Role of Immune Cells in Immunosuppressive Drug-Induced Hypertension

免疫细胞在免疫抑制药物诱发的高血压中的作用

基本信息

批准号：
8732802
负责人：
BRETT M MITCHELL
金额：
$ 36.38万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732802
关键词：
Adoptive Transfer Affect Allograft Tolerance Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Ascaridil Autoimmune Diseases Autoimmunity Blood Pressure Blood Vessels Calcineurin Cardiovascular Diseases Cells Clinical Research Cyclosporine Data Development Endothelial Cells Exhibits FK506 Figs - dietary Functional disorder Genetic Goals Graft Rejection Hypertension Immune Immune system Immunosuppressive Agents Incidence Inflammatory Interleukin-17 Long-Term Effects Lymphocyte Molecular Mus Organ Organ Transplantation Patients Pharmaceutical Preparations Play Regulatory T-Lymphocyte Reporting Research Role Severities T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Tacrolimus Techniques Testing Therapeutic immunosuppression Transplantation Work blood pressure regulation cytokine injured prevent public health relevance

项目摘要

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.

描述（由申请人提供）：免疫抑制药物减少了移植后器官排斥的发生率和自身免疫性疾病的严重程度；但是，这些药物会引起内皮功能障碍和高血压，这是其使用的主要限制。当前建议的目的是阐明由免疫抑制药物Cyclosporine A（CSA）和FK506（他克莫司）改变内皮功能和血压调节的T细胞改变的T细胞改变的免疫机制。我们将测试总体假设，即有益的调节T细胞（Tregs）中CSA和FK506诱导的降低，有害TH17细胞的增加有助于内皮功能障碍和高血压的发展。为了检验这一假设，我们将追求3个目标。具体目标1将检查Treg衍生和TH17细胞衍生的细胞因子对内皮功能和血压调节的影响。如果由CSA和FK506引起的Tregs减少和增加的Th17细胞会导致内皮功能障碍和高血压，则源自这些T细胞亚群的细胞因子应直接调节内皮功能和血压。具体而言，IL-17应直接诱导内皮功能障碍和高血压，这应该由Tregs或Treg衍生的细胞因子预防。具体目标2将确定经CSA处理和FK506处理的小鼠对内皮功能的淋巴细胞的直接影响。用CSA或FK506治疗的小鼠的淋巴细胞应直接引起内皮细胞和从对照小鼠分离的血管中的内皮功能障碍。此外，在抑制Th17细胞或增强Treg的TH17细胞后，与CSA处理或FK506处理的小鼠孵育后，分离的对照内皮细胞和血管应表现出正常的内皮功能。具体目标3将确定淋巴细胞在CSA诱导的和FK506诱导的高血压中的作用。 Th17细胞的缺乏和/或Treg的增强应使CSA治疗和FK506治疗的小鼠的血压正常化。另外，从经CSA处理或FK506处理的小鼠中T细胞转移到对照小鼠中应引起内皮功能障碍和高血压。为此，我们将使用内皮细胞，分离的血管和小鼠的Tregs和Th17细胞的药理和/或遗传扰动的各种组合。目的的完成将确定负责预防CSA和FK506引起的内皮功能障碍和高血压的可能疗法的分子机制。