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

基本信息

批准号：
8073301
负责人：
STEVEN R DUNCAN
金额：
$ 45.02万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/8073301
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

项目摘要

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，对通常的医疗治疗难治性，并且预后却令人沮丧。我们的研究小组以及其他研究的最新发现包括IPF患者的适应性免疫过程的证据，这些证据符合自身免疫的常规标准。除其他观察结果外，IPF患者队列具有针对热休克蛋白70的自身抗体，以及病原体的证据，并且这种自身免疫反应的存在与患病患者的随后结果较差有关。自身免疫反应往往是自我延续的，并且通常对非特异性免疫抑制剂治疗的反应较差。致病性自身免疫反应的存在可能有助于IPF对先前治疗的不懈性质和耐火性。这些和其他相关的发现使我们提出了此应用的中心假设：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法阐明IPF自身抗体的致病机制，这些测定法测量患者衍生的IgG对原发性人肺细胞的影响（特定目标1），发现其他临床上重要的IPF自身抗体，通过使用高通量抗原阵列（特定的特定目标）（特定的材料2），并通过详细igg进行igg cloning ig for ig for cloning ig for ig for ig for ig for ig for ig cloning ig cloning ig for ig cloning ig。这些研究的结果将导致对有助于IPF进展的自身免疫过程的更多了解和欣赏，从而挑战当前疾病发病机理的范式，并确定可以对单个IPF患者预测有用的免疫生物测定。最重要的是，这里的发现将导致对IPF患者（例如特定的抗B细胞剂）进行机械专注，可能更有效的免疫调节的临床试验的临床试验，以进一步兴趣和理由。相关性（请参阅说明）：特发性肺纤维化（IPF）是老年人的可怕，通常是致命的肺部疾病。众所周知，没有医疗治疗对IPF有效。我们发现证据表明自身免疫似乎与IPF有关，其中患者自己的免疫系统会攻击肺部。这些发现增加了针对这些自身免疫过程的治疗方法可能对IPF更有效的可能性。同样，有一种感觉，所提供的自身抗体数据很容易被误解，并且必须在基于这种方法的疗法之前进行大量工作。