Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome
John A. Belperio, … , Israel F. Charo, Robert M. Strieter
John A. Belperio, … , Israel F. Charo, Robert M. Strieter
Published August 15, 2001
Citation Information: J Clin Invest. 2001;108(4):547-556. https://doi.org/10.1172/JCI12214.
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Article

Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome

Abstract

Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is characterized by perivascular/bronchiolar leukocyte infiltration. BOS is characterized by persistent peribronchiolar leukocyte recruitment leading to airway fibrosis and obliteration. The specific mechanism(s) by which these leukocytes are recruited are unknown. Because MCP-1, acting through its receptor CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persistent recruitment of leukocytes and, ultimately, rejection. We found that elevated levels of biologically active MCP-1 in human bronchial lavage fluid (BALF) were associated with the continuum from acute to chronic allograft rejection. Translational studies in a murine model of BOS demonstrated increased MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expression. Loss of MCP-1/CCR2 signaling, as seen in CCR2–/– mice or in WT mice treated with neutralizing antibodies to MCP-1, significantly reduced recruitment of mononuclear phagocytes following tracheal transplantation and led to attenuation of BOS. Lymphocyte infiltration was not reduced under these conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogenesis of BOS.

Authors

John A. Belperio, Michael P. Keane, Marie D. Burdick, Joseph P. Lynch III, Ying Ying Xue, Aaron Berlin, David J. Ross, Steven L. Kunkel, Israel F. Charo, Robert M. Strieter

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Figure 1

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(a) MCP-1 protein levels in unconcentrated BALF from healthy lung transp...
(a) MCP-1 protein levels in unconcentrated BALF from healthy lung transplant recipients compared with those of lung transplant recipients with BOS and lung transplant recipients with acute lung allograft rejection, displayed using a box plot summary. Horizontal line represents the median, the box encompasses the 25th to 75th percentiles, and the error bars encompass the 10th to 90th percentiles for MCP-1 protein levels. (b) The period, in months after lung transplantation, when the BALF was obtained for the three groups displayed, using a box plot summary. (c) BALF MCP-1 from patients with acute rejection and BOS is biologically active as determined by mononuclear cell chemotaxis. There was significantly more chemoattraction to the acute rejection and BOS BALF compared with that of healthy transplant recipients. Neutralizing antibodies to MCP-1 inhibited chemoattraction in the acute rejection and BOS groups, but not the healthy group. *P < 0.05. (d–g) BOS lung section (×400). (d and f) Lack of nonspecific staining with NRS; (e and g) anti-human MCP-1 antibodies demonstrating immunolocalization to columnar epithelium and mononuclear cells. HPF, high power field; AR, acute rejection.