The Role of Humoral Autoimmunity in Idiopathic Pulmonary Fibrosis

体液自身免疫在特发性肺纤维化中的作用

• 批准号: 8259733
• 负责人: STEVEN R DUNCAN
• 金额: $ 40.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259733
• 关键词: Accounting; Alleles; Animal Model; Antibodies; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biological Assay; Biological Markers; Cells; Characteristics; Clinical; Clinical Trials; Cloning; Complement; Data; Disease; Elderly; Epitopes; Genes; Glucocorticoids; Hamman-Rich syndrome; Heat-Shock Proteins 70; Human; Immune system; Immunoglobulin G; Immunologics; Immunosuppressive Agents; Individual; Injury; Instruction; Investigation; Lead; Lung; Lung diseases; Measures; Mediating; Medical; Methods; Mus; Nature; Outcome; Outcome Measure; Pathogenesis; Patients; Plasma; Plasmapheresis; Play; Principal Investigator; Process; Property; Refractory; Regimen; Research; Respiratory physiology; Role; Scleroderma; Specificity; Specimen; Stratification; Syndrome; T-Lymphocyte; TNFRSF5 gene; Tissues; Work; autoreactivity; base; clinically relevant; cohort; cytotoxicity; disease phenotype; immunoregulation; in vitro Assay; in vivo Model; interest; lung injury; novel; outcome forecast

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a dreaded fibrotic lung disease that is refractory to usual medical treatments and has a dismal prognosis. Recent findings of our research group, as well as others, include evidence of adaptive immunologic processes in IPF patients that fulfill conventional criteria of autoimmunity. Among other observations, a cohort of IPF patients have autoantibodies against heat shock protein 70, along with evidence of pathogenecity, and the presence of this autoimmune response is associated with worse subsequent outcomes of the afflicted patients. Autoimmune responses tend to be self-perpetuating, and often respond poorly to nonspecific immunosuppressant treatments. The presence of pathogenic autoimmune responses could contribute to the unremitting nature and refractoriness of IPF to previous treatments. These and other, related findings lead us to posit the central hypothesis of this application: Antibody-mediated autoimmunity can play an important role in IPF progression. The research proposed here will elucidate pathogenic mechanisms of IPF autoantibodies by in vitro assays that measure effects of patient-derived IgG on primary human lung cells (Specific Aim 1), discover other clinically-important IPF autoantibodies by use of high-throughput antigen arrays (Specific Aim 2), and provide materials for later detailed investigations by cloning IgG genes of IPF patients (Specific Aim 3). The findings of these studies will result in greater understanding and appreciation of autoimmune processes that contribute to IPF progression, thereby challenging current paradigms of disease pathogenesis, and identify immunologic bioassays that could be useful for prognostications of individual IPF patients. Most importantly, the findings here will result in further interest and justification for a clinical trial of mechanistically-focused, and potentially more efficacious, immune modulation of IPF patients (e.g., specific anti-B-cell agents), to follow in subsequent incremental continuation proposals. RELEVANCE (See instructions): Idiopathic pulmonary fibrosis (IPF) is a dreaded, and usually fatal lung disease of older adults. No medical treatments are known to be effective for IPF. We have found evidence that autoimmunity appears to be involved in IPF, in which the patient's own immune system attacks the lung. These findings raise the possibility that treatments that target these autoimmune process may be more effective for IPF. Also, there was a sense that the autoantibody data provided may be easily misinterpreted and that much work must precede a therapy based on this approach.

描述(申请人提供)：特发性肺纤维化(IPF)是一种可怕的纤维性肺部疾病，对常规药物治疗无效，预后不佳。我们研究组以及其他研究小组的最新发现包括IPF患者的适应性免疫过程符合传统的自身免疫标准的证据。在其他观察中，一组IPF患者具有针对热休克蛋白70的自身抗体，并有致病证据，这种自身免疫反应的存在与患者随后更糟糕的结局相关。自身免疫反应往往是自我维持的，对非特异性免疫抑制剂治疗的反应往往很差。病理性自身免疫反应的存在可能导致IPF的顽固性和对以往治疗的顽固性。这些和其他相关的发现使我们提出了这一应用的中心假设：抗体介导的自身免疫可以在IPF的进展中发挥重要作用。本研究将通过体外检测患者来源的免疫球蛋白对原代人肺细胞的作用来阐明IPF自身抗体的致病机制(特异性目标1)，利用高通量抗原阵列发现其他具有临床意义的IPF自身抗体(特异性目标2)，并通过克隆IPF患者的免疫球蛋白基因为以后的详细研究提供材料(特异性目标3)。这些研究的结果将有助于更好地理解和评价导致IPF进展的自身免疫过程，从而挑战目前疾病发病机制的范式，并确定有助于IPF患者个体预后的免疫生物测定方法。最重要的是，这里的发现将进一步引起对IPF患者(例如，特定的抗B细胞药物)机械地、潜在地更有效地进行免疫调节的临床试验的兴趣和理由，以便在随后的增量继续方案中遵循。相关性(见说明)：特发性肺纤维化(IPF)是一种可怕的、通常是老年人致命的肺部疾病。目前还没有对IPF有效的药物治疗方法。我们发现有证据表明，自身免疫似乎与IPF有关，在IPF中，患者自身的免疫系统攻击肺部。这些发现提出了一种可能性，即针对这些自身免疫过程的治疗可能对IPF更有效。此外，有一种感觉是，提供的自身抗体数据可能很容易被误解，在基于这种方法的治疗之前必须做很多工作。