Role of Immune Cells in Immunosuppressive Drug-Induced Hypertension

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Immunosuppressive drugs reduce the incidence of organ rejection following transplantation and the severity of autoimmune diseases; however these drugs can cause endothelial dysfunction and hypertension which is a major limitation to their use. The objective of the current proposal is to elucidate the immunological mechanisms by which alterations in T cells caused by the immunosuppressive drugs cyclosporine A (CsA) and FK506 (tacrolimus) alter endothelial function and blood pressure regulation. We will test the overall hypothesis that CsA- and FK506-induced decreases in beneficial regulatory T cells (Tregs) and increases in detrimental Th17 cells contribute to the development of endothelial dysfunction and hypertension. To test this hypothesis we will pursue 3 aims. Specific Aim 1 will examine the effects of Treg-derived and Th17 cell-derived cytokines on endothelial function and blood pressure regulation. If decreased Tregs and increased Th17 cells caused by CsA and FK506 contribute to the endothelial dysfunction and hypertension, then cytokines derived from these T cell subsets should directly modulate endothelial function and blood pressure. Specifically, IL-17 should directly induce endothelial dysfunction and hypertension and this should be prevented by Tregs or Treg- derived cytokines. Specific Aim 2 will determine the direct effects of lymphocytes from CsA-treated and FK506-treated mice on endothelial function. Lymphocytes from mice treated with CsA or FK506 should directly cause endothelial dysfunction in endothelial cells and blood vessels isolated from control mice. Additionally, isolated control endothelial cells and blood vessels should exhibit normal endothelial function following incubation with lymphocytes from CsA-treated or FK506-treated mice following inhibition of Th17 cells or augmentation of Tregs. Specific Aim 3 will determine the role of lymphocytes in CsA-induced and FK506- induced hypertension. Deficiency of Th17 cells and/or augmentation of Tregs should normalize blood pressure in CsA-treated and FK506-treated mice. Additionally, adoptive transfer of T cells from CsA-treated or FK506- treated mice into control mice should cause endothelial dysfunction and hypertension. To this end, we will use various combinations of pharmacologic and/or genetic perturbations of Tregs and Th17 cells in endothelial cells, isolated blood vessels, and mice. Completion of the aims will identify the molecular mechanisms responsible for, as well as possible therapies to prevent, the endothelial dysfunction and hypertension caused by CsA and FK506.