Hochregulation Ca2+ aktivierter K+ Kanäle in humanen T-Lymphozyten bei akuter Nierentransplantatrejektion

Die Nierentransplantation ermöglicht terminal niereninsuffizienten Patienten ein Leben unabhängig von der Dialyse. Eine häufige und sowohl klinisch als auch ökonomisch relevante Komplikation der Transplantation stellt jedoch die akute Transplantatrejektion dar, die innerhalb von Wochen bis Monaten n...

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Bibliographic Details
Main Author: Kämpfe, Doris
Contributors: Hoyer, Joachim (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2009
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Table of Contents: Acute rejection is a major prognostic factor for long term renal transplant survival. A reliable, sensitive, and specific early marker for acute rejection is still missing. In the cellular mechanism of the immune response, up-regulation of K+channel functions is an early and crucial step in the activation of T-lymphocytes by promoting membrane potential-driven Ca2+-influx and cell proliferation. In the present study it was tested whether K+ channel function is altered after renal transplantation. Methods: 46 patients were studied longitudinally after renal transplantation for a follow-up period of 21 days. 6 of these patients developed acute renal allograft rejection as determined by histologic analysis of renal biopsies. In addition we includes 5 other patients who were hospitalised within the study period due to an acute renal allograft rejection. Functional expression of the K+ channels in T-lymphocytes from peripheral blood was analysed before transplantation, and on predefined days 1, 3, 7 and 14 up to 21 days after transplantation, and during acute rejection on day 0, 2 and 6 by use of the patch-clamp technique. Results: T-lymphocytes expressed two types of K+-channels with the characteristics of the voltage-gated K+-channel (Kv1.3) and the intermediate-conductance Ca2+-activated K+-channel (IKCa). The Kv1.3 current was found to be the predominat K+-current in T-lymphocyts of healthy individuals as well as in patients with chronic kidney disease before transplantation. The IKCa current component was low. After renal transplantation IKCa functions remained constant in T-lymphocytes from patients without acute renal allograft rejection. In contrast, in T-lymphocytes from patients with acute renal allograft rejection, we observed a significant increase in IKCa -currents. IKCa function returned to the level before rejection after immunosuppressive therapy. Regarding the Kv1.3 current we saw a significant increase in T-lymphocytes from patients without acute renal allograft rejection. In T-lymphocytes from patients with acute allograft rejection the Kv1.3 function remained constant until the day of the rejection. At this point we also observed a significant increase of the Kv1.3 current. Comparing the two groups before transplantation it could be shown that the group without rejection showed a slight but significant upregulation of the IKCa-function. Conclusion: The steep up-regulation of IKCa -currents in T-lymphocytes from patients developing acute renal allograft rejection could serve as a new diagnostic marker. Moreover, blockade of the IKCa by highly selective inhibitors might represent a new pharmacotherpeutical strategy in the prevention of acute renal allograft rejection.