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DOI: 10.1055/s-0031-1297427
The intermediate-conductance potassium channel as a potential new target for the prevention of airway allograft rejection
Aims: The intermediate-conductance potassium channel KCa3.1 is expressed and up-regulated in activated lymphocytes and proliferating vascular smooth cells and fibroblasts.
Methods: Tracheas from CBA donors were heterotopically transplanted into the greater omentum of C57/Bl6 mice. Recipients in the treatment group received TRAM-34 (120mg/kg/d i.p.) for 5 days (for acute rejection study) or 28 days (for chronic rejection study). KCa3.1-/- mice were used as control (KO-group). Histopathology was used to determine the degree of luminal obliteration. Cellular immune response was evaluated by Elispots and immunohistochemistry of grafts for CD3+ cells. The role of KCa3.1 channels in cell proliferation and activation was investigated in vitro in smooth muscle cells (SMCs) and fibroblasts.
Results: Elispots showed significantly reduced IFNg and IL4 spot frequencies in the KO (IFNg: 68, IL4: 13) and TRAM-34 (IFNg: 74, IL4: 4) groups compared to the untreated allogeneic group (IFNg: 124, IL4: 19) (IFN: p≤0.015 untreated vs. KO/TRAM34; IL4: p=0.005 untreated vs. TRAM34). Immunohistochemistry revealed significantly reduced CD3+ cells in the KO and TRAM34 groups (1568 and 1647 cells/mm2 compared to 3835 the untreated group; p<0.001). Luminal obliteration was significantly inhibited in the KO-and TRAM-34-groups compared to the untreated allogeneic grafts (p≤0.032). There was no significant difference between KO-and TRAM-34-groups. KCa3.1 channels were found up-regulated in SMCs and fibroblasts after stimulation, and TRAM-34 potently inhibited cell proliferation in vitro.
Conclusions: Our findings suggest that KCa3.1 channels are involved in the systemic immune response after transplantation and the development of OAD, identifying KCa3.1 as therapeutic target.