An Autoimmune Basis for Pulmonary Hypertension.

描述（由申请人提供）：自身免疫长期以来与肺动脉高压（PH）有关，但尚未系统地检查作为这种经常致命的疾病的根本原因。结缔组织病和病毒感染是与PH密切相关的全身性疾病，以自身免疫为特征或具有自身免疫倾向。利用血管内皮生长因子受体（VEGFR）阻断诱导PH的实验模型，很明显自身免疫损伤实际上可能引发这种疾病。先前已经证明，VEGFR阻断会导致肺血管内皮细胞凋亡，如果动物暴露于低氧血症，PH将随之发生。然而，与大多数实验模型一样，该实验模型不能重现常压环境下患者PH的临床演变。初步研究结果表明，在丹佛海拔条件下，如果给缺乏T细胞的实验动物（即胸腺裸鼠）施用VEGFR阻断后，会发生严重的PH，但如果这些动物恢复淋巴细胞，则不会发生严重的PH。这些开创性的观察结果构成了修订后的R01提案的基础。这个项目的首要假设是ph的发展有自身免疫基础。这种自身免疫可能是缺乏适当的调节性T细胞活性的结果。我将确定CD4或CDS细胞群是否负责预防经VEGFR阻断治疗的无胸大鼠的PH，并验证T细胞亚群足以预防VEGFR阻断诱导的无胸大鼠PH的一般假设。这一目标的另一个组成部分将是证明对PH的保护与预防抗内皮抗体形成相关。特异性目的II将是确定VEGFR阻断剂诱导的无胸大鼠脾细胞PH保护是否具有时间依赖性，以验证PH可能在假定的起始阶段被阻止，但在进展阶段变得不可逆的假设。特异性目的III将确定是否可以在CD4耗竭的健康大鼠中诱导PH，并将验证野生型大鼠获得性免疫缺陷足以使这些动物对VEGFR阻断诱导的PH敏感的假设。如果可以确定PH与自身免疫事件有关，合理的治疗设计可以更好地考虑这种经常致命的疾病的早期疾病发病机制。

DESCRIPTION (provided by applicant): Autoimmunity has long been associated with pulmonary hypertension (PH) but has not been systematically examined as a root cause for this frequently fatal condition. Connective tissue disease and viral infections are systemic disorders that are strongly linked with PH and are characterized by or have a propensity to autoimmunity. Using an experimental model of vascular endothelial growth factor receptor (VEGFR) blockade-induced PH, it is evident that autoimmune injury may actually initiate this disease. It has been previously demonstrated that VEGFR blockade leads to pulmonary vascular endothelial cell apoptosis and that if animals are exposed to hypoxemia, PH will ensue. However, this experimental model, as with most experimental models, can not recreate the clinical evolution of PH which occurs in patients living in normoxic environments. Preliminary findings demonstrate that severe PH will develop following VEGFR blockade in Denver altitude conditions if administered to experimental animals that lack T cells (i.e. the athymic nude rat) but not if lymphocytes are restored to these animals. These seminal observations have formed the basis for this revised R01 proposal. The overarching hypothesis for this project is that there is an autoimmune basis for the development of PH. This autoimmunity may be the result of a lack of appropriate regulatory T cell activity. Specific Aim I will determine whether CD4 or CDS cell populations are responsible for preventing PH in athymic rats treated with VEGFR blockade and test the general hypothesis that T cell subsets are sufficient to prevent VEGFR blockade-induced PH in athymic rats. An additional component of this Aim will be to demonstrate that protection from PH correlates with prevention of anti-endothelial antibody formation. Specific Aim II will be to determine whether spleen cell protection of VEGFR blockade-induced PH in athymic rats is time-dependent to test the hypothesis that PH may be prevented during a putative initiation phase but becomes irreversible during a progressive phase. Specific Aim III will be to determine whether PH can be induced in euthymic rats with CD4 depletion and will test the hypothesis that acquired immunodeficiency in wild type rats is sufficient to render these animals susceptible to VEGFR blockade-induced PH. If it can be determined that PH has its roots in autoimmune events, rational therapeutic design can better consider early disease pathogenesis in this frequently lethal condition.