Nephritis is a common complication of the human autoimmune disease systemic lupus erythematosus (SLE). Mice of the MRL-Faslpr strain spontaneously develop a disease that is similar to SLE. It has been shown that macrophages (MO) are prominent in lupus nephritis in the MRL-Faslpr strain and that upon activation, MO destroy renal resident cells during inflammation. Colony Stimulating Factor-1 (CSF-1), the principal MO growth factor, is required to promote lupus nephritis in MRL-Faslpr mice. The actions of CSF-1 are mediated exclusively by the CSF-1 receptor (CSF-1 R). There are three individual CSF-1 isoforms, a cell surface CSF-1 (csCSF), a secreted proteoglycan (spCSF) and a secreted glycoprotein (sgCSF). We hypothesize that CSF-1 and CSF-1 R bearing cells are central in the pathogenesis of lupus nephritis. In order to test this hypothesis, we propose: 1) to determine whether over-expressing CSF-1 systemically accelerates lupus nephritis and the systemic illness in MRL-Faslpr mice; 2) to determine the role(s) of the individual CSF-1 isoforms in lupus nephritis and systemic illness in MRL-Faslpr mice; and 3) to determine whether eliminating CSF-1 signaling during disease in MRL-Faslpr mice can halt the progression of lupus nephritis and the systemic illness.
These aims will allow us to evaluate the potential therapeutic value of blocking/eliminating CSF-1 mediated signals in the treatment of lupus nephritis and other macrophage-mediated illnesses. Kidney inflammation is a major cause of morbidity and mortality in lupus patients. This inflammation is mediated in large part by a subset of white blood cells known as macrophages that destroy tissue within the kidney. It has been shown that CSF-1, the principle macrophage growth factor, promotes kidney inflammation in mice that spontaneously develop a disease that shares many of the characteristics of human lupus. We will use these mice to determine the specific mechanisms of CSF-1 dependent inflammation and establish whether the CSF-1 pathway is a potential therapeutic target for lupus and other macrophage-mediated kidney diseases in humans.. ? ? ?
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| Menke, Julia; Lucas, Julie A; Zeller, Geraldine C et al. (2007) Programmed death 1 ligand (PD-L) 1 and PD-L2 limit autoimmune kidney disease: distinct roles. J Immunol 179:7466-77 |
