Gene transfer of RANTES elicits autoimmune renal injury in MRL-Fas(1pr) mice.
We report that the beta-chemokine RANTES, a chemoattractant for macrophages and T cells, is up-regulated in the MRL-Fas(1pr) kidney prior to injury, but not normal kidneys (MRL-++, C3H-++) and increases with progressive injury. Furthermore, we establish an association between RANTES expression in the kidney and renal damage using a gene transfer approach. Tubular epithelial cells genetically modified to secrete RANTES infused under the renal capsule incites interstitial nephritis in MRL-Fas(1pr), but not MRL-++ or C3H-++ mice. RANTES recruits predominantly macrophages (M phi) and CD4+ and CD8+ T cells. In contrast, gene transfer of CSF-1, another molecule up-regulated simultaneously with RANTES in MRL-Fas(1pr) kidneys, promotes the influx of M phi, CD4+ T cells and the unique double-negative (DN) T cells (CD4-, CD8-), which are prominent in diseased MRL-Fas(1pr) kidneys. Thus, RANTES and CSF-1 recruit distinct T cell populations into the MRL-Fas(1pr) kidney. In addition, delivery of RANTES and CSF-1 into the kidney of MRL-Fas(1pr) mice causes an additive increase in pathology. We suggest that the complementary recruitment of T cell populations by RANTES (CD4, CD8) and CSF-1 (CD4, DN) promotes autoimmune nephritis in MRL-Fas(1pr) mice.
Moore
K J
KJ
Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, Massachusetts, USA.
Wada
T
T
Barbee
S D
SD
Kelley
V R
VR
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D018946:Chemokine CCL5 / Q000235:genetics* / Q000494:pharmacology; D018014:Gene Transfer Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D018946:Chemokine CCL5; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor