This thesis emphasizes the presence of minor H antigen specific immune responses directly after birth, which will be present throughout life. The presence of minor H antigen mismatched... Show moreThis thesis emphasizes the presence of minor H antigen specific immune responses directly after birth, which will be present throughout life. The presence of minor H antigen mismatched microchimeric cells obtained through pregnancy from a mother or a child play a crucial role in this. Subsequent immunization against minor H antigens can lead to both cytotoxic and tolerogenic responses. Furthermore HA-1 specific T cells can share the same TCR Vbeta, yet being functionally different. The here performed studies enhances our understanding of immune reactions after HSCT and if applicable after renal transplantation, especially regarding the birth order effect and the assumed less favourable role of women as transplant donors. Show less
Rood, J.J. van; Claas, F.H.J.; Brand, A.; Tilanus, M.G.J.; Kooten, C. van 2014
Currently, there is no treatment available that restores anatomy and function after spinal cord injury. This thesis explores transplantation of bone marrow-derived mesenchymal stem cells (bone... Show moreCurrently, there is no treatment available that restores anatomy and function after spinal cord injury. This thesis explores transplantation of bone marrow-derived mesenchymal stem cells (bone marrow stromal cells; BMSCs) as a therapeutic approach for spinal cord repair. BMSCs secrete neurotrophic factors, enabling neuroprotection/tissue sparing in a rat model of spinal cord injury. In this model system, bone marrow stromal cell-mediated tissue sparing leads to motor and sensory function improvements. Moreover, we show that BMSCs__ neuroprotective ability can be enhanced by genetically modifying the cells to overexpress brain-derived neurotrophic factor. However, survival of BMSCs in the injured spinal cord is poor and limits their repair capacity. We investigated the effect of three immunosuppressig agents, Minocycline, Methylprednisolone and Cyclosporine, on macrophage suppression and BMSC survival. All three d rugs effectively reduced the macrophage response, without improving transplanted BMSC survival. Transplanting the cells within the reverse thermal gel ESHU, did significantly improve BMSC survival which was associated with increased tissue sparing and improved functional recovery. These effects are likely due to ESHU__s anti-oxidative properties. Future research will need to focus on combinations of neuroprotective BMSC transplants with axonal regenerating promoting therapies to further optimize BMSC-based therapy for spinal cord injury. Show less
The studies in this thesis describe the systematical search for factors involved in the pathophysiology of human renal I/R injury. Many of the processes assumed to be involved in renal I/R injury... Show moreThe studies in this thesis describe the systematical search for factors involved in the pathophysiology of human renal I/R injury. Many of the processes assumed to be involved in renal I/R injury based on animal studies could not be confirmed in our clinical study in humans. However, we found new evidence of complement activation and endothelial cell activation in human renal I/R injury. Moreover, there were large differences between deceased and living donor kidneys; brain dead donor kidneys have a unique proinflammatory cytokine release after reperfusion. Finally it appears that both brain dead and cardiac dead donor kidneys are not able to upregulate their metabolism-related genes upon reperfusion as living donor kidneys do, indicating that failure to restart metabolism may be a factor expanding I/R injury. All of these findings contribute to the understanding of renal I/R injury in humans and instigate the further search for therapeutical modalities to limit renal I/R injury. Show less
Ringers, J.; Torren, C.R. van der; Linde, P. van de; Boog, P.J.M. van der; Mallat, M.J.K.; Bonifacio, E.; ... ; Fijter, J.W. de 2013
Transplant recipients generally require lifelong treatment with immunosuppressive medication to prevent rejection of the graft by their immune system. Inhibitors of the enzyme calcineurin,... Show moreTransplant recipients generally require lifelong treatment with immunosuppressive medication to prevent rejection of the graft by their immune system. Inhibitors of the enzyme calcineurin, including cyclosporin A and tacrolimus, constitute a very potent class of immunosuppressants that has revolutionized transplant medicine. However, their reputation has been showing cracks due to the severe side-effects associated with long-term use of these drugs, including an explosively increased risk of developing skin cancer. The pathophysiological mechanism of this phenomenon is not known, although a number of hypotheses have been put forward. In this dissertation, we show that oxidative stress, mainly derived from exposure to UVA radiation, may locally augment the effects of the calcineurin inhibitors; we propose that overly strong suppression of calcineurin activity may result in malignancy formation due to disruption of tumor-suppressive signaling pathways or disturbed immunosurveillance in skin. Show less
Pancreas transplantation and islet of Langerhans transplantation are potential solutions to treat patients with type 1 diabetes. However, pancreas grafts are scarce and there is a shortage of donor... Show morePancreas transplantation and islet of Langerhans transplantation are potential solutions to treat patients with type 1 diabetes. However, pancreas grafts are scarce and there is a shortage of donor pancreata relative to the number of patients needing a transplant. The aim of this thesis was to further optimize pancreas graft survival in pancreas transplantation and to optimize islet isolation outcomes in islet of Langerhans transplantation, leading to better use of available organs. The focus in pancreas transplantation should be on optimizing recipients to improve graft survival and on improving quality of pancreata procured by centers not performing pancreas transplantation (for example, by training procurement surgeons to optimize pancreas procurement, thereby increasing the number of transplantable organs. In islets transplantation, it is recommended that the reporting of donor, pancreas and isolation factors should become more standardized, which would enable us to determine more accurately which factors are important predictors for islet isolation outcome. Furthermore, if more biomedical factors (e.g. the presence of hyperemic islets) would be reported in addition to the other factors, we would be able to assess the independent effect of these biomedical factors for islet isolation outcome and eventually the effect on islet transplantation in the clinical setting. Show less
