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

摘要 结节性硬化症是一种由生殖系功能丧失引起的常染色体显性遗传病。 TSC1或TSC2基因突变。肾脏疾病，包括血管肌脂肪瘤、囊肿和癌症， 是TSC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阳性的巨噬细胞增加，并高表达 免疫检查点分子B7-H3(PD-L1的同源物)在人TSC肾囊肿中的表达 血管肌脂肪瘤。我们还证明了B7-H3在体内通过一种机制促进TSC2缺失细胞的生长 这需要CD8 T细胞。 这些数据和其他数据导致了我们的中心假设：免疫抑制的巨噬细胞与B7-H3一起 TSC2缺陷细胞的表达促进了TSC的肾脏疾病。这是一个关键的翻译推论 假设免疫抑制巨噬细胞和B7-H3是TSC的潜在治疗靶点。 目的1：明确巨噬细胞参与肾脏表现的机制。 台糖公司。我们将检验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/或间接地促进细胞生长。 目的2：探讨B7-H3对TSC相关肾脏免疫微环境的影响 疾病。我们将验证B7-H3通过抑制CD8 T细胞功能来促进TSC2缺失细胞生长的假设。 目的：探讨联合靶向巨噬细胞和B7-H3治疗TSC的临床前疗效。我们将测试 假设同时针对免疫抑制的巨噬细胞和B7-H3将导致持久的、持久的 TSC1或TSC2缺失导致的肾脏疾病临床前模型的反应。 我们希望这个项目能通过确定免疫机制来产生科学影响。 TSC2阴性细胞在肾脏中的生长。这些机制可能具有广泛的含义，因为巨噬细胞 被认为在其他肾脏疾病中起关键作用，包括常染色体显性遗传性多囊肾病 (ADPKD)。我们的创新领域包括我们的新奇、与翻译相关的假设以及技术 创新，包括CITE-SEQ、空间法典和纳米串转录剖析，以及一本未出版的小说 TSC建立小鼠肾病模型(ROSA26-CreERT2 Tsc2f/f)。

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 In unpublished data, we found increased immunosuppressive CD206-positive macrophages and high expression of the immune checkpoint molecule B7-H3 (a homolog of PD-L1) in human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).