Transplantation is the golden standard for the treatment of end-stage renal disease. During this process, the transplanted organ is often damaged. In this thesis, we investigated whether activation... Show moreTransplantation is the golden standard for the treatment of end-stage renal disease. During this process, the transplanted organ is often damaged. In this thesis, we investigated whether activation of the complement system, part of our innate immune system, plays a local role. We reviewed that properdin, the only known positive regulator of the complement system, was detected in serum, plasma and urine from patients with various complement-mediated renal diseases. In protocol biopsies obtained 10 days after transplantation, properdin was found deposited in addition to complement activation markers. Next, we showed that dendritic cells secrete properdin and a decrease in properdin levels during dendritic cell- T-cell interaction resulted in reduced T-cell proliferation and activation. We also showed that properdin is able to bind to surfaces of both viable and dead cells, contributing to complement activation. Macrophages can also produce properdin and negative regulators factor H and its splice variant FHL-1. Increasing knowledge on complement factor production by other cells than hepatocytes, including immune cells, hints towards a local role of the complement system in various processes. These findings contribute to a better understanding of the local role of the complement system and are important for the applications of (new) complement-inhibiting drugs. Show less
The 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... Show moreThe 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. Show less
