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(American Journal of Pathology. 2005;167:637-649.)
© 2005 American Society for Investigative Pathology

Blocking of Monocyte Chemoattractant Protein-1 during Tubulointerstitial Nephritis Resulted in Delayed Neutrophil Clearance

Ping Li^*, Gabriela E. Garcia^*, Yiyang Xia, Wei Wu^*, Christine Gersch, Pyong Woo Park, Luan Truong^¶, Curtis B. Wilson^||, Richard Johnson and Lili Feng^*

From the Department of Medicine,^* Renal and Infectious Disease Sections, and the Department of Pathology,^¶ Baylor College of Medicine, Houston, Texas; Torrey Pines Biolabs, Houston, Texas; the Department of Medicine, Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, Florida; and the Department of Immunology,|| The Scripps Research Institute, La Jolla, California

The chemokine monocyte chemoattractant protein (MCP)-1 has been implicated in the monocyte/macrophage infiltration that occurs during tubulointerstitial nephritis (TIN). We investigated the role of MCP-1 in rats with TIN by administering a neutralizing anti-MCP-1 antibody (Ab). We observed significantly reduced macrophage infiltration and delayed neutrophil clearance in the kidneys of TIN model rats treated with the anti-MCP-1 Ab. To exclude the possibility that an observed immune complex could affect the resolution of apoptotic neutrophils via the Fc receptor, TIN model rats were treated with a peptide-based MCP-1 receptor antagonist (RA). The MCP-1 RA had effects similar to those of the anti-MCP-1 Ab. In addition, MCP-1 did not affect macrophage-mediated phagocytosis of neutrophils in vitro. Deposition of the anti-MCP-1 Ab in rat kidneys resulted from its binding to heparan sulfate-immobilized MCP-1, as demonstrated by the detection of MCP-1 in both pull-down and immunoprecipitation assays. We conclude that induction of chemokines, specifically MCP-1, in TIN corresponds with leukocyte infiltration and that the anti-MCP-1 Ab formed an immune complex with heparan sulfate-immobilized MCP-1 in the kidney. Antagonism of MCP-1 in TIN by Ab or RA may alter the pathological process, most likely through delayed removal of apoptotic neutrophils in the inflammatory loci.

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