Thesis (M.S.)--University of Wisconsin-Madison, 1993. / Typescript. Appendix B in Chinese. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 70-78).

Acute and chronic rejection continue to be the most important problems in maintaining a functioning organ allograft. Despite advances in immunosuppression, organs are still damaged or destroyed by the recipient's immune system. In order to protect the transplanted organ it is necessary to overwhelm the host's immune system and thus expose the host to the complications of invasion from fungi, bacteria, protazoa, reduction in oncologic surveillance, and reduction of stem cell production. Donor specific immunosuppression would provide graft protection and allow maintenance of the host's immunologic competence. Graft enhancement has been described for many years. Current practice uses this principle by pretransfusing prospective kidney transplant recipients with type specific blood. Previous work has supported the concept that this clinical effort can be produced by certain cells in the blood, specifically, lymphocytes. To study the effects of preimmunization with T or B lymphocytes and platelets in a rat heterotopic heart transplant model, the following experiments were performed. Experiment 1: The effect of pretransplant immunization with lxlO7 donor specific T cells or B cells showed that T cells have little affect on rejection of heterotopic heart allograft and B cells caused prolongation of graft function. This effect is species specific and not due to a pure anti-idiotype phenomenon. Experiment 2: The effect of heating the purified T and B cells at 56°C for 30 minutes is known to denature the presenting protein antigens on the cell membranes without destroying the cell membrane. After pretransplant immunization, seven days prior to heterotopic heart transplant in the rat model, the previously observed prolongation of graft survival after nonheated B cell immunization was still present but not as marked. Experiment 4: The effect of pretransplant immunization of donor specific T and B cells treated by heating to 85°C for 10 minutes followed by heterotopic heart graft showed that there was a significant prolongation of the engrafted heart following immunization with the denatured B cells. Cellular proteins are denatured by this pretreatment but polysaccharides are not. Experiment 5: The effect of pretransplant immunization with purified donor specific platelets followed by heterotopic heart rat transplant showed no prolongation or shortening of graft survival. It is concluded that, in the heterotopic rat heart transplant model, immunization with purified T cells 7 days prior to transplant has little effect on rejection. When B cells are immunized in the same way, graft survival is prolonged. If the cells are heated to 56°C for 30 minutes this effect is reduced but not eliminated. This effect indicates that denaturation of protein HLA antigens on the presenting cell surface reduces the enhancing effect of the intact antigens on B cells. By denaturing, the presenting B cell protein graft enhancement is still present, suggesting the phenomenon of graft enhancement is not totally dependent on protein antigens but may have a contribution from mucopolysaccharides or other carbohydrates. Donor specific purified platelet pretransplant immunizations produced no statistically significant prolongation of either PV6 or F₁ heart grafts. This observation is consistent with the findings that purified T cell immunization do not produce graft enhancement. / Surgery, Department of / Medicine, Faculty of / Graduate

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Hyperlipidemia is prevalent following heart transplantation, and may play a role in the development of late graft atherosclerosis. The charts of 35 heart transplant recipients (n = 32 males and 3 females) were reviewed retrospectively up until three years post transplantation, to describe a time-course of hypercholesterolemia after transplantation, and to determine the mechanisms involved in its pathogenesis. All patients received prednisone, cyclosporine, and azathioprine for immunosuppression. A progressive rise in both serum cholesterol (2.4 $ pm$ 0.4 mmol/l, p $<$ 0.01), and body weight (8.4 $ pm$ 1.6 kg, p $<$ 0.01) were observed during the first 8 and 10 months respectively. Levels stabilized thereafter, remaining above pretransplant levels. Triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations were all above normal limits following transplantation. Tapering of prednisone dose had a significant effect on serum cholesterol levels, whereas diet had a beneficial effect on body weight. A randomized, controlled, dietary intervention study then followed to further assess the effect of dietary intervention on minimizing or preventing post transplantation hyperlipidemia and weight gain. Five patients were counselled the Step One Lipid-Lowering diet, two patients were controls. All study patients demonstrated a lower overall increase in serum cholesterol levels than other transplant recipients. Reported nutritional intakes were similar between both groups. Increases in body weight were related to increases in body fat. Patients in the diet group demonstrated improvements in their level of nutrition knowledge, which correlated with lower serum cholesterol levels. Changes in serum cholesterol were also associated with appetite, hunger, perceived interest, perceived benefits, perceived barriers, and attitudes toward food. Changes in body weight were associated with appetite, hunger, perceived barriers, and stress. As

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Background Organ donation may occur after death determination by neurological criteria or by circulatory criteria (DCC). This thesis evaluates two controversial practices specific to DCC: (1) antemortem heparin administration to DCC donors with the aim of improving organ function, and (2) cardiac donation after DCC, which has not yet been adopted in Canada. Objectives (1) Describe antemortem heparin practices in DCC and explore its effects on transplant outcomes. (2) Describe the opinions, concerns, and insights of Canadian healthcare providers and the public regarding cardiac DCC. Methods Project 1: Systematic review and meta-regression analysis of published studies examining antemortem heparin in DCC donation. Projects 2 and 3: A qualitative interview study to evaluate the perspectives of healthcare providers and a mixed methods study involving focus groups with members of the Canadian public. Results Project 1: We found broad variability in the dosing and timing of heparin administration in DCC. While there were no clinical trials, meta-regression analysis detected no benefit to antemortem heparin in liver transplantation. Projects 2 and 3: Among healthcare providers, we found broad support for cardiac DCC but concerns about potential lack of support by the public. Among members of the public, we found majority support for cardiac DCC with priorities including respect for the wishes of dying individuals and ensuring that they are treated with dignity. Conclusions While preliminary results failed to demonstrate the benefit of antemortem heparin administration to DCC donors, high-quality clinical trials are needed to better evaluate the risks and benefits. Regarding cardiac DCC, despite healthcare providers’ concerns about lack of public support, most public stakeholders engaged in our study were supportive. The multi-modal approach of this thesis may serve as a model for evaluating other controversial practices in deceased organ donation. / Thesis / Candidate in Philosophy / Organs that are donated and transplanted from deceased individuals save thousands of lives every year. Some organs are donated after death by circulatory criteria (i.e., after the heart has stopped beating). We evaluated two controversial practices in organ donation after death is determined by circulatory criteria: (1) giving heparin, a blood thinner, just before death, and (2) heart donation after death is determined by circulatory criteria. In Project 1, our review of existing literature showed broad differences in heparin use around the time of death and heparin had no benefits on liver transplant outcomes. In Project 2, we found that healthcare providers and members of the public supported heart donation after death is determined by circulatory criteria but expressed concerns that are important to consider when establishing heart donation programs. Our approach of using multiple methods to evaluate practices in organ donation can serve as one model for evaluating other controversial practices in organ donation.

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Primarily expressed by trophoblast cells, human leukocyte antigen-G (HLA-G) plays an essential role in maintaining maternal-fetal immune tolerance. Having previously been detected following heart transplantation, we sought to establish the value of HLA-G in identifying freedom from moderate or severe rejection post-heart transplant, and the capability of its expression in vitro. After assessing myocardial HLA-G expression through immunohistochemistry, we demonstrated that it was significantly more prevalent in non-rejecting than rejecting heart transplant recipients. Utilizing vascular endothelial and smooth muscle cell culture models, we also determined that while HLA-G expression remains tightly regulated, its expression in vitro can be induced following progesterone treatment in a dose-dependent manner. Hence, HLA-G may reliably identify patients with a low immunological risk of developing subsequent clinically significant rejection post-heart transplant. Furthermore, HLA-G expression can be induced in cultured endothelial and smooth muscle cells, which might represent a strategy to protect against allograft rejection and vasculopathy.

Primarily expressed by trophoblast cells, human leukocyte antigen-G (HLA-G) plays an essential role in maintaining maternal-fetal immune tolerance. Having previously been detected following heart transplantation, we sought to establish the value of HLA-G in identifying freedom from moderate or severe rejection post-heart transplant, and the capability of its expression in vitro. After assessing myocardial HLA-G expression through immunohistochemistry, we demonstrated that it was significantly more prevalent in non-rejecting than rejecting heart transplant recipients. Utilizing vascular endothelial and smooth muscle cell culture models, we also determined that while HLA-G expression remains tightly regulated, its expression in vitro can be induced following progesterone treatment in a dose-dependent manner. Hence, HLA-G may reliably identify patients with a low immunological risk of developing subsequent clinically significant rejection post-heart transplant. Furthermore, HLA-G expression can be induced in cultured endothelial and smooth muscle cells, which might represent a strategy to protect against allograft rejection and vasculopathy.