ENHANCED RESPONSE OF MACROPHAGES TO CSF-1 IN AUTOIMMUNE MICE - A GENE-TRANSFER STRATEGY

Mice with the MRL background have a genetic propensity for autoimmune lupus nephritis. The lpr mutation on the MRL, but not the C3H backgrou nd, induces rapid and fatal renal injury in which macrophages (M phi) are prominent. We previously established that CSF-1 accompanies M phi accumulation in the kidney of MRL-lpr mice. Furthermore, CSF-1 introdu ced into the kidney incites renal injury in mice with the lpr mutation , but not congenic strains. Notably, CSF-1 induces more severe tissue injury in MRL-lpr than in C3H-lpr mice. We hypothesized that M phi fro m the MRL background respond more readily to CSF-1 than normal strains . We establish herein the following: 1) glomerular M phi and bone marr ow M phi (BMM phi) from MRL-lpr mice proliferate similarly to CSF-1;2) MRL BMM phi proliferate more vigorously to CSF-1 than normal strains (C3H, BALB/c) or another strain with lpr (C3H-lpr); and 3) modulation of CSF-1 receptor expression by CSF-1 is more rapid in MRL than C3H BM M phi. We used a gene transfer strategy to deliver CSF-1 into the kidn ey to evaluate M phi response to CSF-1. We genetically modified tubula r epithelial cells to produce CSF-1 (CSF-1-TECs) and placed these cell s with BMM phi under the renal capsule. CSF-1-TEC + BMM phi caused a g reater accumulation of M phi in the implant site and interstitium of M RL +/+ than C3H +/+ mice. Furthermore, CSF-1-TEC + BMM phi caused a le sion consisting of M phi in MRL +/+ mice, extending from the implant i nto the adjacent cortex. We suggest that the response of MRL M phi to CSF-1 is responsible for the notable accumulation of M phi in the MRL- lpr kidney.