An Autoimmune Basis for Pulmonary Hypertension.

肺动脉高压的自身免疫基础。

• 批准号: 7842158
• 负责人: Mark Robert Nicolls
• 金额: $ 24.01万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842158
• 关键词: Address; Altitude; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Apoptosis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B Cell Proliferation; B-Lymphocytes; Blood Vessels; CD4 Positive T Lymphocytes; Calcinosis; Cell Proliferation; Cells; Clinical; Collagen; Connective Tissue Diseases; Cytoprotection; Deposition; Development; Disease; Endothelial Cells; Endothelium; Environment; Esophageal motility disorders; Event; Evolution; Experimental Models; HIV; Hashimoto Disease; Hepatitis C; Herpesviridae; Human; Hypoxemia; Immune Tolerance; Immune response; Immune system; Inflammation; Injury; Interleukin-4; Life; Link; Lung; Lymphocyte; Mature B-Lymphocyte; Modeling; Nude Rats; Pathogenesis; Patients; Peripheral; Phase; Plant Roots; Plasma Cells; Polymyositis; Population; Prevention; Pulmonary Hypertension; Rat-1; Rattus; Relative (related person); Research Personnel; Resistance; Scleroderma; Seminal; Site; Sjogren' s Syndrome; Spleen; Systemic Lupus Erythematosus; T cell regulation; T-Lymphocyte; T-Lymphocyte Subsets; Telangiectasis; Testing; Therapeutic; Time; Variant; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Virus Diseases; acquired immunodeficiency; anti-endothelial cell antibody; base; design; interest; mast cell; prevent; programs; reconstitution; research study

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.

描述（由申请人提供）：自身免疫性长期以来与肺动脉高压（PH）相关，但尚未系统地检查其是否为这种常见致死性疾病的根本原因。结缔组织病和病毒感染是与PH密切相关的全身性疾病，其特征为自身免疫或具有自身免疫倾向。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，自身免疫性损伤实际上可能引发这种疾病。以前已经证明，VEGFR阻断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，该实验模型不能再现在常氧环境中生活的患者中发生的PH的临床演变。初步研究结果表明，如果给予缺乏T细胞的实验动物（即无胸腺裸大鼠），在丹佛海拔条件下VEGFR阻断后将发生严重PH，但如果淋巴细胞恢复到这些动物中则不会发生。这些开创性的意见构成了修订后的R01提案的基础。该项目的总体假设是，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。具体目标I将确定CD4或CDS细胞群是否负责预防接受VEGFR阻断治疗的无胸腺大鼠的PH，并检验T细胞亚群足以预防无胸腺大鼠中VEGFR阻断诱导的PH的一般假设。该目的的另一个组成部分是证明PH保护与预防抗内皮抗体形成相关。具体目标II将确定无胸腺大鼠中VEGFR阻断诱导的PH的脾细胞保护是否具有时间依赖性，以检验PH可能在假定的起始阶段被预防但在进展阶段变得不可逆的假设。具体目标III将确定PH是否可以诱导正常胸腺大鼠CD4耗竭，并将测试的假设，即获得性免疫缺陷野生型大鼠足以使这些动物对VEGFR阻断诱导PH敏感。如果可以确定PH有其根源的自身免疫事件，合理的治疗设计可以更好地考虑在这种经常致命的条件下早期疾病的发病机制。

项目成果

Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry.

• DOI: 10.1378/chest.13-3014
• 发表时间: 2014-12
• 期刊: Chest
• 影响因子: 9.6
• 作者: Chung L;Farber HW;Benza R;Miller DP;Parsons L;Hassoun PM;McGoon M;Nicolls MR;Zamanian RT
• 通讯作者: Zamanian RT