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 KCa3.1 and Kv1.3, 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 (KCa3.1 inhibitor; 120 mg/kg d) plus Stichodactyla helianthus toxin (ShK, Kv1.3 inhibitor; 80 μg/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 KCa3.1 and Kv1.3 channels may represent a novel alternative therapy for prevention of kidney allograft rejection.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2601-2606 |
| Number of pages | 6 |
| Journal | Transplantation Proceedings |
| Volume | 41 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jul 2009 |
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ASJC Scopus subject areas
- Surgery
- Transplantation
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Blockade of T-Lymphocyte KCa3.1 and Kv1.3 Channels as Novel Immunosuppression Strategy to Prevent Kidney Allograft Rejection. / Grgic, I.; Wulff, Heike; Eichler, I.; Flothmann, C.; Köhler, R.; Hoyer, J.
In: Transplantation Proceedings, Vol. 41, No. 6, 07.2009, p. 2601-2606.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Blockade of T-Lymphocyte KCa3.1 and Kv1.3 Channels as Novel Immunosuppression Strategy to Prevent Kidney Allograft Rejection
AU - Grgic, I.
AU - Wulff, Heike
AU - Eichler, I.
AU - Flothmann, C.
AU - Köhler, R.
AU - Hoyer, J.
PY - 2009/7
Y1 - 2009/7
N2 - 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 KCa3.1 and Kv1.3, 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 (KCa3.1 inhibitor; 120 mg/kg d) plus Stichodactyla helianthus toxin (ShK, Kv1.3 inhibitor; 80 μg/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 KCa3.1 and Kv1.3 channels may represent a novel alternative therapy for prevention of kidney allograft rejection.
AB - 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 KCa3.1 and Kv1.3, 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 (KCa3.1 inhibitor; 120 mg/kg d) plus Stichodactyla helianthus toxin (ShK, Kv1.3 inhibitor; 80 μg/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 KCa3.1 and Kv1.3 channels may represent a novel alternative therapy for prevention of kidney allograft rejection.
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U2 - 10.1016/j.transproceed.2009.06.025
DO - 10.1016/j.transproceed.2009.06.025
M3 - Article
VL - 41
SP - 2601
EP - 2606
JO - Transplantation Proceedings
JF - Transplantation Proceedings
SN - 0041-1345
IS - 6
ER -