The CCL2/CCR2 Axis in Primary Graft Dysfunction and Bronchiolitis Obliterans Syndrome Following Lung Transplantation

Purpose Primary graft dysfunction (PGD) following lung transplantation is a risk factor for chronic allograft rejection in the form of bronchiolitis obliterans syndrome (BOS). Previous studies have implicated the C-C chemokine receptor type 2 (CCR2)/C-C chemokine ligand 2 (CCL2) biological axis in both acute and chronic lung allograft rejection. Plasma levels of CCL2 are also elevated during PGD. This study investigated the levels of CCL2 within the local milieu of the allograft immediately following transplantation, and assessed the association between this axis, the severity of PGD, and the subsequent development of BOS. Methods and Materials A retrospective study of 81 adult lung transplant recipients with available bronchoalveolar lavage (BAL) specimens collected 24 hours after transplantation was performed. PGD grade was determined at 72 hours according to standard criteria. Levels of CCL2 were measured in BAL fluid, and compared in subjects by PGD grade. Kaplan-Meier plots of freedom from BOS were created based on dichotomized levels of CCL2 and compared by log-rank testing. Immunohistochemistry was performed for CCL2 and CCR2 on biopsies obtained from multiple recipients with PGD. Results CCL2 was significantly elevated (p Conclusions CCL2 is elevated within the local allograft milieu during primary graft dysfunction and may serve as a biomarker predictive for the early development of BOS. Moreover, expression of the ligand and its receptor at sites of small airway ischemic injury and repair suggest a possible causal role for this axis in the subsequent development of BOS.