An Autoimmune Basis for Pulmonary Hypertension.

描述(由申请人提供)：自体免疫长期以来一直与肺动脉高压(PH)有关，但尚未被系统地研究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，具有自身免疫的特点或倾向。使用血管内皮生长因子受体(VEGFR)阻断诱导的PH的实验模型，很明显，自身免疫损伤实际上可能是这种疾病的始作俑者。已有研究表明，阻断VEGFR可导致肺血管内皮细胞凋亡，如果动物暴露于低氧血症，就会继而发生PH。然而，这个实验模型和大多数实验模型一样，不能再现在常氧环境下发生的PH的临床演变。初步研究结果表明，在丹佛高原条件下，如果对缺乏T细胞的实验动物(即裸鼠)使用VEGFR，将会出现严重的PH，但如果这些动物的淋巴细胞得到恢复，则不会发生严重的PH。这些开创性的观察形成了修订后的R01提案的基础。这个项目的主要假设是，PH的发生有自身免疫基础。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。具体目的I将确定在接受VEGFR阻断治疗的无瘤大鼠中，CD4或CDS细胞群是否对预防PH负有责任，并检验T细胞亚群足以预防无瘤大鼠VEGFR阻断引起的PH的普遍假设。这一目标的另一个组成部分将是证明对PH的保护与防止抗内皮细胞抗体的形成相关。具体目的二将是确定VEGFR阻断诱导的无瘤大鼠的脾细胞保护是否具有时间依赖性，以检验这一假说，即在假定的起始阶段可以预防PH，但在进展阶段变得不可逆转。具体目标三将是确定是否可以在CD4耗竭的心境良好的大鼠中诱导PH，并将检验这样的假设，即野生型大鼠的获得性免疫缺陷足以使这些动物对VEGFR阻断诱导的PH易感。如果可以确定PH是自身免疫事件的根源，合理的治疗设计可以更好地考虑这种经常致命的情况下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.