Mechanisms of immunosuppression in the development and progression of renal disease in Tuberous Sclerosis Complex

免疫抑制在结节性硬化症肾病发生和进展中的机制

• 批准号: 10658079
• 负责人: Elizabeth P Henske
• 金额: $ 53.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658079
• 关键词: Adult; Angiomyolipoma; Antibodies; Area; Autosomal Dominant Polycystic Kidney; Benign; Bilateral; Body mass index; CD276 gene; CD8-Positive T-Lymphocytes; Carcinoma; Cause of Death; Cell Proliferation; Cell Surface Proteins; Cell Survival; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Trials; Complex; Couples; Cyst; Cystic kidney; Data; Development; Disease; Epithelium; FRAP1 gene; Fatty acid glycerol esters; Genetic; Growth; Hemorrhage; Homologous Gene; Human; Immune; Immunological Models; Immunosuppression; In Vitro; Individual; Infection; Kidney; Kidney Diseases; Knockout Mice; Lead; Lesion; Life; Lipids; Macrophage; Membrane Glycoproteins; Morbidity - disease rate; Morphology; Mus; Myeloid-derived suppressor cells; Null Lymphocytes; PKD1 gene; Pathway interactions; Patients; Peptides; Phenotype; Play; Polycystic Kidney Diseases; Pre-Clinical Model; Proteins; Proteomics; Renal Angiomyolipoma; Renal Cell Carcinoma; Seizures; Smooth Muscle; Specimen; TSC1 gene; TSC1/2 gene; TSC2 gene; Testing; Therapeutic; Tuberous Sclerosis; Work; antibody detection; autosome; cell growth; clinical development; early childhood; human data; immune checkpoint; immunoregulation; immunosuppressive macrophages; improved; in vivo; infancy; inhibitor; innovation; loss of function mutation; mTOR inhibition; mortality; mouse model; nano-string; novel; novel therapeutic intervention; preclinical efficacy; programmed cell death ligand 1; protein complex; response; single-cell RNA sequencing; therapeutic target; transcriptomic profiling; tumor-immune system interactions

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline loss-of-function mutations in the TSC1 or TSC2 gene. Renal disease, which includes angiomyolipomas, cysts, and carcinomas, is the second leading cause of morbidity and mortality in TSC. In unpublished data, we found increased immunosuppressive CD206-positive macrophages and high expression of the immune checkpoint molecule B7-H3 (a homolog of PD-L1) in human TSC renal cysts and angiomyolipomas. We also demonstrate that B7-H3 promotes TSC2-null cell growth in vivo via a mechanism that requires CD8+ T cells. These and other data lead to our central hypothesis: immunosuppressive macrophages together with B7-H3 expression on TSC2-deficient cells promote renal disease in TSC. A key translational corollary of this hypothesis is that immunosuppressive macrophages and B7-H3 are potential therapeutic targets for TSC. Aim 1: To identify the mechanisms through which macrophages contribute to the renal manifestations of TSC. We will test the hypothesis that immunosuppressive macrophages promote TSC1- and TSC2-deficient cell growth directly, and/or indirectly via inhibition of CD8+ T cell function. Aim 2: To determine how B7-H3 remodels the immune microenvironment of TSC-associated renal disease. We will test the hypothesis that B7-H3 promotes TSC2-null cell growth by inhibiting CD8+ T cell function. Aim 3: To investigate the preclinical efficacy of co-targeting macrophages and B7-H3 in TSC. We will test the hypothesis that targeting both immunosuppressive macrophages and B7-H3 will lead to long-lasting, durable responses in preclinical models of renal disease driven by loss of Tsc1 or Tsc2. We expect this project to have scientific impact by identifying the immune mechanisms responsible for the growth of TSC2-null cells in the kidney. These mechanisms may have broad implications, since macrophages are believed to play a key role in other renal diseases, including autosomal dominant polycystic kidney disease (ADPKD). Our areas of innovation include our novel, translationally relevant hypotheses as well as technical innovation, including CITE-seq, spatial CODEX and nanoString transcriptomic profiling, and a novel, unpublished mouse model of renal disease in TSC (Rosa26-CreERT2 Tsc2f/f).

抽象的 结节硬化症复合物（TSC）是一种由种系功能丧失引起的常染色体显性疾病 TSC1或TSC2基因中的突变。肾脏疾病，包括血管肌瘤，囊肿和癌， 是TSC中发病率和死亡率的第二大原因。 在未发表的数据中，我们发现免疫抑制CD206阳性巨噬细胞和高表达增加 人类TSC肾脏囊肿中的免疫检查点B7-H3（PD-L1的同源物）和 血管肌层。我们还证明了B7-H3通过一种机制促进体内TSC2-NULL细胞的生长 这需要CD8+ T细胞。 这些和其他数据导致了我们的中心假设：免疫抑制巨噬细胞与B7-H3一起 TSC2缺陷细胞上的表达促进TSC中的肾脏疾病。这是关键的翻译推论 假设是免疫抑制巨噬细胞和B7-H3是TSC的潜在治疗靶标。 目的1：确定巨噬细胞对肾脏表现贡献的机制 TSC。我们将测试免疫抑制巨噬细胞促进TSC1-和TSC2缺陷的假设 通过抑制CD8+ T细胞功能直接和/或间接生长。 目标2：确定B7-H3如何重塑与TSC相关肾脏的免疫微环境 疾病。我们将检验以下假设：B7-H3通过抑制CD8+ T细胞功能促进TSC2无效细胞的生长。 AIM 3：研究共同靶向巨噬细胞和TSC中B7-H3的临床前功效。我们将测试 靶向免疫抑制巨噬细胞和B7-H3的假设将导致持久，耐用 由TSC1或TSC2损失驱动的肾脏疾病模型的反应。 我们希望该项目通过确定负责的免疫机制会产生科学影响 TSC2无效细胞在肾脏中的生长。这些机制可能具有广泛的影响，因为巨噬细胞 据信在其他肾脏疾病中起关键作用，包括常染色体显性多囊性肾脏疾病 （ADPKD）。我们的创新领域包括我们的小说，翻译相关的假设以及技术 创新，包括Cite-Seq，空间法典和纳米弦转录组合分析，以及新颖的，未出版的 TSC中肾脏疾病的小鼠模型（ROSA26-CREERT2 TSC2F/F）。