J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/04/1371/10 $2.00
Volume 185, Number 7, April 7, 1997 1371-1380

RANTES and Monocyte Chemoattractant Protein-1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis

By Clare M. Lloyd,^*¶ Andrew W. Minto,^* Martin E. Dorf,^§ Amanda Proudfoot, Timothy N.C. Wells, David J. Salant,^* and Jose-Carlos Gutierrez-Ramos^¶

From the ^* Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118;  The Center for Blood Research, Incorporated and Department of Genetics and the ^§ Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115;  Glaxo Institute for Molecular Biology, Geneva, CH1228 Switzerland; and ^¶ Millennium Pharmaceuticals Inc., Cambridge Massachusets 02139

The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.

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