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.
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