|Institution:||Technische Universitt Darmstadt|
|Full text PDF:||http://tuprints.ulb.tu-darmstadt.de/6614/|
In the present thesis I examine the effect of ionizing radiation on normal and leukemic immune cells. Stimulation of freshly isolated peripheral blood lymphocytes (PBLs) by mitogens like phytohemagglutinin (PHA-L) or by a specific T-cell activator that crosslinks different clusters of differentiation (CD) causes an immune activation. The latter is associated with a strong increase in the cell diameter. In addition the electrophysiological properties and the ion channel composition of the plasma membrane of PBLs are altered. In the present thesis I show that a similar increase in cell diameter occurs in response to irradiation of immune cells with low doses of X-ray. This indicates that ionizing radiation (IR) triggers a signaling cascade, which results in an immunomodulation or activation of PBLs. This irradiation phenomena was studied here in more detail with Jurkat cells, a T-cell progenitor cell line derived from a patient with acute T-cell leukemia, a specific type of acute lymphatic leukemia (ALL).The data show that IR elicits in these cells a dose dependent increase in cell diameter. The latter is similar to the increase in the cell diameter of PBLs after immune stimulation. The IR induced increase in cell diameter originates from two different sources: one is the IR dependent arrest of the cell cycle in G2, the second one is associated with an immune activation. The second component can also be triggered by external application of hydrogen peroxide (H2O2), a reactive oxygen species (ROS), and inhibited by immunosuppressant drugs like cyclosporine A. The morphological changes in irradiated Jurkat cells are associated with changes in the electrical properties including an upregulation of a calcium dependent potassium channel. Furthermore the expression of the interleukin-2-receptor alpha chain (CD25), which is expressed in activated and regulatory T-cells, was found. Adhesion assays and single molecule microscopy furthermore show that IR also triggers cell-cell and cell-surface adhesion, a process that is mediated by upregulation and clustering of integrin--1 due to IR. All these cellular responses to IR are similar to those found in T-cells after immune activation.The finding that ionizing radiation elicits an increase in cell size in immune cells, enhanced expression of adhesion molecules and altered ion channel composition in the plasma membrane leads to the hypothesis that IR presumably effects an immunological activation or modulation of these cells. This immunomodulation could explain why low dose IR can be beneficial in the treatment of patients suffering from e.g. chronic inflammation and autoimmune diseases like rheumatoid arthritis. Furthermore the finding that integrin--1 mediated adhesion is increased in Jurkat cells after IR could be of importance for the clinical treatment of leukemia patients. Here treatment is often a combination of chemotherapy and radiotherapy. On the background of the present data it is possible that radiation treatment could have previously unknown negative sideAdvisors/Committee Members: Thiel, Gerhard (advisor), Laube, Bodo (advisor).