Neuropeptides, Immunity, and Lung Injury

神经肽、免疫和肺损伤

• 批准号: 6805100
• 负责人: Mary E. Sunday
• 金额: $ 29.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805100
• 关键词: antigen presentation; antioxidants; baboons; bombesin; bombesin like peptide; bronchopulmonary dysplasia; cooperative study; developmental immunology; dosage; immunity; immunotherapy; inflammation; laboratory mouse; lung development; lung injury; messenger RNA; monoclonal antibody; neuroendocrine system; neuropeptides; nonhuman therapy evaluation; premature infant animal; respiratory disease /disorder therapy; respiratory pharmacology

DESCRIPTION (provided by applicant): Our overall hypothesis is that BLP is an early mediator of lung injury, arrested alveolarization and immunodeficiency in BPD. Urine BLP levels are elevated shortly after birth in infants who develop BPD. BLP can mediate lung injury: anti-BLP blocking antibody 2A11 protects against BPD in both baboon models. We are exploring the mechanisms by which this occurs, especially pro-inflammatory cascades. Our recent data suggest that immunodeficiency might contribute to BPD: 2A11 treatment abrogates thymic cortical involution and increases thymic nurse cells, which function in negative selection against self-reactive T cells. We will test our hypothesis using five Specific Aims: AIM 1: To determine the optimal dosage schedule and dose-response for 2A11 in the 125d/PRN x 21 days model of BPD. We will compare 2A11 to a humanized antibombesin antibody. AIM 2: To determine long-term outcomes at 6 months after giving anti-BLP antibodies in the 125d/PRN model of BPD using the optimal dose and treatment schedule. AIM 3: To analyze normal ontogeny of the baboon immune system in lung, spleen and thymus, including both innate and acquired immunity [macrophage/dendritic cells (M/DC), endothelial cells, and T cells. Functional assays may include cell proliferation, apoptosis, expression of cell differentiation markers, cytokine production, chemotaxis, respiratory burst, phagocytosis and antigen presentation in vitro. We will also assess RNA levels for the three BLP receptors and other markers as indicated. AIM 4: To test the hypotheses that 125d/PRN baboons are immunodeficient, that this contributes to BPD, and that 2A11 abrogates this immunodeficiency. We will establish functional baboon immune systems in vivo in immunodeficient mice (scid-boon): Baboon immunity will be tested in the host mice + BLP, 2A11, antioxidants, or other interventions for BPD. In AIM 5 we will determine whether greater therapeutic efficacy can be achieved using combinations of treatments shown to individually improve outcomes in the 125d/PRN model of BPD: 2A11, antioxidant mimetics, and nitric oxide (NO). We also plan collaborative studies to determine mechanisms by which 2A11 restores microvasculature formation in developing lung. This investigation should further clarify underlying cellular defects in BPD and permit the introduction of novel multi-modality treatments.

描述（由申请人提供）： 我们的总体假设是，BLP是BPD中肺损伤，肺泡化和免疫缺陷的早期介体。出生后不久，患有BPD的婴儿后不久，尿液BLP水平升高。 BLP可以介导肺损伤：抗BLP阻断抗体2A11在两种狒狒模型中都可以防止BPD。我们正在探索发生这种情况的机制，尤其是促炎的级联反应。我们最近的数据表明，免疫缺陷可能有助于BPD：2A11治疗消除了胸腺皮质的不合适并增加胸腺护士细胞，胸腺护士细胞可对自反应性T细胞进行负选择作用。我们将使用五个特定目的测试我们的假设：目标1：确定BPD的125D/PRN X 21天模型中2A11的最佳剂量时间表和剂量反应。我们将将2A11与人源化抗体抗体进行比较。 AIM 2：使用最佳剂量和治疗时间表在125D/PRN模型中给出抗BLP抗体后6个月的长期结局。目标3：分析肺，脾脏和胸腺的狒狒免疫系统的正常锻炼，包括先天和获得的免疫[巨噬细胞/树突状细胞（M/DC），内皮细胞和T细胞。功能分析可能包括细胞增殖，凋亡，细胞分化标记的表达，细胞因子产生，趋化性，呼吸爆发，吞噬作用和抗原表现在体外。我们还将评估三种BLP受体和其他标记的RNA水平。目标4：测试125D/PRN狒狒是免疫缺陷的假设，这有助于BPD，并且2A11消除了这种免疫缺陷。我们将在免疫缺陷的小鼠（SCID-BOON）中在体内建立功能性狒狒免疫系统：将在宿主小鼠 + BLP，2A11，抗氧化剂或其他BPD的干预措施中测试狒狒免疫力。在AIM 5中，我们将使用显示的治疗方法的组合可以确定可以单独改善BPD：2A11，抗氧化剂模仿和一氧化氮（NO）中的预后的组合来确定更大的治疗功效。我们还计划协作研究，以确定2A11恢复发育中肺中微脉管形成的机制。这项研究应进一步阐明BPD中的潜在细胞缺陷，并允许引入新型的多模式处理。