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Autoantibody blockade in neonatal lupus

新生儿狼疮的自身抗体阻断

基本信息

批准号：
10170280
负责人：
ANTONIO LA CAVA
金额：
$ 19.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-22 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170280
关键词：
Adrenal Cortex Hormones Affect Animal Disease Models Animal Model Antibodies Antibody Specificity Antigens Autoantibodies Biological Birth Cardiac conduction system Child Child Mortality Clinical Management Combined Modality Therapy Complication Congenital Heart Block Cross-Sectional Studies Data Death Rate Deposition Development Disease Fetal Heart Fetus Fibrosis Future Glucocorticoids Goals Half-Life Heart Heart Block Heart Transplantation Human Immune Immunosuppression Impairment Incidence Injury Intervention Intravenous Immunoglobulins Investigation Leptin Life Link Mediating Modality Modification Morbidity - disease rate Mothers Mus Neonatal lupus erythematosus Organ Pacemakers Pathogenesis Pathologic Pathway interactions Patients Pharmaceutical Preparations Placenta Plasma Plasmapheresis Pregnant Women Prevention Production Prognosis Protocols documentation Public Health Ribonucleoproteins Risk Risk Reduction Secondary to Signal Transduction Sjogren&apos s Syndrome System Systemic Lupus Erythematosus Testing Therapeutic Intervention Tissues Treatment Efficacy antibody transfer base child bearing diagnostic biomarker experimental study heart damage high risk improved improved outcome in vivo in vivo evaluation infant death infection risk mortality mouse model passive transport pre-clinical pregnant promoter prospective seropositive side effect tissue injury

项目摘要

ABSTRACT Anti-Sjögren's syndrome antigen A (SSA) autoantibodies are primarily found in patients with Sjögren's syndrome and systemic lupus erythematosus (SLE), where they represent a useful diagnostic marker whose pathological significance remains to be clarified. Importantly, the presence of anti-SSA autoantibodies in pregnant mothers associates with a high risk to bear children that develop neonatal lupus with irreversible damage of the heart conduction system. The development of congenital heart block secondary to maternal seropositivity for anti-SSA autoantibodies associates with child mortality rate of up to 30% and the requirement of a pacemaker within the first year of life in about 64% of the cases. This elevated morbidity and dire prognosis have not changed in years mainly because of the difficulty to reduce the burden of maternal anti- SSA autoantibodies that cause the damage to the fetal heart. Here we propose to inhibit SSA autoantibody production in pregnant mothers for the prevention of heart tissue injury in their fetuses. Building on preliminary data that identified leptin as a promoter of the production of anti-SSA autoantibodies in mice and that showed the efficacy of leptin inhibition in reducing circulating anti-SSA autoantibodies, we aim to test whether leptin antagonism in anti-SSA-positive pregnant mice can reduce fetal heart tissue injury in neonatal lupus, and delineate the underlying mechanisms. Goal of these studies is to have a preclinical proof-of-concept of a new modality of intervention in neonatal lupus, to improve outcomes and to limit the highly disabling/fatal consequences of this condition.

摘要抗干燥综合征抗原A（SSA）自身抗体主要见于干燥综合征患者，综合征和系统性红斑狼疮（SLE），其中它们代表有用的诊断标志物，病理学意义尚待阐明。重要的是，抗SSA自身抗体的存在，怀孕的母亲与患新生儿狼疮的高风险有关，心脏传导系统的损害。产妇继发先天性心脏传导阻滞的发生抗SSA自身抗体的血清阳性与高达30%的儿童死亡率有关，在64%的病例中，在出生后的第一年内植入了起搏器。这种高发病率和可怕的预后多年来没有改变，主要是因为难以减轻产妇抗- SSA自身抗体导致胎儿心脏受损。在这里，我们建议抑制SSA自身抗体在怀孕母亲的生产，以防止心脏组织损伤，在他们的胎儿。在初步数据表明瘦素是小鼠抗SSA自身抗体产生的促进剂，瘦素抑制在减少循环抗SSA自身抗体中的功效，我们旨在测试瘦素是否抗SSA阳性妊娠小鼠的拮抗作用可减少新生儿狼疮中胎儿心脏组织的损伤，描绘了潜在的机制。这些研究的目的是对一种新的药物进行临床前概念验证。新生儿狼疮的干预方式，以改善结局并限制高度致残/致命性这种情况的后果。