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

Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is char acterized by perivascular/bronchiolar leukocyte infiltration. BOS is charac terized by persistent peribronchiolar leukocyte recruitment leading to airw ay fibrosis and obliteration. The specific mechanism(s) by which these leuk ocytes are recruited are unknown. Because MCP-1, acting through its recepto r CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persist ent recruitment of leukocytes and, ultimately, rejection. We found that ele vated levels of biologically active MCP-1 in human bronchial lavage fluid ( BALF) were associated with the continuum from acute to chronic allograft re jection. Translational studies in a murine model of BOS demonstrated increa sed MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expr ession. Loss of MCP-1/CCR2 signaling, as seen in CCR2(-/-) mice or in WT mi ce treated with neutralizing antibodies to MCP-1, significantly reduced rec ruitment of mononuclear phagocytes following tracheal transplantation and l ed to attenuation of BOS. Lymphocyte infiltration was not reduced under the se conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogene sis of BOS.