T cell triggering events and hypertension

我们实验室在过去几年的研究表明，T细胞在高血压的发展中是必不可少的。我们发现，同时缺乏T和B淋巴细胞的RAG-1“‘”小鼠，无论是对慢性低剂量血管紧张素II输注还是对DOCA盐挑战，都会产生非常迟钝的高血压反应。过继转移T淋巴细胞，而不是B淋巴细胞，可以完全恢复对这些刺激的升压反应。我们发现血管紧张素II刺激组织归巢标志物CCR5的T细胞表达略有增加 和CD44，它们是效应性T细胞的特征。我们认为这对高血压的发生很重要，因为我们发现高血压小鼠主动脉和肠系膜血管周围血管周围脂肪中T细胞的渗透显著增加。这个项目要检验的总体假设是，通过不同的机制激活T细胞显着增强了高血压对挑战的反应，这些挑战通常对血压没有或只有很小的影响，免疫调节剂治疗是治疗高血压的一种有前途的方法。在目标1中，我们将通过用牙科病原体牙龈卟啉单胞菌(P.gigivalis)的抗原免疫小鼠来检验这一假设，然后提供包括血管紧张素II、DOCA-盐高血压和高血压中枢刺激在内的高血压刺激。将采用促进THI和TH2细胞极化的刺激。初步数据表明，以前对小鼠的免疫会在小剂量血管紧张素II攻击时导致严重高血压，而血管紧张素II通常会导致轻微的血压上升。IL-17是一种重要的致炎细胞因子，不依赖于TH1/TH2细胞因子，我们发现它存在于血管紧张素II处理的小鼠的血管内皮和血管周围组织中。我们在IL17‘’小鼠身上的初步数据表明，它有助于血管紧张素-11诱导 高血压。我们将通过研究IL-17缺陷的小鼠来研究IL-17在幼鼠对血管紧张素II和DOCA盐高血压的反应中的作用，以及在牙龈假单胞菌裂解物免疫刺激后的小鼠中IL-17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增加和伴随的肾一氧化氮减少，这在缺乏T和B细胞的小鼠中是不存在的。我们还发现，RAG1‘’小鼠在血管紧张素II刺激下表现出显著的利尿和利钠作用。在目标3中，我们将研究T细胞在血管紧张素诱导的高血压过程中对这些肾脏参数的作用，并确定免疫前是否增强了这些影响。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细胞激活或组织归巢来预防高血压。 总之，这些研究将提供有关高血压潜在炎症过程的新信息，并有望为这种常见疾病提供新的治疗策略。

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