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

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.