Blockade of T-Lymphocyte KCa3.1 and Kv1.3 Channels as Novel Immunosuppression Strategy to Prevent Kidney Allograft Rejection

I. Grgic, Heike Wulff, I. Eichler, C. Flothmann, R. Köhler, J. Hoyer

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2601-2606
Number of pages6
JournalTransplantation Proceedings
Volume41
Issue number6
DOIs
StatePublished - Jul 2009

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Immunosuppression
Allografts
T-Lymphocytes
Kidney
Macrophages
Therapeutics
Periodic Acid
Calcium Signaling
Helianthus
Graft Rejection
Hematoxylin
Eosine Yellowish-(YS)
Immunosuppressive Agents
Complementary Therapies
Lymphocyte Activation
Cyclosporine
TRAM 34

ASJC Scopus subject areas

  • Surgery
  • Transplantation

Cite this

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 journalArticle

Grgic, I. ; Wulff, Heike ; Eichler, I. ; Flothmann, C. ; Köhler, R. ; Hoyer, J. / Blockade of T-Lymphocyte KCa3.1 and Kv1.3 Channels as Novel Immunosuppression Strategy to Prevent Kidney Allograft Rejection. In: Transplantation Proceedings. 2009 ; Vol. 41, No. 6. pp. 2601-2606.
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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.",
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