title: Targeting the Kv1.3 potassium channel for immunosuppression in vascularized composite allotransplantation - a pilot study.
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.
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Theresa
authors.initials: T
authors.lastname: Hautz
authors.forename: Christoph
authors.initials: C
authors.lastname: Krapf
authors.forename: Johanna
authors.initials: J
authors.lastname: Grahammer
authors.forename: Bettina
authors.initials: B
authors.lastname: Zelger
authors.forename: Tilman
authors.initials: T
authors.lastname: Hickethier
authors.forename: Christoph
authors.initials: C
authors.lastname: Seger
authors.forename: Nadine
authors.initials: N
authors.lastname: Eberhart
authors.forename: Christoph
authors.initials: C
authors.lastname: Wallner
authors.forename: Franka
authors.initials: F
authors.lastname: Messner
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
authors.forename: Andrea
authors.initials: A
authors.lastname: Griesmacher
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
authors.forename: W P Andrew
authors.initials: WP
authors.lastname: Lee
authors.forename: Raimund
authors.initials: R
authors.lastname: Margreiter
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glossmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schneeberger
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology / Q000637:transplantation; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008297:Male; D010865:Pilot Projects; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000097:blood; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016038:Skin Transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood; D014181:Transplantation Immunology; D014184:Transplantation, Homologous; D014315:Triterpenes / Q000008:administration & dosage / Q000097:blood
chemical_list: D007166:Immunosuppressive Agents; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D014315:Triterpenes; C118657:correolide; D016559:Tacrolimus