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

• 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
• 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

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.

说明(申请人提供)：免疫抑制药物可降低移植后器官排斥反应的发生率和自身免疫性疾病的严重程度；然而，这些药物可导致内皮功能障碍和高血压，这是其使用的主要限制。本研究的目的是阐明免疫抑制剂环孢素A(CsA)和他克莫司(FK506)引起的T细胞改变改变内皮功能和血压调节的免疫学机制。我们将检验总体假设，即CsA和FK506诱导的有益调节性T细胞(Tregs)减少和有害Th17细胞增加有助于内皮功能障碍和高血压的发展。为了验证这一假设，我们将追求三个目标。具体目标1将研究Treg来源的细胞因子和Th17细胞来源的细胞因子对内皮功能和血压调节的影响。如果CsA和FK506引起的Tregs减少和Th17细胞增加导致内皮功能障碍和高血压，那么这些T细胞亚群产生的细胞因子应该直接调节内皮功能和血压。具体地说，IL-17应该直接导致内皮功能障碍和高血压，这应该被Treg或Treg衍生的细胞因子预防。特异性目标2将确定CsA和FK506处理的小鼠淋巴细胞对内皮功能的直接影响。经CsA或FK506处理的小鼠淋巴细胞应直接导致对照小鼠分离的内皮细胞和血管内皮细胞功能障碍。此外，分离的对照内皮细胞和血管在抑制Th17细胞或增强Tregs后与CsA处理或FK506处理的小鼠的淋巴细胞孵育后应表现出正常的内皮功能。特异性目标3将确定淋巴细胞在环孢素A诱导的高血压和FK506诱导的高血压中的作用。在CsA和FK506治疗的小鼠中，Th17细胞缺陷和/或Tregs的增加应该可以使血压恢复正常。此外，将CsA或FK506治疗的小鼠的T细胞过继转移到对照组小鼠应该会导致内皮功能障碍和高血压。为此，我们将在内皮细胞、分离的血管和小鼠中使用各种药物和/或遗传扰动的组合对Tregs和Th17细胞进行干扰。这些目标的完成将确定导致CsA和FK506引起的内皮功能障碍和高血压的分子机制以及可能的治疗方法。