T cell triggering events and hypertension

T 细胞触发事件和高血压

• 批准号: 7788442
• 负责人: David G Harrison
• 金额: $ 36.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788442
• 关键词: Adipose tissue; Adoptive Transfer; Affect; Angiotensin II; Angiotensins; Antigens; Aorta; Autoimmune encephalitis; B-Lymphocytes; Blood Pressure; Blood Vessels; CCR5 gene; CD4 Positive T Lymphocytes; CD44 gene; Cell Adhesion Molecules; Cells; Characteristics; Chronic; DOCA; Data; Dental; Development; Disease; Diuresis; Dose; Employee Strikes; Endothelium; Event; Excretory function; Exhibits; Fatty acid glycerol esters; Functional disorder; Homing; Hypertension; Hypotension; IL17 gene; Immune response; Immunization; Infiltration; Inflammation; Inflammatory; Infusion procedures; Interleukin-17; Kidney; Laboratories; Lyme Disease; Mediating; Mesentery; Mus; NADPH Oxidase; Natriuresis; Nerve; Neuraxis; Nitric Oxide; Organ; Periodontitis; Peripheral; Play; Porphyromonas gingivalis; Prevention; Process; Production; Psoriasis; Reactive Oxygen Species; Relative (related person); Research; Resistance; Rheumatoid Arthritis; Role; Signal Transduction; Site; Sodium; Sodium Chloride; Stimulus; Subfornical Organ; Superoxides; Surface; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Vascular Diseases; Work; chemokine; cytokine; hypertension prevention; hypertension treatment; immunoregulation; kidney medulla; kidney vascular structure; lymph nodes; pathogen; polarized cell; prevent; response; treatment strategy; vasoconstriction

Research in our laboratory in the last several years has shown that T cells are essential for the development of hypertension. We have found that RAG-1"'" mice, which lack both T and B lymphocytes, develop very blunted hypertensive responses to either chronic low-dose angiotensin II infusion or to DOCA-salt challenge. Adoptive transfer of T, but not B, lymphocytes completely restores the pressor responses to these stimuli. We have found that angiotensin II stimulates a modest increase in T cell expression of the tissue homing markers CCR5 and CD44, which are characteristic of effector T cells. We believe this is important for the genesis of hypertension because we find a striking increase in infiltration of T cells into the perivascular fat around both the aorta and mesenteric vessels in hypertensive mice. The overall hypothesis to be tested in this project is that T cell activation via diverse mechanisms markedly augments the hypertensive response to challenges that normally have no or only minimal effect on blood pressure and that therapy with immunomodulatory agents is a promising approach for treatment of hypertension. In aim 1, we will test this hypothesis by immunizing mice with antigen from the dental pathogen Porphyromonas gingivalis (P. gingivalis) and then present hypertensive stimuli including angiotensin II, DOCA-salt hypertension and a central stimulus for hypertension. Stimuli that promote THi and TH2 cell polarization will be employed. Preliminary data indicate that previous immunization of mice leads to severe hypertension upon challenge with a low dose of angiotensin II that normally causes minimal increase in blood pressure. An important proinflammatory cytokine, independent of TH1/TH2 cytokines, is IL-17, which we find to be present in the endothelium and perivascular tissues of angiotensin IItreated mice. Our preliminary data in IL17''" mice indicate that it contributes to angiotensin ll-induced hypertension. We will examine the role of IL-17 in the response to angiotensin II and DOCA salt hypertension in naive mice and in mice after immunological stimulation with P. gingivalis lysate by studying IL-17 deficient mice. In preliminary data, we have found that angiotensin II stimulates an increase in renal medullary superoxide levels and a concomitant decrease in renal nitric oxide, and that this is absent in mice lacking T and B cells. We also find that RAG1''' mice exhibit a striking diuresis and natriuresis when challenged with angiotensin II. In aim 3, we will examine the role of T cells on these renal parameters during angiotensin llinduced hypertension and determine if pre-immunization enhances these effects. Finally in aim 4, we will test the potential for two therapies that can affect either T cell activation or tissue homing to prevent hypertension. In summary, these studies will provide new information regarding the inflammatory processes underlying hypertension and promise to provide new treatment strategies for this common disease

我们实验室过去几年的研究表明，T细胞对高血压的发展至关重要。我们已经发现，缺乏T和B淋巴细胞的RAG-1小鼠对慢性低剂量血管紧张素II输注或DOCA-盐攻击产生非常迟钝的高血压反应。T淋巴细胞（而非B淋巴细胞）的连续转移可完全恢复对这些刺激的升压反应。我们发现血管紧张素II刺激T细胞表达组织归巢标记物CCR 5的适度增加 和CD 44，它们是效应T细胞的特征。我们相信这对于高血压的发生是重要的，因为我们发现高血压小鼠的主动脉和肠系膜血管周围的血管周围脂肪中T细胞浸润显著增加。在这个项目中要测试的总体假设是，通过不同的机制，T细胞活化显着增强高血压的反应，通常没有或只有很小的影响，血压的挑战，免疫调节剂的治疗是一个有前途的方法治疗高血压。在目标1中，我们将通过用来自牙齿病原体牙龈卟啉单胞菌（P. gingivalis）的抗原免疫小鼠来测试这一假设，然后呈现高血压刺激物，包括血管紧张素II、DOCA盐高血压和高血压的中枢刺激物。将采用促进TH 1和TH 2细胞极化的刺激。初步数据表明，小鼠的先前免疫接种在用低剂量的血管紧张素II激发后导致严重的高血压，所述血管紧张素II通常引起血压的最小增加。一个重要的促炎细胞因子，独立于TH 1/TH 2细胞因子，是IL-17，我们发现它存在于血管紧张素II治疗的小鼠的内皮和血管周围组织。我们在IL 17小鼠中的初步数据表明，它有助于血管紧张素II诱导的 高血压我们将通过研究IL-17缺陷小鼠来检查IL-17在幼稚小鼠和用牙龈卟啉单胞菌裂解物免疫刺激后的小鼠中对血管紧张素II和DOCA盐高血压的应答中的作用。在初步数据中，我们发现血管紧张素II刺激肾髓质超氧化物水平的增加和伴随的肾一氧化氮的减少，而这在缺乏T和B细胞的小鼠中是不存在的。我们还发现，RAG 1小鼠表现出显着的利尿和尿钠排泄时，与血管紧张素II的挑战。在目标3中，我们将检查T细胞在血管紧张素诱导的高血压期间对这些肾脏参数的作用，并确定预免疫是否增强这些作用。最后，在目标4中，我们将测试两种疗法的潜力，这两种疗法可以影响T细胞活化或组织归巢，以预防高血压。 总之，这些研究将提供有关高血压基础炎症过程的新信息，并有望为这种常见疾病提供新的治疗策略