T CELLS/MACROPHAGE GROWTH FACTOR/AUTOIMMUNE RENAL INJURY

T 细胞/巨噬细胞生长因子/自身免疫性肾损伤

• 批准号: 6150587
• 负责人: Vicki Rubin Kelley
• 金额: $ 20.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150587
• 关键词: CD28 molecule; CD40 molecule; CD95 molecule; T cell receptor; T lymphocyte; autoimmune disorder; colony stimulating factor; cytotoxic T lymphocyte; disease /disorder model; epithelium; gene deletion mutation; gene expression; gene targeting; genetically modified animals; helper T lymphocyte; immunocytochemistry; interstitial nephritis; kidney disorder; laboratory mouse; messenger RNA; pathologic process; phenotype; polymerase chain reaction; systemic lupus erythematosus; tissue /cell culture

DESCRIPTION (Adapted from Investigator's Abstract): Mice deficient in Fas antigen as a consequence of inheriting Faslpr, fail to initiate apoptosis and eliminate potentially autoreactive T cells. Introduction of Faslpr into the MRL background leads to progressive autoimmune renal injury. Faslpr does not invariably cause severe autoimmune kidney disease, however, as the interaction of Faslpr with non-autoimmune genetic backgrounds does not induce renal injury. Rather, Faslpr converts mild, indolent kidney injury, in mice with the MRL background (MRL-++) into rapid and severe disease. Macrophage growth factor, CSF-1, is expressed in MRL-Faslpr and MRL-++ mice prior to renal injury. The investigators can circumvent the requirement for the MRL genes and incite renal injury in non-autoimmune C3H-Faslpr mice by directly introducing CSF-1 into the kidney. By comparison, CSF-1 does not incite renal injury in normal mice. The investigators hypothesize that select autoreactive T cells are required for CSF-1 incited autoimmune kidney disease. They propose to examine renal injury in two systems in the MRL strains. One system uses a gene transfer approach that delivers CSF-1 into the kidney and incites local, antibody-independent, interstitial nephritis. The other system is spontaneous disease composed of interstitial, glomerular, and perivascular inflammation. They will determine the T cell phenotypes associated with CSF-1-incited renal injury, and establish whether T cells in CSF-1-incited and spontaneous renal injury are distinctive. They will compare the CSF-1-induced kidney infiltrating T cells in Faslpr strains that are prone (MRL-Faslpr) or resistant (DBA/2-Faslpr, C3H-Faslpr) to renal injury. They will determine the T cells required for CSF-1-incited autoimmune renal injury through genetic deletion of selected T cell subsets. They will analyze MRL-Faslpr and MRL-++ strains crossed with T cell-deficient "knockout" mice lacking a/b TCR, g/d TCR, a/b and g/d TCR, CD4 T cells, CD8 and double negative T cells, as well as CD40 ligand. These studies will specifically address the impact of alterations in the T cell repertoire on kidney disease. Finally, the investigators will identify T cells responsible for CSF-1-incited autoimmune renal injury using adoptive transfer studies. They will determine which T cell subsets are sufficient to incite renal destruction by introducing select T cells into MRL-++, and T cell-deficient MRL-Faslpr kidneys without disease, and test the impact on renal injury.

描述（改编自研究者摘要）：Fas 缺陷的小鼠 抗原作为遗传 Faslpr 的结果，无法启动细胞凋亡 并消除潜在的自身反应性 T 细胞。 Faslpr引入 MRL 背景会导致进行性自身免疫性肾损伤。 法斯普 然而，并不一定会导致严重的自身免疫性肾病，因为 Faslpr 与非自身免疫遗传背景的相互作用不会 诱发肾损伤。 相反，Faslpr 可以转化轻度、惰性肾损伤， 具有 MRL 背景 (MRL-++) 的小鼠会出现快速且严重的疾病。 巨噬细胞生长因子 CSF-1 在 MRL-Faslpr 和 MRL-++ 小鼠中表达 肾损伤之前。 调查人员可以规避这一要求 MRL 基因并在非自身免疫性 C3H-Faslpr 小鼠中诱发肾损伤 直接将CSF-1引入肾脏。 相比之下，CSF-1 不 引起正常小鼠的肾损伤。 研究人员假设 CSF-1 诱导的自身免疫肾需要选择自身反应性 T 细胞 疾病。 他们建议在 MRL 中检查两个系统的肾损伤 菌株。 一个系统使用基因转移方法将 CSF-1 递送至 肾脏并引发局部、非抗体依赖性间质性肾炎。 另一个系统是自发性疾病，由间质组成， 肾小球和血管周围炎症。 他们将确定 T 细胞 与 CSF-1 诱发的肾损伤相关的表型，并确定是否 CSF-1 刺激和自发性肾损伤中的 T 细胞是独特的。 他们 将比较 Faslpr 菌株中 CSF-1 诱导的肾脏浸润 T 细胞 容易（MRL-Faslpr）或耐药（DBA/2-Faslpr、C3H-Faslpr）的肾病 受伤。 他们将确定 CSF-1 激发所需的 T 细胞 通过对选定的 T 细胞亚群进行基因删除而导致自身免疫性肾损伤。 他们将分析与 T 杂交的 MRL-Faslpr 和 MRL-++ 菌株 缺乏a/b TCR、g/d TCR、a/b 和g/d TCR 的细胞缺陷“敲除”小鼠， CD4 T 细胞、CD8 和双阴性 T 细胞，以及 CD40 配体。 这些 研究将专门解决 T 细胞改变的影响 肾脏疾病曲目。 最后，调查人员将确定 T 使用过继细胞对 CSF-1 引发的自身免疫性肾损伤负责 转学。 他们将确定哪些 T 细胞亚群足够 通过将选择的 T 细胞引入 MRL-++ 和 T 来刺激肾脏破坏 细胞缺陷的 MRL-Faslpr 肾脏没有疾病，并测试对 肾损伤。