Systemic autoimmune nephritogenic components induce CSF-1 and TNF-α in MRL kidneys. MKL-Fas^lpr mice are an appealing strain to understand the importance of cytokines in the pathogenesis of autoimmune renal destruction, since injury is rapid and predictable. Colony stimulating factor 1 (CSF-1) and tumor necrosis factor alpha (TNF-α) are detected in the kidney and circulation prior to renal injury and continue to increase with progressive renal damage in MRL-Fas^lpr, Fas deficient mice, but not the congenic Fas intact MRL- + + strain. Delivery of CSF-1, but not TNF-α, into the kidney via gene transfer incites local renal injury. By comparison, dual gene transfer of CSF-1 and TNF-α incites autoimmune renal injury that is far more severe than CSF-1 alone. The purpose of this study was to establish whether CSF-1 and TNF-α expression in the kidney of MRL-Fas^lpr mice induced by a circulating stimulant resulted from a primary defect in the kidney. Therefore, we transplanted (Tx) a MRL-+ + kidney without CSF-1, TNF-α and renal injury into an MRL-Fas^lpr recipient after removing nephritic kidneys expressing CSF-1 and TNF-α. The Tx kidneys were examined after 2, 4, 5, 6, and 12 weeks. CSF-1 and TNF-α were rapidly induced in the MRL-+ + Tx kidney. CSF-1 and TNF-α were evident by two weeks and continually increased for 12 weeks post-transplantation. Within several weeks, the rapid expansion of Mφ and T cells and induction of glomerulonephritis and interstitial nephritis in the MRL-++ Tx kidney was similar to the age-matched native MRL-Fas^lpr kidney. In conclusion, we have constructed an experimental transplantation system that can explore whether cytokine expression in the kidney induced by a circulating stimulant is a result of a primary defect in the kidney. Using this approach, we established that the MRL-Fas^lpr kidney is not defective, but rather a circulating stimulant in the MRL-Fas^lpr mouse can induce CSF-1, TNF-α and renal injury in a normal MRL-+ + kidney. Thus, we exclude an intrinsic defect in the MRL-Fas^lpr kidney as the pathogenic mechanism responsible for tissue damage. We suggest purging the circulation of molecules that induce CSF-1 and TNF-α as a therapeutic strategy for autoimmune renal injury.