Cellular trafficking in haematological and immunological disorders

Abstract

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 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.