The homing of both immune cells and their malignant counterparts is, amongst others, determined by the interaction between locally produced chemokines and their corresponding receptors. In this... Show moreThe homing of both immune cells and their malignant counterparts is, amongst others, determined by the interaction between locally produced chemokines and their corresponding receptors. In this thesis we have addressed the involvement of distinct chemokine/chemokine receptor combinations in directing this cellular trafficking to specific organs. First, their role in the migration of leukaemic cells to extramedullary sites was investigated. Additionally, chemokine-guided T cell migration was studied in a patient with an inherited immunodeficiency (Omenn Syndrome), characterised by generalised erythrodermia of the skin. Allogeneic haematopoietic stem cell transplantation (HSCT) is the treatment of choice for both Leukaemia and Omenn Syndrome. A major drawback of this treatment is the occurrence of Graft-versus-Host Disease (GvHD). This complication results from migration of activated donor T cells to skin, liver and gut, where these cells induce inflammation and life threatening tissue destruction. We have investigated which chemokine/chemokine receptor interactions facilitate this migration to GvHD-affected skin in acute GvHD and also looked into the involvement of mHag-specific T cells in the onset of acute GvHD after gender mismatched HSCT. Finally, we studied chemokine receptor expression by T cells in chronic GvHD patients (a long-term complication of allogeneic HSCT) with fasciits as main clinical feature. Show less
This thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis... Show moreThis thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis of potential improvements in risk stratification and possible treatment adaptation, in order to decrease relapse frequency and disease-related death. Firstly, to study the role of chemokine receptor/ligand interactions in the context of extramedullary leukaemia, we analyzed the homing receptor expression on leukemic blast cells in skin or intestine, peripheral blood and bone marrow of patients with T-ALL en AML, respectively. Secondly, the treatment results of 132 children, who received an allogeneic HLA-identical SCT for acute leukaemia was evaluated, showing the effect of biologically effective TBI dose on relapse risk. Thirdly, to optimize the use of Cyclosporin A(CsA) for adequate Graft-versus-host disease(GVHD) prophylaxis and to avoid drug toxicity, we investigated the pharmacokinetics of CsA in children after SCT, and showed that monitoring CsA exposure early after SCT may provide a tool to influence outcome. Finally, to gain a better understanding of the mechanism of chimerism induction of endothelial and epithelial cells following allogeneic SCT, the occurrence of chimerism in relation to the conditioning regimen, time interval after SCT and development of GVHD was studied. Show less
