Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection.
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.
Grgic
I
I
Department of Internal Medicine and Nephrology, University Hospital, Philipps-University, Marburg, Germany.
Wulff
H
H
Eichler
I
I
Flothmann
C
C
Köhler
R
R
Hoyer
J
J
D000818:Animals; D003064:Cnidarian Venoms / Q000494:pharmacology; D006084:Graft Rejection / Q000517:prevention & control*; D007165:Immunosuppression Therapy / Q000379:methods*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D003064:Cnidarian Venoms; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C491575:Kcnn4 protein, rat; D011720:Pyrazoles; C095391:ShK neurotoxin; C411671:TRAM 34; D051662:Kv1.1 Potassium Channel