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. 2009 Jul-Aug;41(6):2601-6.
doi: 10.1016/j.transproceed.2009.06.025.

Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection

I Grgic  1 , H Wulff, I Eichler, C Flothmann, R Köhler, J Hoyer
Affiliations

Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection

I Grgic et al. Transplant Proc. 2009 Jul-Aug.

Abstract

Currently, there is an unmet clinical need for novel immunosuppressive agents for long-term prevention of kidney transplant rejection as alternatives to the nephrotoxic calcineurin inhibitor cyclosporine (CsA). Recent studies have shown that K(+) channels have a crucial role in T-lymphocyte activity. We investigated whether combined blockade of the T-cell K(+) channels K(Ca)3.1 and K(v)1.3, both of which regulate calcium signaling during lymphocyte activation, is effective in prevention of rejection of kidney allografts from Fisher rats to Lewis rats. All recipients were initially treated with CsA (5 mg/kg d) for 7 days. In rats with intact allograft function, treatment was continued for 10 days with either CsA (5 mg/kg d), or a combination of TRAM-34 (K(Ca)3.1 inhibitor; 120 mg/kg d) plus Stichodactyla helianthus toxin (ShK, K(v)1.3 inhibitor; 80 microg/kg 3 times daily), or vehicle alone. Kidney sections were stained with periodic acid-Schiff or hematoxylin-eosin and histochemically for markers of macrophages (CD68), T-lymphocytes (CD43), or cytotoxic T-cells (CD8). Our results showed that treatment with TRAM-34 and ShK reduced total interstitial mononuclear cell infiltration (-42%) and the number of CD43+ T-cells (-32%), cytotoxic CD8+ T-cells (-32%), and CD68+ macrophages (-26%) in allografts when compared to vehicle treatment alone. Efficacy of TRAM-34/ShK treatment was comparable with that of CsA. In addition, no visible organ damage or other discernible adverse effects were observed with this treatment. Thus, selective blockade of T-lymphocyte K(Ca)3.1 and K(v)1.3 channels may represent a novel alternative therapy for prevention of kidney allograft rejection.

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Figures

Figure 1
Figure 1
Increased expression of KCa3.1 and Kv1.3 channels in LEW T-lymphocytes after MLR (stimulated for 4 days with irradiated F344 splenocytes). (A) Representative traces of Kv1.3 and KCa3.1 currents in unstimulated LEW rat T-cells (upper panel) and after allogeneic stimulation (lower panel). Voltage-dependent Kv1.3 currents were sensitive to ShK and the voltage-independent KCa3.1 current component was sensitive to the selective KCa3.1 blocker TRAM-34. (B) Quantification of KCa3.1 and Kv1.3 channel numbers per cell in stimulated and unstimulated T-cells. Data are given as mean ± SEM.
Figure 2
Figure 2
Inhibition of KCa3.1 and Kv1.3 channels suppresses LEW/F344 MLR. The plot shows dose-dependent effects of TRAM-34 and ShK and of the combination of both on [3H]-thymidine incorporation after 5 days of MLR. Data are given as mean ± SD, n = 3 for each data point.
Figure 3
Figure 3. In vivo blockade of KCa3.1 and Kv1.3 inhibits mononuclear cell infiltration into renal allografts in vivo
(A) Left panel: Photographs display representative areas of PAS-stained cross sections from rat kidney grafts seventeen days after transplantation (magnification ×400). Note reduced tubulointerstitial infiltrates in allografts from TRAM-34/ShK- and CsA-treated animals compared to vehicle-treated controls. Right panel: Histopathological evaluation of cross sections from kidney allografts with TRAM-34/ShK (n=7), CsA (n=5), or vehicle (Ve; n=7) treatment. Non-treated animals with isografts (Iso; n=3) served as negative controls. (B) Left panel: Photographs display representative areas of kidney graft cross sections stained for T-cell marker CD43 (W3/13 Ab) seventeen days after transplantation (magnification ×400). Right panel: Histopathological evaluation of cross sections. (C) Histopathological evaluation of sections stained for cytotoxic T-cell marker CD8 (MRC OX-8Ab). Note that CD8+ T-cells were not detectable in isografts. (D) Histopathological evaluation of CD68+ macrophage infiltration (ED1Ab) . Data are given as mean ± SEM; *P<0.05, **P<0.01.
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