1(hi) cells, while decreasing lymphoid cells. In vitro we observed that BEN enhances the suppressive function of myeloid-derived suppressor cells (MDSCs) while impairing the proliferation of T-and B-cells. These results advocate for the consideration of PT-BEN as a new therapeutic platform for clinical implementation in h-BMT.