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: 10548204
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548204
• 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; Collaborations; Data; Data Analyses; Dialysis procedure; Disease; Eligibility Determination; End stage renal failure; Evolution; Fibrosis; Flow Cytometry; Funding; Future; Genetic Transcription; Genomics; Goals; Graft Rejection; Haptens; Hospitals; Human; Hypersensitivity; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunooncology; Immunotherapy; Infection; Infiltration; Inflammation; Inflammatory; Injury to Kidney; Interstitial Nephritis; Investigation; Kidney; Kidney Diseases; Kidney Transplantation; 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; Proliferating; Proton Pump Inhibitors; Proximal Kidney Tubules; Public Health; Renal Replacement Therapy; Research; Risk; Risk Factors; Role; Sampling; Signal Transduction; Stains; T cell infiltration; T cell receptor repertoire sequencing; T cell response; T-Cell Activation; T-Cell Immunologic Specificity; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Therapeutic; Tissue Sample; Transplant Recipients; Transplantation; Up-Regulation; Woman; allograft rejection; anti-CTLA4; anti-PD-1; antigen-specific T cells; autoreactivity; cancer immunotherapy; cancer infiltrating T cells; checkpoint therapy; complementarity-determining region 3; design; dimensional analysis; experience; feasibility testing; high dimensionality; human disease; human tissue; immune cell infiltrate; 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.

项目摘要 癌症免疫疗法已成为许多癌症的标准疗法。但是，它与急性有关 肾脏损伤，导致死亡率显着增加。急性间质性肾炎是最常见的急性 肾脏损伤，影响2-3％的接受免疫检查点抑制剂（ICIS）的患者。另外，有40％ 接受ICIS的肾脏移植患者患有急性排斥反应，一旦发生拒绝，有65％的人损失 同种异体移植，需要肾脏替代疗法。理解ICI相关急性的机制 肾脏损伤和寻找疗法至关重要。我的K08项目旨在了解免疫的作用 肾脏注射中的检查点分子（PD-1和CTLA-4），使用新型动物模型 特有在肾脏近端小管中和跟踪抗原特异性T细胞中的表达新抗原肽 四聚体染色技术在动物中的反应。结果表明抗原的存在 特定的T细胞和ICIS触发免疫球对孩子的浸润，模仿急性间质性肾炎 在接受ICIS治疗的癌症患者中可见。虽然动物模型是解决精确分子的理想选择 该疾病的机制，发现对人类疾病的适用性有一个限制。 我最近领导的最大的多中心临床研究发现，与ICI相关的肾脏损伤发生了很多 与非kidney移植患者相比，肾脏移植受者的速度更快，更健壮。发现 导致了我的中心假设，即肾脏移植受者中已经存在的供体抗原特异性T细胞 在ICIS存在的情况下快速激活，增殖，并导致直接肾脏损伤。在这项试点研究中，我 建议使用人体组织样品进行高维分析，以跟踪抗原特异性T细胞 单细胞RNA测序和T细胞受体（TCR）曲目分析。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 肾脏活检样本，从癌症ICI治疗后急性移植抑制的患者获得 与Dana Faber Cancer Institute和单细胞基因组核心与免疫肿瘤学中心合作 杨百翰和妇女医院。该试点项目测试了高维分析的可行性 患有ICI相关肾脏损伤患者的未来前瞻性临床试验的患者样品。如果可行， 我们将将这些分析纳入预期临床试验，最终将有助于了解 患有癌症治疗的患者的急性间质性肾炎和急性移植排斥的机制 免疫疗法。