Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection

抗原特异性 T 细胞在免疫治疗相关急性间质性肾炎和肾同种异体移植排斥中的作用

• 批准号: 10351987
• 负责人: Naoka Murakami
• 金额: $ 13.43万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351987
• 关键词: ANCA vasculitis; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Allografting; Animal Model; Animals; Antigens; Archives; Autoantigens; Autoimmune; Autoimmunity; Biology; Biopsy; Biopsy Specimen; Blood specimen; CTLA4 gene; Cancer Patient; Cells; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Data; Data Analyses; Dialysis procedure; Disease; End stage renal failure; Evolution; Fibrosis; Funding; Future; Genetic Transcription; Genomics; Goals; Graft Rejection; Haptens; Hospitals; Human; Hypersensitivity; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunooncology; Immunotherapy; Infection; Infiltration; Inflammation; Inflammatory; Injury to Kidney; Institutes; Interstitial Nephritis; Investigation; Kidney; Kidney Diseases; Kidney Transplantation; Lead; Lymphocyte; Malignant Neoplasms; Membranous Glomerulonephritis; Molecular; Multi-site clinical study; Multiomic Data; Observational Study; Organ; Patient-Focused Outcomes; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Pilot Projects; Play; Proliferating; Proton Pump Inhibitors; Proximal Kidney Tubules; Public Health; Renal Replacement Therapy; Research; Risk; Risk Factors; Role; Sampling; Signal Transduction; Specificity; Stains; T cell receptor repertoire sequencing; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Therapeutic; Tissue Sample; Transplant Recipients; Transplantation; Tumor-infiltrating immune cells; Up-Regulation; Woman; allograft rejection; anti-CTLA4; anti-PD-1; antigen-specific T cells; autoreactivity; base; cancer immunotherapy; checkpoint therapy; complementarity-determining region 3; design; dimensional analysis; experience; feasibility testing; high dimensionality; human disease; human tissue; immune checkpoint; improved; ischemic injury; kidney allograft; kidney biopsy; mortality; multiple omics; neoantigens; nephrogenesis; next generation sequencing; novel; peripheral blood; prevent; programmed cell death protein 1; prospective; response; single-cell RNA sequencing; therapy development; tumor

Project Summary Cancer immunotherapy has become a standard therapy for many cancers. However, it’s associated with acute kidney injury, resulting in significantly increased mortality. Acute interstitial nephritis is the most common acute kidney injury, affecting 2-3% of the patients receiving immune checkpoint inhibitors (ICIs). In addition, 40% of the kidney transplant patients receiving ICIs suffer from acute rejection, and once rejection occurs, 65% lose allograft and require renal replacement therapy. Thus, understanding the mechanisms of ICI-associated acute kidney injury and finding therapies is critical. My K08 project aims to understand the roles of immune checkpoint molecules (PD-1 and CTLA-4) in kidney inflammation, by using the novel animal models that express neoantigen peptides specifically in kidney proximal tubules and tracking antigen-specific T cell response in the animals by tetramer staining technique. The results showed that the presence of antigen- specific T cells and ICIs trigger the immune cell infiltration to the kidneys, mimicking acute interstitial nephritis seen in the cancer patients treated with ICIs. While animal models are ideal to address the precise molecular mechanisms of the disease, there’s a limitation in the applicability of the findings to the human disease. The largest multicenter clinical study that I led recently found that the ICI-associated kidney injury occurs much faster and more robust in kidney transplant recipients compared to non-kidney transplant patients. The findings led to my central hypothesis that pre-existing donor antigen-specific T cells in the kidney transplant recipients are quickly activated, proliferated in the presence of ICIs, and cause direct kidney injury. In this pilot study, I propose to perform high dimensional analyses using human tissue samples to track antigen-specific T cells by single cell RNA sequencing and T cell receptor (TCR) repertoire analysis. We will analyze the TCR clonotype and phenotype of antigen-specific T cells, using the archived peripheral blood mononuclear cells, tumor and kidney biopsy samples, obtained from the patients who had acute graft rejection after cancer ICI therapy, by collaborating with Center of Immuno-Oncology at Dana Faber Cancer Institute and single cell genomics core at Brigham and Women’s Hospital. This pilot project tests the feasibility of the high dimensional analysis of the patient samples for a future prospective clinical trial in the patients with ICI-associated kidney injury. If feasible, we will incorporate these analyses in the prospective clinical trial, which will eventually help understand the mechanism of acute interstitial nephritis and acute graft rejection in the patients treated with cancer immunotherapy.

项目概要 癌症免疫疗法已成为许多癌症的标准疗法，但它与急性癌症有关。 肾损伤，导致死亡率显着增加。急性间质性肾炎是最常见的急性病。 肾损伤，影响 2-3% 接受免疫检查点抑制剂 (ICIs) 治疗的患者，此外还有 40% 的患者。 接受ICIs的肾移植患者会出现急性排斥反应，一旦发生排斥反应，65%的患者会损失 同种异体移植并需要肾脏替代治疗因此，了解 ICI 相关急性的机制。 我的 K08 项目旨在了解免疫的作用。 通过使用新型动物模型，肾脏炎症中的检查点分子（PD-1 和 CTLA-4） 在肾近曲小管中特异性表达新抗原肽并追踪抗原特异性 T 细胞 通过四聚体染色技术对动物进行反应，结果表明存在抗原。 特定 T 细胞和 ICI 触发免疫细胞浸润至肾脏，类似于急性间质性肾炎 在接受 ICI 治疗的癌症患者中观察到，而动物模型是解决精确分子生物学问题的理想选择。 由于该疾病的机制，这些发现对人类疾病的适用性存在限制。 我最近领导的最大的多中心临床研究发现，ICI 相关的肾损伤发生率很高。 与非肾移植患者相比，肾移植受者的治疗速度更快、更稳健。 引出了我的中心假设：肾移植受者体内预先存在供体抗原特异性 T 细胞 在 ICI 存在的情况下会迅速激活、增殖，并导致直接肾损伤。 提议使用人体组织样本进行高维分析，以追踪抗原特异性 T 细胞 单细胞 RNA 测序和 T 细胞受体 (TCR) 库分析 我们将分析 TCR 克隆型。 使用存档的外周血单核细胞、肿瘤和抗原特异性 T 细胞的表型 肾活检样本，取自癌症 ICI 治疗后出现急性移植排斥反应的患者， 与达纳法伯癌症研究所的免疫肿瘤学中心和单细胞基因组学核心合作 布莱根妇女医院该试点项目测试了高维分析的可行性。 如果可行的话，用于未来对 ICI 相关肾损伤患者进行前瞻性临床试验的患者样本。 我们将把这些分析纳入前瞻性临床试验，这最终将有助于了解 癌症患者急性间质性肾炎及急性移植物排斥反应的机制 免疫疗法。