Systemic autoimmune nephritogenic components induce CSF-1 and TNF-alpha in MRL kidneys.
MRL-Faslpr 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-alpha) are detected in the kidney and circulation prior to renal injury and continue to increase with progressive renal damage in MRL-Faslpr, Fas deficient mice, but not the congenic Fas intact MRL-(++) strain. Delivery of CSF-1, but not TNF-alpha, into the kidney via gene transfer incites local renal injury. By comparison, dual gene transfer of CSF-1 and TNF-alpha 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-alpha 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-alpha expression in the kidney of MRL-Faslpr 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-alpha and renal injury into an MRL-Faslpr recipient after removing nephritic kidney expressing CSF-1 and TNF-alpha. The Tx kidneys were examined after 2, 4, 5, 6, and 12 weeks. CSF-1 and TNF-alpha were rapidly induced in the MRL-(++) Tx kidney. CSF-1 and TNF-alpha were evident by two weeks and continually increased for 12 weeks post-transplantation. Within several weeks, the rapid expansion of M phi and T cells and induction of glomerulonephritis and interstitial nephritis in the MRL-(++) Tx kidney was similar to the age-matched native MRL-Faslpr 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-Faslpr kidney is not defective, but rather a circulating stimulant in the MRL-Faslpr mouse can induce CSF-1, TNF-alpha and renal injury in a normal MRL-(++) kidney. Thus, we exclude an intrinsic defect in the MRL-Faslpr kidney as the pathogenic mechanism responsible for tissue damage. We suggest purging the circulation of molecules that induce CSF-1 and TNF-alpha as a therapeutic strategy for autoimmune renal injury.
Wada
T
T
Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Naito
T
T
Griffiths
R C
RC
Coffman
T M
TM
Kelley
V R
VR
D000818:Animals; D001327:Autoimmune Diseases / Q000097:blood / Q000378:metabolism*; D005921:Glomerulonephritis / Q000209:etiology; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000378:metabolism*; D009393:Nephritis / Q000097:blood / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor