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: 6664771
• 负责人: Vicki Rubin Kelley
• 金额: $ 0.72万
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6664771
• 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（改编自调查员的摘要）：FAS缺乏的小鼠 抗原由于遗传FASLPR，无法启动凋亡 并消除潜在的自身反应性T细胞。 将FASLPR引入 MRL背景导致进行性自身免疫性肾脏损伤。 faslpr 但是，不会总是引起严重的自身免疫性肾脏疾病，因为 FASLPR与非自动免疫遗传背景的相互作用不 诱导肾脏损伤。 相反，FASLPR转化了轻度，懒惰的肾脏损伤， 在MRL背景（MRL - ++）的小鼠中，快速和严重疾病。 巨噬细胞生长因子CSF-1在MRL-FASLPR和MRL - ++小鼠中表达 在肾脏受伤之前。 调查人员可以规避 通过非自动免疫C3H-FASLPR小鼠的MRL基因和促进肾脏损伤 直接将CSF-1引入肾脏。 相比之下，CSF-1没有 促进正常小鼠的肾脏损伤。 调查人员假设 CSF-1煽动的自身免疫性肾脏需要选择自动反应性T细胞 疾病。 他们建议检查MRL的两个系统中的肾脏损伤 菌株。 一个系统使用将CSF-1传递到的基因转移方法 肾脏和刺激局部，抗体独立的间质性肾炎。 另一个系统是自发疾病，由间质疾病组成 肾小球和血管周炎。 他们将确定T细胞 与CSF-1的肾脏损伤相关的表型，并确定是否是否 CSF-1成立和自发性肾脏损伤中的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 易于（MRL-FASLPR）或耐药性（DBA/2-FASLPR，C3H-FASLPR） 受伤。 他们将确定CSF-1成立所需的T单元 通过选定的T细胞子集的遗传缺失，自身免疫性肾脏损伤。 他们将分析与t交叉的MRL-FASLPR和MRL - ++菌株 缺乏A/B TCR，G/D TCR，A/B和G/D TCR的细胞缺陷的“敲除”小鼠， CD4 T细胞，CD8和双负T细胞以及CD40配体。 这些 研究将特别解决T细胞改变的影响 关于肾脏疾病的曲目。 最后，调查人员将确定 使用收养的细胞负责CSF-1的自身免疫性肾脏损伤 转移研究。 他们将确定哪些T细胞子集足够 通过将选定的T细胞引入MRL - ++和T 缺乏细胞的MRL-FASLPR肾脏没有疾病，并测试对 肾脏受伤。