Prof. dr. W. Weimar, Prof. dr. Carla C. Baan
After organ transplantation the immune system becomes activated after interaction with donor cells. Induction of specific cytokine- and chemokine expression profiles and cross-talk between various immune competent cells result in effector, regulatory and memory immune mechanisms. Ultimately this will lead to destruction of the grafted organ. Therefore, manipulation of the immune system is necessary for successful organ transplantation. This may be achieved by prescribing immunosuppressive medication, allowing the engraftment. In the clinical organ transplant setting this has resulted in successful short time, but not long term results. Patients still need continual immunosuppression and therefore suffer from enhanced risks of infections, malignancies and cardiovascular mortality, while at the same time chronic allograft loss is not prevented.
The field of clinical transplant immunology focuses on strategies to induce clinical operational tolerance, i.e. drug-free graft survival. For this purpose it is essential to explore in detail the donor-specific effector, regulatory and memory immune responses in relation to graft acceptance and failure. The identification of suppressor cells with donor specific properties has opened an important new area of cellular immunotherapy and individual immunosuppression.
The main theme includes two subthemes:
- Donor specific effector mechanisms and immune tolerance
- Cytokines and chemokines in transplantation
The subthemes covers projects aiming to:
- To investigate donor specific effector T-cells (i.e. cytotoxic T-cells, helper T-cells) in an attempt to understand the immunological pathways leading to success or failure.
- To determine the in vivo induction of tolerogenic regulatory (i.e. CD25+brightFoxp3+) T-cells in organ transplant patients weaned from immunosuppressive medication.
- To study the role of cytokines in anti-donor responses and immune regulation. These molecules affect proliferation, differentiation, death, and the function of cells involved in rejection and operational tolerance.
- To study the role of immunological and non-immunological factors like cold ischemia and reperfusion in the development of chronic allograft dysfunction.
Scientific achievements during the last 5 years:
- Renal and cardiac allograft recipients are hyporesponsive towards donor antigens > 2 years after transplantation.
- Immune reactivity after HLA identical living related kidney transplantation can be analyzed by measuring the number of IFN-g Elispots.
- Immune regulation is the consequence of an immune response. High FOXP3 mRNA levels are measured during allogeneic responses in vivo and in vitro and suggest that regulatory activities of CD25 bright+ T-cells or the generation of these cells is an intrinsic part of activation.
- Immunosuppressive agents to prevent rejection interfere with the induction of FOXP3 mRNA and may actually hinder the development of tolerance.
- Identification of specific chemokine receptors expression profiles in cardiac allograft recipients. Accelerated trafficking of T-cells to the lymphoid tissues via chemokine receptors may increase the risk for rejection.
- The immunosuppressive agents cyclosporine and anti-CD25 monoclonal antibodies hinder the mechanisms by which the immune system eliminates alloreactive cells. They affect apoptotic pathways.
- The frequency of Dendritic Cells (DC) is low and remains low in immunosuppressed allograft recipients.
- Genetic profiles enabled us to identify patients at risk for complications after heart and kidney transplantation.
- Expression levels of HIF-1a, the transcription factor that is induced in the adaptive response to hypoxia and critical for initiating the transcriptional activation of growth factors, correlated with cold ischemia time after kidney transplantation. High mRNA expression levels of cytoprotective genes i.e. heme oxygenase-1 and vascular endothelial growth factor at the moment of transplantation are correlated with graft function early after clinical kidney transplantation.
Future plans: special goals and approach
Tapering the immunosuppressive load is an important issue for transplant patients. In these studies we will focus on suppressor T-cells that regulate basic immune processes and are designed to maintain tolerance. Antigen specific CD4+CD25+brightFoxp3+ regulatory T-cells have emerged as the regulator of immunity to foreign antigens and might therefore be the target for therapeutic intervention and therapy. The objective is to induce operational tolerance in stable allograft recipients by weaning them from the immunosuppressive medication. These autologous Tregs will also be expanded and functionally characterized as a first step to Treg based immunotherapy.
Studies to unravel the mechanism by which the immune system via cytokine pathways trigger graft acceptance. Furthermore, trails with new immunosuppressive agents will be monitored to gain insight in drug related side effects and how the immune system mediates anti-donor responses.