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Autoimmunity in Cardiopulmonary Toxicities from Radiotherapy andImmunotherapy

放射治疗和免疫治疗引起的心肺毒性中的自身免疫

基本信息

批准号：
10763129
负责人：
BO LU
金额：
$ 60.69万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
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：
2020-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10763129
关键词：
Address Adoption Adverse event Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Biological Blood Blood specimen CD19 gene CD4 Positive T Lymphocytes Cancer Patient Cardiac Cardiopulmonary Cells Chest Clinical Clinical Research Collaborations Combined Modality Therapy Complement Diagnosis Diagnostic tests Discipline Early Diagnosis Excess Mortality Exposure to Foundations Goals Heart Humoral Immunities IL17 gene Immune Immunologist Immunotherapy Inflammatory Injury Innate Immune Response Institution Intervention Investigation Knockout Mice Laboratories Lead Life Link LoxP-flanked allele Lung Malignant neoplasm of lung Measures Mediating Modeling Monitor Mus Natural Immunity Outcome PD-1 blockade Patients Pre-Clinical Model Production Quality of life Radiation Oncologist Radiation therapy Role Sampling Serum Structure of parenchyma of lung T-Lymphocyte Testing Therapeutic Toxic effect Toxicity Attenuation Universities Validation Wild Type Mouse Work adaptive immune response adaptive immunity anti-CD20 anti-PD-1 anti-PD1 therapy autoimmune toxicity bench to bedside cytokine humoral immunity deficiency immune checkpoint improved improved outcome inhibitor irradiation mouse model neutrophil new therapeutic target novel novel diagnostics novel marker pharmacologic pre-clinical predictive marker prevent programmed cell death protein 1 prospective response therapeutic target translational study

项目摘要

Summary Cardiopulmonary toxicities following thoracic radiotherapy and PD-1 blocking immunotherapy have a major impact on quality of life and survival. Therefore, there is an unmet need to have early diagnostic test and intervention for fatal toxicities. Our proposal aims to understand immune mechanisms that modulate potentially life-threatening cardiopulmonary toxicities. We propose to study the toxicities in both mouse models and patients by analyzing blood samples. To achieve our goals, we have assembled a collaborative team across three institutions with a group of expert consultants in order to identify biological correlates and therapeutic targets to ameliorate these autoimmune toxicities. Our prior studies showed excessive mortality in mice simultaneously exposed to radiotherapy and PD-1 inhibition, which we show is dependent on both the cytokine IL-17A and the B-cell. Since both Th17/IL-17A and humoral immunity are implicated in autoimmune diseases, we hypothesize that toxicities result from the unchecked adaptive Th17 response due to PD-1 blockade, combined with autoantibodies against heart and lung tissues generated by the pro-inflammatory B- lymphocytes. We will employ mouse models and pharmacological inhibitors to dissect the underlying autoimmune mechanisms and measure key components of Th17 and B-cell response in prospectively collected blood samples from lung cancer patients undergoing combine radiotherapy and immunotherapy. Aim 1: To determine whether IL-17A/Th17 responses mediate the toxicities. We hypothesize that both innate and adaptive immunity contributes to the toxicities through the link of IL-17A. We will generate KO mice unable to produce IL-17A through either neutrophils or CD4 T cells. We expect that the toxicities are attenuated when Th17/IL-17A are blunted in these mouse models. To determine whether IL-17A/Th17 can be used as predictive biomarkers for the toxicities, we will examine dynamic changes of Th17/IL-17A in serum samples from our patients. Aim 2: To determine the role of humoral response in mediating the toxicities. We hypothesize that pro-inflammatory Tbet+ B-lymphocytes drive autoantibody production which results in the toxicities. We will use Tbetflox/flox CD19cre mice as our model, in which mature Tbet+ B cells are absent. This approach will be complemented by pharmacological depletion of B cells using anti-CD20 or by neutralizing autoantibodies with IVIg in wild-type mice. We expect that the toxicities are attenuated in these models. Furthermore, we will test whether pharmacological inhibitors of Th17/IL-17A reduce Tbet+ B cells and autoantibodies. Finally, the rise of autoantibodies in blood will be captured in mice and patients as a surrogate for the toxicities. Our study of basic mechanisms in preclinical models, combined with analysis of patient samples, will lead to novel diagnostics for early detection and improved therapies for severe cardiopulmonary toxicities.

摘要胸部放射治疗和PD-1阻断免疫治疗后的心肺毒性是主要的对生活质量和生存的影响。因此，有一种尚未得到满足的需求，即进行早期诊断测试和对致命毒物的干预。我们的建议旨在了解免疫调节机制潜在的危及生命的心肺毒性。我们建议研究这两种小鼠模型的毒性。和病人通过分析血液样本。为了实现我们的目标，我们组建了一个协作团队跨三个机构和一组专家顾问，以确定生物相关性和治疗靶点，以改善这些自身免疫毒性。我们之前的研究表明，同时暴露于放射治疗和PD-1抑制的小鼠，我们发现这依赖于两者细胞因子IL-17A和B细胞。由于Th17/IL-17A和体液免疫都与自身免疫有关疾病，我们假设毒性是由PD-1引起的未经检查的适应性Th17反应引起的阻断，结合抗心和肺组织的自身抗体，由促炎症的B- 淋巴细胞。我们将使用小鼠模型和药物抑制剂来剖析潜在的自身免疫机制及Th17和B细胞应答关键成分的前瞻性检测采集接受放射治疗和免疫治疗的肺癌患者的血液样本。目的1：确定IL-17A/Th17反应是否介导毒性反应。我们假设两者都是先天免疫和获得性免疫通过IL-17A参与毒性作用。我们将产生KO小鼠不能通过中性粒细胞或CD4T细胞产生IL-17A。我们预计毒副作用是在这些小鼠模型中，当Th17/IL-17A被钝化时，这种作用减弱。以确定IL-17A/Th17是否可以作为毒性的预测生物标志物，我们将检测血清中Th17/IL-17A的动态变化我们病人的样本。目的2：确定体液反应在调节毒物。我们假设促炎的Tbet+B淋巴细胞驱动自身抗体的产生导致了毒副作用。我们将使用Tbetflx/Flox CD19cre小鼠作为我们的模型，在该模型中，成熟的Tbet+B细胞缺席。这一方法将通过使用抗CD20或通过药物消耗B细胞来补充用IVIg中和野生型小鼠的自身抗体。我们预计这些药物的毒性会减弱。模特们。此外，我们将测试Th17/IL-17A的药物抑制剂是否会减少Tbet+B细胞和自身抗体。最后，血液中上升的自身抗体将在小鼠和患者身上被捕获作为替代对毒物的影响。我们对临床前模型的基本机制的研究，结合对患者的分析样本，将导致早期发现的新诊断方法和改善严重心肺疾病的治疗毒物。