1,721,316 research outputs found
Towards tolerance inducing strategies in kidney transplantation.
Get PDFThe ultimate goal in the transplantation field is the induction and maintenance of donor specific tolerance. Treg cells that control immune responses to alloantigens give opportunities for tolerogenic therapies in transplantation. However, it is important to investigate the mechanisms of tolerance induction in order to use the optimal strategy. Therefore, we exploded both natural towards NIMA that can be induced during fetal life and induced tolerance by modulation of DC. Naturrally induced tolerance towards NIMA can have an influence on transplant outcome later in life. In this thesis we explored the influence of NIMA on the alloreactive T cells repetoire in healthy individuals and additionally we focused on the NIMA effect in patients transplanted with a NIMA haplotype mismatched kidney graft. In order to actively induce tolerance, we modulated DC to generate Treg cells, since this may be of clinical relevance in the future for patients that are on the waiting list for transplantation. In this thesis we explored the possibility of using modulated DC for the induction of transplantation tolerance in a fully allogeneic setting in mice. Furthermore we describe an in vitro system for the use of human modulated DC to induce Treg cells. We show that two differentially modulated human DC can lead to different types of Treg cells. Finally, we examined the possibility to use in vitro tools to measure a possible tolerant state in patients. Monitoring of e.g. Treg cells and/or cytokines may give an indication which patients are at risk for rejection and which patients are more predisposed to tolerance. We describe the Elispot technique as a possible tool to monitor patients that received a renal allograft. In conclusion , this thesis contributes to the fundamental understanding of both natural and induced tolerance in transplantation and gives a handhold for future research. As donor-specific tolerance is still far away from the clinic, the in vitro monitoring tool described in this thesis may contribute to the optimalization of immunosuppressive therapies in transplant recipients.LEI Universiteit LeidenBloedtransfusie en Transplantatie immunologie
Allogeneic haematopoietic stem cell donation and transplantation across the MHC class I barrier: "Faster is better than more. More is better than less".
Get PDFMany patients in need of haematopoietic stem cell transplantation do not reach transplantation. An analysis on all unrelated donor searches for Dutch patients performed between 1987 and 2000 showed a significant decrease of the percentage of patients for whom no donor was available. Between 1996 and 2000, the efficiency of the donor search and transplantation process was the biggest constraint for patients of Northwest European origin. Thirty percent of patients became medically unfit for transplantation during the process, due to the duration of the process. Major Histocompatibility complex (MHC) differences between donor and patient can preclude successful transplantation. The assumption that highly diverged MHC class I molecules lead to more T cell alloreactivity was challenged. Single highly diverged (>=5alpha5beta) MHC class I molecules did not elicit an immune response by allogeneic CTL in vitro. I propose that in generating a T cell repertoire with a sufficiently narrow responsive for self-MHC, positive thymic selection limits the capacity to recognize allogeneic MHC molecules whose structure and sequence have diverged extensively. Its clinical relevance was evaluated. We could subdivide the donor-recipient pairs with a negative CTLp assay into a prognostic favourable and unfavourable group based on the (>=5alpha5beta) MHC mismatch category.LEI Universiteit LeidenJurriaanse stichting, Innogenetics, NRC (National Reference Center for Histocompatibility), Roche Pharmaceuticals, Novartis, Astellas, Bio-sys, Corning, Diamed, Dutch Transplantation FoundationBloedtransfusie en Transplantatie immunologie
Costimulation blockade and regulatory T-cells in a non-human primate model of kidney allograft transplantation
Get PDFSuccessful tolerance induction therapies in rodents are for the most part unsuccessful in larger primates. Costimulation blockade by anti-CD40 or anti-CD40 + anti-CD86 in the life-supporting kidney allograft model in the rhesus monkey prevented graft rejection during treatment but did not induce tolerance. Costimulation blockade has to be integrated in conventional immunosuppressive therapies. However, conventional immunosuppressive drugs may antagonize the immunoregulatory effects of costimulation blockade. We describe how costimulation blockade prevented graft rejection in the immediate post transplantation period. CsA treatment was initiated only after 42 days post transplantation and this had a beneficial effect on graft survival, resulting in two of 4 monkeys surviving long-term without additional immunosuppressive treatment. Furthermore we found no beneficial effect of ATG induction therapy on costimulation blockade treatment. ATG induced rapid reappearance of CD8+ memory T-cells in the peripheral blood, possibly responsible for the observed accelerated rejection. Infiltrating cells in kidney graft biopsies and tissues revealed high expression of FOXP3 and other regulatory T-cell markers during rejection. We also have described the phenotypic and functional characteristics of naturally occurring regulatory T-cells in rhesus monkeys.Dutch Kidney Foundation (Nierstichting) Dutch Transplantation Society (NTV) PanGenetics BV BPRCUBL - phd migration 201
Maternal recognition of the (semi) allogeneic fetus during implantation and pregnancy
Get PDFThe recognition of __self__ and __none-self__ is one of the most important mechanisms for the human immune system whether or not to mediate a response. Cells identified as __self__ are tolerated whereas __non-self__ cells induce a cytotoxic reaction. However, during pregnancy the maternal immune system has to tolerate the presence of __non-self__ cells in maternal tissue, as the fetus is semi-allogeneic expressing both maternal and paternal antigens. This immunological acceptance of the __non-self__ fetus for the duration of pregnancy is called the immunological paradox. In this thesis we focused on the maternal immune recognition during implantation, pregnancy and pregnancy complications. Though pregnancy is sometimes considered as an immune deficient condition, both the innate as the adaptive immunity are activated and several aspects of these immune systems are studied in this thesis.Afdeling Verloskunde LUMC, BMA BV (Mosos), Chipsoft BV, Greiner Bio-One, Memidis Pharma BV, Nationaal Referentie Centrum voor Histocompatibiliteit , Stichting HELLP Syndroom , ZonMWUBL - phd migration 201
Challenges in unrelated hematopoietic stem cell transplantation. Access | Donor search and selection | Outcome
Get PDFThe studies described in this thesis are aimed at improving the whole spectrum of unrelated HSCT in order to help as many patients in need of HSCT as possible. It covers three different but related topics; from access to HSCT to optimizing donor search and selection of acceptable mismatches to improving HSCT outcome. In chapter 2 we investigate access to HSCT in the Netherlands for children with relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) to see whether patients eligible for HSCT are actually offered one and what might be the reasons for not referring a patient. Chapter 3 describes the role frequent HLA haplotypes may play in donor search and what the effect may be on HSCT outcome. In chapter 4 we propose an algorithm constructed by logistic regression analysis for prediction of CTL alloreactivity. It is based on number, position and physicochemical compatibility of AA differences in class I HLA molecules. This algorithm may be effective in identifying mismatched donors acceptable for HSCT. Before we can use this algorithm clinical validation is needed. Therefore we tried to translate the use of this algorithm from in vitro CTLp assay to in vivo HSCT. Studies aiming at the prediction of outcome of HSCT are described in chapter 5. Finally in chapter 6 we tested an algorithm developed by the transplantation group in Cambridge, which focused on electrostatic and hydrophobic properties of AA differences in class I HLA molecules, on the population we used for development of our own algorithm. Their algorithm was developed for prediction of humoral alloreactivity in organ transplantation and we wondered what could be the additional impact of a similar approach on cellular alloreactivity in HSCT.Europdonor Foundation; Stichting NRC; WMDA; GendxUBL - phd migration 201
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Characterization of B cell responses in relation to organ transplantation
Get PDFAntibody-mediated rejection is increasingly recognised within the transplantation community as a cause or contributing factor in the rejection of transplanted organs. The humoral immune response towards allografts involves B cells that, after T cell dependent activation, can differentiate into antibody producing cells. Whereas there are several therapeutic entities to treat cellular rejection, at present, no standard treatment for humoral rejection exists. The first part of this thesis describes the effects of different maintenance immunosuppressive drugs directly on B cells, as well as the effect on T cell help in vitro. The data presented in these chapters show differential effects of the drugs on B cells and T cell help. Furthermore, the effects of novel, experimental drugs on the in vitro activation of B cells are described. The second part of this thesis describes the development of a novel technique for monitoring the humoral alloimmune response. By using this technique, patients at risk for humoral rejection may be identified. The last part describes the difficulties and pitfalls of monitoring T cells that respond to alloantigen via the indirect pathway of allorecognition. In an alloimmune response, these are the T cells that provide help to B cells to become fully activated.Symbio Herborn Group, Stichting NRC, Astellas Pharma B.V., Novartis Pharma B.V., Baxter B.V., BD Biosciences, Greiner Bio-One, VPS Diagnostics, Clean Air Techniek B.V., Genome Diagnostics, Millipore B.V. and Corning B.V.UBL - phd migration 201
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Predicting outcome of acute kidney transplant rejection using
Get PDFAcute kidney transplant rejection is an important risk factors for adverse graft outcome. Once diagnosed, it remains difficult to predict the risk of graft loss and the response to anti-rejection treatment. The aim of this thesis was to identify biomarkers during acute rejection, which predict the response to corticosteroid therapy and renal allograft survival. We demonstrated that steroid resistance is a multifactorial condition, in which both immunological and non-immunological factors are involved. Response to steroid therapy correlates with the expression level and characteristics of allograft infiltrating T cells and macrophages, indicating that steroid resistance resides in specific cell populations and is not a feature of all lymphocytes. In addition, zinc regulation plays a role in the response to corticosteroids. Increased expression of zinc-regulating molecules may diminish the zinc-requiring anti-inflammatory effects of corticosteroids. Therefore, kidney transplant recipients may benefit from additional zinc intake to optimize steroid signaling. Furthermore, we demonstrated that a multivariate prediction model, containing biomarkers related to different aspects of corticosteroid signaling, offers the best prognostic value for assessing steroid response. Finally, we demonstrated that determination of S100A8 and S100A9 expression levels in renal allograft tissue can be used for assessing the risk of renal allograft loss over time.UBL - phd migration 201
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