Spelling suggestions: "subject:"gvhd"" "subject:"vhd""
31 |
Evaluation of IL2 and HLA on the Homeostasis and Function of Human CD4 and CD8 T CellsDurost, Philip A. 15 September 2017 (has links)
Homeostasis of human T cells is regulated by many factors that control proliferation, differentiation of effector cells and generation of memory. Our current knowledge of the mechanisms controlling human T cell homeostasis in vivo is based on experiments in small animal models. However many differences exist between immune systems of mice and humans, including cell composition, function, and gene expression. Humanized mouse models have shown great value in the study of human immunobiology. I have used novel humanized mouse models to examine the role of human MHC (HLA) and human IL2 in CD8 T cell and CD4 regulatory T cell (Treg) homeostasis. To study human CD8 T cells I engrafted CD8 T cells from healthy donor PBMC into NOD-scid IL2rgnull (NSG) mice that lacked expression of murine MHC and that expressed HLA-A2. My data demonstrate that CD8 T cell survival and effector function required the presence of HLA-A2, helper function from human CD4 T cells and exogenous human IL2. To study human Treg homeostasis I used NSG mice engrafted with human fetal thymus and hematopoietic stem cells (BLT model). NSG-BLT mice support the growth of human thymic tissue and enable the efficient development of HLA-restricted Treg and conventional T cells. Using an AAV vector to express human IL2, I demonstrated that functional human Treg but not conventional T cells increased in number in NSG-BLT mice and that this coincided with increases in activated human NK cells. Overall my research has revealed that HLA and human IL2 have an essential role in human T cell survival and function in vivo.
|
32 |
A Phenotypic Analysis of Involucrin-Membrane-Bound Ovalbumin Mice after Adoptive Transfer of Ovalbumin-Specific CD8⁺ T Cells / OVA特異的CD8陽性T細胞の移入によるinvolucrin-mOVAマウスの表現型解析Nakagawa, Yujin 24 November 2022 (has links)
京都大学 / 新制・論文博士 / 博士(医学) / 乙第13516号 / 論医博第2266号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 河本 宏, 教授 濵﨑 洋子, 教授 森本 尚樹 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM
|
33 |
Targeting T Cell Glycolysis to Mitigate Graft-versus-Host DiseaseEzhakunnel, Kevin 01 January 2021 (has links)
Hematological cancers account for nearly ten percent of cancer cases diagnosed annually in the United States. Patients who fail to respond to chemotherapy or radiotherapy must often undergo a bone marrow transplant to treat their malignancy. A significant complication following this procedure is Graft versus Host Disease (GvHD), which occurs when donor T cells mount an immune response against recipient tissues. Immunological research has highlighted the role of aberrant T cell metabolism, specifically a shift toward aerobic glycolysis, as a key driver behind the occurrence of this condition. The transcription factor FoxK1 has been revealed to be a key regulator of the cell's ability to induce aerobic glycolysis. Utilizing established GvHD murine models and novel CRISPR-Cas9 techniques, this study investigates how controlling this important pathway by FoxK1 may limit the damage inflicted by GvHD. Our studies reveal that depleting FoxK1 in donor T cells has a protective effect following transplants by promoting an immunosuppressive phenotype in donor T cells. These results suggest that FoxK1 may hold promise as a future cellular target for cellular therapies administered to transplant patients to prevent the occurrence of GvHD. Continued research is needed to ascertain the precise mechanisms that afford FoxK1 this protective role.
|
34 |
Biomedical Imaging of Stem Cells Using Reporter GenesWang, Fangjing 17 May 2010 (has links)
No description available.
|
35 |
Traitement de la maladie du greffon contre l’hôte chronique par la photophérèse extra corporelle au TH9402 : m écanisme de régulation de la maladie du greffon contre l’hôte chronique par les cellules T régulatricesBastien, Jean-Philippe 08 1900 (has links)
La maladie du greffon contre l’hôte (GVHD) est la principale cause de mortalité et de morbidité suite aux greffes de cellules souches hématopoïétiques. Plusieurs patients demeurent réfractaires aux traitements actuels ce qui rend nécessaire le développement de nouvelles stratégies afin de combattre cette maladie. Dans l’étude qui suit, nous avons utilisé un nouvel agent thérapeutique, le TH9402, une molécule photosensible et démontré qu’elle permet, lorsqu’exposée à la lumière visible (514 nm), d’éliminer sélectivement les cellules T activées in vivo tout en préservant les cellules T au repos et les cellules T régulatrices (Tregs). Les Tregs ainsi préservés peuvent abroger la réponse alloréactive par la sécrétion d’IL-10 ou par contact cellule-cellule via un mécanisme impliquant le CTLA-4. Nous avons découvert que la signalisation du CTLA-4 était associée à une hausse de la population Treg in vitro. Cette hausse est due à la conversion de cellules T CD4+CD25- en Tregs et non à une prolifération sélective des Tregs.
Dans la deuxième partie de cette étude, nous avons démontré que la signalisation de CTLA-4 était associée à une augmentation de l’expression de la protéine Indoleamine 2,3 dioxygenase (IDO). Ces effets nécessitent la déplétion du tryptophane ainsi que de la protéine de phase aigue GCN2. Finalement, nous avons observé que l’infusion de cellules traitées au TH9402 chez des patients souffrant de GVHD chronique est associée à une augmentation de la population Treg chez ces patients sans causer de lymphopénie ni de diminution de la réponse immunitaire dirigée contre les antigènes viraux. Ces résultats suggèrent que le traitement au TH9402 pourrait représenter une approche particulièrement intéressante pour le traitement de la GVHD chronique réfractaire aux traitements actuels. De plus, l’augmentation de l’expression d’IDO pourrait être utilisée comme valeur prédictive de la réponse du patient au traitement. Ceci pourrait permettre d’améliorer la qualité de soins ainsi que de la qualité de vie des patients souffrant de GVHD chronique. / Graft versus host disease (GVHD) is the primary cause of mortality and morbidity following hematopoietic stem cell transplantation. Many patients remain refractory to current treatments, emphasizing the need to develop new therapeutic strategies. In the present study, we have used a novel therapeutic agent, TH9402, and shown that once activated by visible light (514 nm), this photosensitizer becomes specifically cytotoxic toward activated T cells while preserving resting T cells and regulatory T cells (Tregs). Preserved Tregs can display anti GVHD activity through IL-10 and CTLA-4 dependent mechanisms. Furthermore, CTLA-4 signaling was associated with an increased Treg population. This increase resulted from FOXP3 induction in CD4+CD25- cells and not selective proliferation of Tregs.
In the second part of this study, we showed that CTLA-4 signaling was associated with enhanced expression of indoleamine 2,3 dioxygenase (IDO). The expression of IDO results in the generation of anti GVHD activity and an increase in the Treg population following TH9402 treatment. This increased Treg population was mediated by tryptophan degradation and implied acute phase protein GCN2 activity. Finally, we show that the infusion of TH9402 treated cells in patients suffering from chronic GVHD resulted in an increase of the Treg population as early as 8 weeks after treatment initiation without causing lymphopenia or hyporesponsiveness toward viral antigens. Furthermore, the increase of IDO corresponded to patient response to treatment. These results suggest that TH9402 represents a most interesting therapeutic approach for patients with refractory chronic GVHD. IDO expression could also be used to predict patient responsiveness to the treatment. This could increase the quality of the treatment as well as the quality of life of patients suffering from refractory chronic GVHD.
|
36 |
Molecular Analysis of Oligoclonal T cells Associated with Graft-Versus-Host Disease Following Allogeneic Stem-cell TransplantationAvent, Kassi 24 April 2012 (has links)
The goal of hematopoietic stem cell transplantation (HSCT) is to induce graft-versus-tumor effect (GVT), which is the recognition of and response against tumor- associated antigens (TAAs) by donor immune cells to clear the recipient of residual tumor. A complication of HSCT as a treatment for hematologic malignancies is graft-versus-host disease (GVHD), which is the recognition and reactivity of donor immune cells against healthy tissues. As of now, the differentiation between GVHD and GVT effects has been a hindrance to the development of effective therapies against GVHD. Certain T cell clones may induce both GVHD and GVT effects, making targeted therapy of GVHD difficult. This project was aimed to uncover differences at a molecular level of the T cell recognition site that exist between patients with GVHD and those with GVHD-free survival following allogeneic HSCT. We found that there are inherent differences in the T cell receptor at a molecular level between patients experiencing GVHD and those that are GVHD-free, suggesting the ability of T cells to distinguish tumor cells from self cells. In addition, the intention was to reveal differences in proportions of engrafted donor T cells and stem cells and the effects of these proportions on the severity, outcome, and prognosis of GVHD. We additionally found that a lower proportion of stem cells to T cells was associated with the trend of GVHD, while a higher frequency of T cells engrafted into host may indicate resistance to treatment and a poor prognosis. These data suggest that allogeneic HSCT may be improved by optimizing the proportion of T cells to stem cells in the transplant as well as developing targeted therapy against GVHD-associated T cell clones while rescuing GVT-associated T cell clones.
|
37 |
Mécanismes d'action des cellules stromales mésenchymateuses dans le traitement de la réaction du greffon contre l'hôteLemieux, William 12 1900 (has links)
La maladie du greffon contre l’hôte (GvHD) est un effet secondaire sérieux de la transplantation de cellules souches hématopoïétiques (HSCT). Cette maladie entraine une haute mortalité et ses symptômes sont dévastateurs. Les traitements actuels de la GvHD comportent plusieurs produits, tels les corticostéroïdes, mais ces derniers sont immunosuppresseurs et leurs effets secondaires sont aussi très dommageables pour les patients et leur guérison. Les cellules stromales mésenchymateuses (MSC) représentent une alternative ou une addition potentielle de traitement pour la GvHD et ces cellules ne semblent pas posséder les effets secondaires des traitements classiques. Un nombre important d’études cliniques faisant l’objet des MSC ont été enregistrées. Malgré cet engouement, le mécanisme de leur immunomodulation reste encore à élucider. Notre objectif est donc de mieux définir ce mécanisme. Nous avons utilisé un modèle simplifié pour simuler la GvHD in vitro. Ce modèle se base sur la stimulation de lymphocytes CD4+ par des cellules dendritiques allogéniques. La mesure de la prolifération de ces cellules stimulées sert d’indicateur de leur réactivité. Selon les résultats obtenus par la technologie CRISPR de génie génétique, les MSC exerceraient leur immunosuppression sur les cellules T CD4+ principalement par la sécrétion de l’enzyme IDO1. Les MSC seraient également capables d’induire certaines cellules CD4+ en cellules régulatrices, un processus indépendant de la sécrétion d’IDO1. Toutefois, ces cellules ne semblent pas correspondre aux cellules Treg conventionnelles. / Graft versus host disease (GvHD) is a very serious side effect of hematopoietic stem cell transplantation (HSCT). This disease results in high mortality and devastating symptoms. Treatments for GvHD include a lot of pharmaceuticals, including corticosteroids, but these are immunosuppressive and their adverse effects cause a lot of damage to the patient and hinder the healing process. Mesenchymal stromal cells (MSC) represent a potential alternative or addition to the GvHD treatment regimen. These cells do not seem to carry the secondary effects associated with classical treatments. A number of studies have been registered concerning MSC. In spite of the spike of interest, the mechanism of immunomodulation deployed by MSC remains to be elucidated. Our objective is to better characterise this mechanism. We have used a simple in vitro model to simulate GvHD. This model is based on the stimulation of CD4+ T cells by allogenic dendritic cells. The measure of the proliferation of the stimulated lymphocytes serves as an indicator of the reactivity. According to the results obtained by CRISPR genetic engineering, MSC exert this immunomodulatory effect on T cells mainly by the secretion of IDO1 enzyme. These MSC are also able to induce T cells to become inhibitory, a process independent of the secretion of IDO1. However, these inhibitory T cells would not correspond to conventional Treg cells.
|
38 |
Prévention de la maladie du greffon contre l'hôte par thérapie photodynamiqueSidi Boumédine, Radia January 2003 (has links)
Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.
|
39 |
Impact de la thérapie photodynamique sur les populations lymphocytaires pouvant être impliquées dans la maladie du greffon contre l'hôteJaafar, Lynn January 2005 (has links)
Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.
|
40 |
Immunosuppressive properties of Wharton's jelly derived mesenchymal stromal cells in the treatment of graft versus host disease in rat modelLopez Rodriguez, Yelica Virginia January 1900 (has links)
Doctor of Philosophy / Department of Anatomy and Physiology / Mark L. Weiss / 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.
|
Page generated in 0.0737 seconds