Browsing by Subject "Transplantation"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Analysis Of Human Leukocyte Antigen (HLA) Immunogenetic Data For Hematopoietic Stem Cell Transplantation And Disease Association
    (2014-12) Gragert, Loren
    The Major Histocompatibility Complex (MHC) of chromosome 6 is the most polymorphic region of the human genome, and is also under very strong selection pressure, resulting in genetic divergence of immune gene variants between human populations. The human leukocyte antigen (HLA) genes located in the MHC region play a central role in the immune system as HLA proteins distinguish self from non-self through antigenic peptide presentation to T-cells. Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many patients with hematologic diseases, but successful transplant requires a high degree of HLA matching between donor and recipient. Unfortunately, HLA-matched donors are not available for all patients. HLA diversity is vast as millions of unique HLA genotypes have been observed worldwide, many of which have high privacy to specific human populations. In response to this HLA-matching challenge, large registries of unrelated donors have been constructed worldwide to provide HLA-matched HSCT to patients. Even with large registries, minority and admixed race/ethnic groups in the United States have lower likelihood than European-Americans of finding an HLA match. Legacy high-throughput HLA typing methods give high levels of typing ambiguity at recruitment, resulting in a lack of initial confirmation that a suitable match exists. Current population genetics techniques fall short in addressing the unique challenges of stem cell registry analytics, resulting in a difficult search process for some patients. This thesis describes new techniques developed to analyze immunogenetics data with direct operational application in the registry setting. Advancement in computational techniques in population genetics to better handle HLA typing ambiguity has improved calculation of HLA haplotype frequencies, prediction of allele-level HLA typing for subjects with typing ambiguity in registry matching algorithms, and projection of HLA match likelihoods as registries expand. These advances have had direct operational impact for National Marrow Donor Program (NMDP) through more rapid identification of suitably-matched donors and optimized allocation of resources in order to serve more patients, especially in underserved minority groups. These computational techniques have also enabled more detailed evaluation of immunogenetic associations with disease, which may lead to new avenues for treatment for cancer and autoimmune diseases.
  • Thumbnail Image
    Item
    Ethics of organ transplantation
    (University of Minnesota, Center for Bioethics, 2004-02) University of Minnesota: Center for Bioethics
  • Thumbnail Image
    Item
    Extending Function and Applications of Isolated Cardiopulmonary Systems
    (2016-11) Howard, Brian
    The use of isolated mammalian hearts has a history that is responsible for a staggering amount of the basic physiological knowledge we have about the cardiovascular system and is a primary gateway between ideas and clinical treatment. Advances in cardiac physiology, surgery, transplantation, pacing, defibrillation, ablation, and pharmacology are derived from this area of research. The work outlined here takes identified issues with experimental preparations, as well as clinical applications, to investigate solutions and directions for their systematic address. Extending the utility and window of viability of the isolated heart and lungs has resulted in clinically applicable advances in drug treatments and assessment tools. Most importantly though, it has the potential to expand the population of acceptable donor organs where there is immediate need and continuous shortfall in supply. My thesis consists of chapters which progress in translational application, making use of novel and comprehensive ways of controlling and investigating isolated cardiovascular systems. In the first chapter, the Visible Heart® preparation is used to replicate and extend a classic temperature experiment in the large isolated porcine heart. This chapter also addresses the clinical applications of optimizing heart function with emerging isolated heart transportation devices; making the best use of efforts to assess and maintain the heart for transplantation. This is followed in chapters 2 using the Visible Heart® system to assess therapeutic drug delivery for treating atrial fibrillation and again preserving a heart’s function for transplantation. The advancement of the isolated heart preparation is further driven by procedural concerns with cryo-ablation technologies to include functional lungs. This comprehensive system is used on actual human heart lung-bloc combinations for investigative purposes and required its own set of unique engineering solutions to produce a viable test platform. It is also this evolution of the isolated heart preparation that was a significant factor in bringing the Lung Organ Care System (OCS™) to the Visible Heart Laboratory as a unique research tool. As a commercial device, the OCS™ device seeks to replace the storage-on-ice standard of care with warm and ventilated perfusion of the lungs independent of the heart. As a laboratory instrument it has allowed new opportunities for investigating both basic lung physiology as well as providing lessons that are clinically applicable. The completely novel thermal monitoring of the lungs in this isolated state are discussed in Chapter 5 which investigates thermal tools and profiling of lung damage for the first time. This provides a whole new paradigm for emerging lung and general organ assessment directly relating identified injury states, overall lung function, and recovery/damage profiles that may help physicians make better use of precious donor lungs. In extending the use of the isolated lungs to an underutilized population of donors, the final chapter, Chapter 6, demonstrates for the first time a controlled study and injury model for donation after cardiac death (DCD). With modification to the current clinical use protocol for the OCS™ device, the viability window for injured lungs is shown to be nearly tripled. The impact of demonstrating viable DCD lungs on this system is the potential to greatly expand the number of lungs for transplantation, which would be invaluable to many currently on a long wait list. My thesis work has produced stable isolated cardio-vasculature systems with direct impact on the design of devices, investigation, therapy and monitoring in the pursuit of bettering the standard of care and expanding the availability of the organs for transplantation. It provides new and unique combinations of heart and lungs tailored to the investigative necessity in human anatomy and a more comprehensively described large mammalian model for anatomy, physiology and acute injury.
  • Thumbnail Image
    Item
    Improving hematopoietic cell transplantation therapeutics:emphasis in pharmacokinetic-pharmacodynamic relationships and pharmacogenomics.
    (2009-12) Long-Boyle, Janel Renee
    Treatment-related mortality and acute graft vs host disease remain prominent clinical problems in nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Hence, the need for improved preparative regimens and immunosuppressive strategies in HCT persists. The research presented in my dissertation will be focused on defining pharmacokinetic-pharmacodynamic relationships, and pharmacogenomics involving two antineoplastic agents, fludarabine and clofarabine, and the immunosuppressive agent, mycophenolate all of which are used in the setting of HCT. Fludarabine is a purine analog commonly used in both adult and pediatric nonmyeloablative allogeneic HCT. Although the pharmacokinetics of fludarabine have been extensively studied in a variety of malignant diseases, very little data is available in nonmyeloablative HCT and the relationship between fludarabine pharmacokinetic parameters and clinical outcomes such as treatment-related mortality have yet to be evaluated. Similarly, no PK data is available for clofarabine; a newer purine analog currently used pediatric patients undergoing HCT for non-hematologic malignancies. Finally, mycophenolic acid pharmacokinetics in HCT recipients displays wide inter- and intra-patient variability in plasma concentrations and low mycophenolate exposure is associated with lower rates of engraftment and greater risk of acute graft vs host disease. Patient characteristics such as weight or body surface area, or clinical markers for hepatic and renal function incompletely explain pharmacokinetic variability suggesting there may be genetic factors influencing mycophenolate metabolism or transport. The methodologies and techniques employed to evaluate each individual agent will differ, including pharmacokinetic and statistical analyses. However, all projects share the common goal of improving patient outcomes and reducing toxicity in this very complex patient population.
  • Thumbnail Image
    Item
    An Investigation of the Role of Psychological Altruism in Living Kidney Donors
    (2015-05) McLaughlin, Michaela
    Altruism is the selfless concern for the wellbeing of others. Multiple researchers have investigated altruism in the general population, but altruism has not been measured in living kidney donors. This study assessed the altruism of 168 living kidney donors, a representative sample from the University of Minnesota Kidney Donor Transplant Program. Three scales measured altruism (Helping Attitudes Scale, Self-Report Altruism Scale, and Altruism and Gift Giving Battery). Participants also responded to items eliciting their suggestions about questions to assess altruism in living kidney donors. Statistical analyses revealed the present sample had significantly higher altruism scores than normative samples on the Helping Attitudes Scale and Self-Report Altruism Scale. There were no significant differences in altruism scores for living related donors (n = 86.5, 62.9, 39.4) versus living unrelated donors (n = 88.5, 66.1, 38.5). Factor analysis of responses to items on the altruism scales yielded four factors: Physical help to stranger; Gifts; Volunteerism rewards; and Risk/ sacrifice in helping. Logistic regression indicated likelihood of being a living unrelated donor increased if participants scored lower on Volunteerism rewards, higher on Risk/sacrifice in helping, and they were older. Content analysis of participants’ responses regarding questions to assess altruism yielded six themes: Questions regarding the donor’s cultural ideas of giving; Questions regarding how much risk and discomfort one is willing to endure for another; Comments regarding personal family obligation or selfish motivation; Questions regarding the donor’s emotional expectations post-donation; Questions regarding the financial and long-term health cost to the donor; and Questions will not capture the true motivation as the decision to donate comes without hesitation. Additional findings and practice, policy and research directions are presented.