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(American Journal of Pathology. 2003;162:1061-1073.)
© 2003 American Society for Investigative Pathology

Mononuclear Cell-Infiltrate Inhibition by Blocking Macrophage-Derived Chemokine Results in Attenuation of Developing Crescentic Glomerulonephritis

Gabriela E. Garcia^*, Yiyang Xia, Jeffrey Harrison, Curtis B. Wilson^*, Richard J. Johnson, Kevin B. Bacon^¶ and Lili Feng^*

From the Department of Immunology,^*The Scripps Research Institute, La Jolla, California; Torrey Pines Biolabs,San Diego, California; the Department of Pharmacology and Therapeutics,University of Florida, Gainesville, Florida; the Department of Medicine,Division of Nephrology, Baylor College of Medicine, Houston, Texas; and Neurocrine Biosciences,^¶San Diego, California

Glomerular monocyte/macrophage (Mo/M) infiltrates play a role in many forms of glomerulonephritis (GN), and the intensity of Mo/M trafficking correlates with the loss of renal function and histological damage. We analyzed the functional role of macrophage-derived chemokine (MDC), a potent mononuclear cell chemoattractant, during the progression of anti-glomerular basement membrane (GBM) antibody (Ab) GN, a model of crescentic GN in the WKY rat, and whether the effects of MDC were dependent on its receptor CCR4. MDC mRNA and protein expression were markedly induced in nephritic glomeruli throughout the disease. Blocking the function of MDC did not affect the developing of the disease from days 2 to 7, but it dramatically blocked Mo/M infiltration in the glomeruli, prevented crescent formation, and reversed renal function impairment during days 7 to 14 of the anti-GBM GN. In this study, we also found that MDC activity on Mo/M in this GN was at least partly dependent on a new variant of CCR4. These results suggest that MDC is critically involved in the development of anti-GBM GN from acute glomerular injury to irreversible tissue damage. In addition, an antagonist to MDC may represent a prime drug target for therapeutic application to intervene in the progression of anti-GBM GN and in other Mo/M-dominant GN.

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