Gene transfer of RANTES elicits autoimmune renal injury in MRL-Faslpr mice

We report that the beta-chemokine RANTES, a chemoattractant for macrophages and T cells, is up-regulated in the MRL-Fas(lpr) kidney prior to injury, but not normal kidneys (MRL-++, C3H-++) and increases with progressive injury. Furthermore, we establish an association between RANTES expression in the kidney and renal damage using a gene transfer approach. Tubular epithelial cells genetically modified to secrete RANTES infused under the renal capsule incites interstitial nephritis in MRL-Fas(lpr), but not MRL-++ or C3H-++ mice. RANTES recruits predominantly macrophages (Mo) and CD4(+) and CD8(+) T cells. In contrast, gene transfer of CSF-1, another molecule up-regulated simultaneously with RANTES in MRL-Fas(lpr) kidneys, promotes the influx of Mo, CD4(+) T cells and the unique double-negative (DN)T cells (CD4(-),CD8(-)), which are prominent in diseased MRL-Fas(lpr) kidneys. Thus, RANTES and CSF-1 recruit distinct T cell populations into the MRL-Fas(lpr) kidney. In addition, delivery of RANTES and CSF-1 into the kidney of MRL-Fas(lpr) mice causes an additive increase in pathology. We suggest that the complementary recruitment of T cell populations by RANTES (CD4, CD8) and CSF-1 (CD4, DN) promotes autoimmune nephritis in MRL-Fas(lpr) mice.