Immune Modulation of Hypertension

描述（由申请人提供）：最近的研究表明，T细胞可以调节动脉压。我们发现，过继转移男性而不是女性的CD 3+，CD 4+和CD 8 + T细胞可以介导雄性Rag 1缺陷小鼠的Ang II依赖性高血压。这些观察结果表明，T细胞的性别特异性决定了免疫系统调节高血压的抵抗力和脆弱性。在目标1中，我们将确定T细胞介导的对由Ang II输注诱导的雄性Rag 1-/-宿主中的高血压的易感性和抵抗性是否是由于性染色体（XX vs XY）对T细胞供体的性腺依赖性或性腺非依赖性作用，以及这些作用如何与终末器官损伤和T细胞反应联系起来。在目标2中，我们将确定在雄性Rag 1-/-宿主中对Ang II输注的性别特异性T细胞亚群应答是否是由于T细胞血管紧张素1型和2型受体（AT 1 R和AT 2 R）的性别差异以及这些受体介导的T细胞效应如何与血压、终末器官损伤和T细胞功能联系。目的3将确定促炎和抗炎细胞因子在CD 4+和CD 8+介导的对Ang II诱导的高血压的易感性和抵抗性中的作用，并将这些发现与终末器官损伤联系起来。在血管紧张素II依赖性高血压模型中，确定T细胞亚特异性和T细胞功能受性别调节的机制可能为绝经前女性与年龄匹配的男性相比高血压延迟发作提供解释。此外，发现与血管紧张素II诱导的高血压抵抗和易感性相关的免疫调节表型可以揭示T细胞亚群特异性靶点和治疗两性高血压的策略。

DESCRIPTION (provided by applicant): Recent studies indicate that T cells can modulate arterial pressure. We found that adoptive transfer of male but not female CD3+, CD4+ and CD8+ T cells can mediate Ang II-dependent hypertension in male Rag1 deficient mice. These observations indicate sex specific ations of T cells determine resistance and vulnerability in the regulation of hypertension by the immune system. In aim 1, we will determine if T cell-mediated susceptibility and resistance to hypertension induced by Ang II infusion in the male Rag1-/- host is due to gonad-dependent or gonad-independent effects of the sex chromosomes (XX vs XY) on the T cell donor and how these effects link to end organ damage and T cell responses. In aim 2, we will determine if sex-specific T cell subset responses to Ang II infusion in the male Rag1-/- host are due to sex differences in T cell angiotensin type 1 and type 2 receptors (AT1R and AT2R) and how these receptor- mediated T cell effects link to blood pressure, end organ damage and T cell function. Aim 3 will determine the role of pro- and anti-inflammatory cytokines in CD4+ and CD8+- mediated susceptibility and resistance to Ang II-induced hypertension and link these findings to end organ damage. Defining the mechanisms by which T cell sub- specification and T cell function are regulated by sex in a model of Ang II-dependent hypertension may provide an explanation for the delayed onset of hypertension in premenopausal women compared with age-matched men. Furthermore, discovering immune regulatory phenotypes associated with resistance and susceptibility to hypertension induced by Ang II could uncover T cell subset specific targets and strategies for treating hypertension in both sexes.