An infiltration of macrophages (MO) in the kidney is common to progressive renal disease. Colony stimulating factor-I, (CSF-I) promotes the recruitment, proliferation, differentiation and survival of MO. The sponsor?s laboratory has established a strong association between CSF-1 and the accumulation/recruitment of MO in the kidney, and that CSF-I plays a critical role prior to and throughout the advancement of kidney injury in MRL-Fas/or mice. Targeting specific molecules responsible for the infiltration of MO into the kidney provides a therapeutic strategy for halting progressive destruction. Therefore, we hypothesize that CSF-1 is a therapeutic target to combat autoimmune kidney disease. We propose to: 1) Determine whether CSF-1 deficient MRL-Faslpr mice are protected from autoimmune nephritis by constructing a CSF-1 deficient MRL-Fas/or strain. We will determine whether protection is exclusive to the kidney or systemic. 2) Determine whether eliminating CSF-1 from the MRL-Fas/or kidney, apart from the entire organism, protects against autoimmune nephritis by transplanting CSF-1 deficient kidneys into syngeneic CSF-1 intact MRL-Faslpr mice with mild and advanced nephritis. 3) Determine whether restoring CSF-1 in adult CSF-1 deficient MRL-Faslpr mice, by using a retroviral gene transfer approach that provides sustained delivery of CSF-1 to a discrete area of the kidney, re-incites autoimmune nephritis. 4) Determine whether blocking CSF-1 expression during nephritis prevents progressive kidney destruction. We will construct a CSF-I receptor antagonist (CSF-1 Fc). CSF-1 Fc will be delivered systemically and specifically into the kidney (gene transfer), during advancing stages of nephritis and we will assess the impact on nephritis. Taken together, these studies will establish whether CSF-1 is a potential therapeutic for human kidney diseases.
| Lenda, Deborah M; Stanley, E Richard; Kelley, Vicki R (2004) Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas(lpr) mice. J Immunol 173:4744-54 |
| Kikawada, Eriya; Lenda, Deborah M; Kelley, Vicki R (2003) IL-12 deficiency in MRL-Fas(lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. J Immunol 170:3915-25 |
