tacrolimus and correolide

Due to the improvement in the understanding of the anti-allogenic immune response, the success of transplantation medicine has increased rapidly over the last two decades. The knowledge that the T-lymphocyte played an integral role in transplant rejection, brought cyclosporine A and FK-506 to the fore as therapeutic immunosuppressants. However, the current mainstays in transplant rejection are not without their problems and many drug companies are exploring the possibilities of improving the available therapies by developing drugs with reduced toxicity, improved long-term survival and efficacy against chronic rejection and improved immunosuppressive selectivity. The advances in the understanding of T-cell activation and lymphocyte trafficking has highlighted ways to improve the existing therapies and more selective immunosuppressant targets.

Topics: Antibodies, Monoclonal; Antimetabolites; Calcineurin Inhibitors; Cyclosporine; Cytokines; Drug Design; Fingolimod Hydrochloride; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Lymphocyte Activation; Molecular Structure; Organ Transplantation; Propylene Glycols; Signal Transduction; Sirolimus; Sphingosine; T-Lymphocytes; Tacrolimus; Triterpenes

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.

Topics: Animals; Graft Rejection; Graft Survival; Hindlimb; Immunosuppression Therapy; Immunosuppressive Agents; Kv1.3 Potassium Channel; Male; Pilot Projects; Potassium Channel Blockers; Rats; Rats, Inbred BN; Rats, Inbred Lew; Skin Transplantation; T-Lymphocyte Subsets; Tacrolimus; Transplantation Immunology; Transplantation, Homologous; Triterpenes