Targeting the Kv1.3 potassium channel for immunosuppression in vascularized composite allotransplantation - a pilot study

Transpl Int. 2013 May;26(5):552-61. doi: 10.1111/tri.12080. Epub 2013 Mar 15.

Abstract

Kv1.3-channels are critically involved in activation and function of effector memory T cells. Blocking Kv1.3-channels was investigated for its effect on skin rejection in a rat limb-transplantation-model. Animals received the Kv1.3-blocker correolide C systemically or locally as intra-graft-treatment in combination with tacrolimus. Systemic (intraperitoneal) administration of correolide C resulted in slight, but significant prolongation of allograft survival compared with untreated and placebo treated controls. In 4/6 correolide C treated animals, histology showed an intact epidermis and a mild infiltrate by day 10. High correolide C plasma trough levels correlated with prolonged allograft survival. A decrease in CD4+ and CD8+ effector memory T cells was observed in allograft skin, peripheral blood and the spleen on day 5. When applied subcutaneously in combination with systemic tacrolimus (30 days+/-anti-lymphocyte serum) detectable, but insignificant prolongation of graft survival was achieved. 2/5 animals showed an intact epidermis and a mild infiltrate until day 45. Tapering systemic tacrolimus and weaning on day 50 resulted in rejection by day 55, regardless of local correolide C treatment. Subcutaneous injection did not lead to systemic plasma levels. The Kv1.3-channel is a potential drug target worth exploring in more detail for immunosuppression in vascularized composite allotransplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control
  • Graft Survival / drug effects
  • Graft Survival / immunology
  • Hindlimb / blood supply
  • Hindlimb / pathology
  • Hindlimb / transplantation
  • Immunosuppression / methods*
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / blood
  • Kv1.3 Potassium Channel / antagonists & inhibitors*
  • Kv1.3 Potassium Channel / immunology*
  • Male
  • Pilot Projects
  • Potassium Channel Blockers / administration & dosage
  • Potassium Channel Blockers / blood
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred Lew
  • Skin Transplantation
  • T-Lymphocyte Subsets / immunology
  • Tacrolimus / administration & dosage
  • Tacrolimus / blood
  • Transplantation Immunology*
  • Transplantation, Homologous
  • Triterpenes / administration & dosage
  • Triterpenes / blood

Substances

  • Immunosuppressive Agents
  • Kv1.3 Potassium Channel
  • Potassium Channel Blockers
  • Triterpenes
  • correolide
  • Tacrolimus