Naito T, Yokoyama H, Moore K J, Dranoff G, Mulligan R C, Kelley V R
Laboratory of Immunogenetics and Transplantation, Brigham & Women's Hospital, Boston, Massachusetts 02115, USA.
Mol Med. 1996 May;2(3):297-312.
CSF-1 expression precedes renal injury in autoimmune MRL-lpr mice and is responsible for macrophage (M phi) proliferation and survival in the kidney. By comparison, C3H-lpr mice do not express CSF-1 in the kidney, and despite the lpr mutation, kidneys remain normal. The purpose of this study was to test the capacity of local and systemic expression of M phi growth factor, CSF-1 to initiate renal injury in normal (C3H-(++), MRL-(++) and autoimmune (C3H-lpr, MRL-lpr) mice.
We designed a gene transfer system to deliver cytokines into the kidney by transducing renal tubular epithelial cells (TEC) using retroviral vectors expressing CSF-1 or another M phi growth factor, GM-CSF. We placed transduced syngeneic cytokine-TEC under the renal capsule of normal and autoimmune prone mice prior to renal injury and evaluated renal pathology at 3, 7, 14, 28, and 90 days postimplant.
CSF-1-TEC and GM-CSF-TEC, but not uninfected TEC, caused extensive local renal injury in strains with the lpr mutation. At 3-7 days the infiltrating cells were mainly M phi, and by 28 days they were predominantly lymphocytes. By comparison, the kidneys of MRL-(++) and C3H-(++) mice remained normal. Implanted genetically modified TEC caused a sustained increase of CSF-1 or GM-CSF in the circulation which did not modify the contralateral kidney.
Gene transfer of M phi growth factors into the kidney initiates severe local renal injury in autoimmune prone mice with the lpr mutation, but does not compromise the kidney in nonautoimmune hosts. Of note, introduction of M phi growth factors into the kidney of C3H-lpr mice which do not spontaneously develop renal injury incites renal damage. These studies offer a gene transfer approach to explore the impact of local and systemic cytokine production on renal injury.
在自身免疫性MRL - lpr小鼠中，集落刺激因子-1（CSF - 1）的表达先于肾损伤，并且负责肾脏中巨噬细胞（Mφ）的增殖和存活。相比之下，C3H - lpr小鼠在肾脏中不表达CSF - 1，尽管存在lpr突变，但其肾脏仍保持正常。本研究的目的是测试巨噬细胞生长因子CSF - 1在正常（C3H -（++）、MRL -（++））和自身免疫性（C3H - lpr、MRL - lpr）小鼠中局部和全身表达引发肾损伤的能力。
我们设计了一种基因转移系统，通过使用表达CSF - 1或另一种巨噬细胞生长因子粒细胞-巨噬细胞集落刺激因子（GM - CSF）的逆转录病毒载体转导肾小管上皮细胞（TEC），将细胞因子递送至肾脏。在肾损伤前，我们将转导的同基因细胞因子-TEC置于正常和自身免疫易感小鼠的肾被膜下，并在植入后3、7、14、28和90天评估肾脏病理情况。
CSF - 1 - TEC和GM - CSF - TEC，而非未感染的TEC，在具有lpr突变的品系中引起广泛的局部肾损伤。在3 - 7天时，浸润细胞主要是巨噬细胞，到28天时则主要是淋巴细胞。相比之下，MRL -（++）和C3H -（++）小鼠的肾脏保持正常。植入的基因修饰TEC导致循环中CSF - 1或GM - CSF持续增加，但未改变对侧肾脏。
将巨噬细胞生长因子基因转移至肾脏会在具有lpr突变的自身免疫易感小鼠中引发严重的局部肾损伤，但不会损害非自身免疫宿主的肾脏。值得注意的是，将巨噬细胞生长因子引入不会自发发生肾损伤的C3H - lpr小鼠的肾脏会引发肾损伤。这些研究提供了一种基因转移方法来探索局部和全身细胞因子产生对肾损伤的影响。
