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（由申请人提供）：特发性肺纤维化（IPF）是一种可怕的纤维化肺部疾病，常规药物治疗难以治愈，且预后不佳。我们的研究小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的证据，这些过程符合自身免疫的传统标准。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，以及致病性的证据，并且这种自身免疫反应的存在与患者随后较差的结果相关。自身免疫反应往往是自我持续的，并且通常对非特异性免疫抑制剂治疗反应不佳。致病性自身免疫反应的存在可能导致 IPF 对先前治疗的持续性和难治性。这些和其他相关发现使我们提出本申请的中心假设：抗体介导的自身免疫可以在 IPF 进展中发挥重要作用。 这里提出的研究将通过体外测定来阐明IPF自身抗体的致病机制，测量患者来源的IgG对原代人肺细胞的影响（具体目标1），通过使用高通量抗原阵列发现其他临床上重要的IPF自身抗体（具体目标2），并通过克隆IPF患者的IgG基因为后续详细研究提供材料（具体目标3）。 这些研究的结果将导致人们更好地理解和认识导致 IPF 进展的自身免疫过程，从而挑战当前的疾病发病机制范式，并确定可用于个体 IPF 患者预后的免疫生物测定。最重要的是，这里的研究结果将引起人们对针对 IPF 患者进行以机制为重点、可能更有效的免疫调节（例如特定抗 B 细胞药物）的临床试验的进一步兴趣和合理性，以遵循后续增量延续建议。相关性（参见说明）：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。目前尚无对 IPF 有效的药物治疗。我们发现证据表明，自身免疫似乎与特发性肺纤维化有关，即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，人们认为所提供的自身抗体数据可能很容易被误解，并且在基于这种方法的治疗之前必须进行大量工作。