Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells

1 Department of Pediatrics, Heme/Oncology/Bone and Marrow Transplant Division and Cancer Center and 2 Department of Physiology, University of Minnesota, Minneapolis, Minnesota 55455; 3 Gladstone Institute, San Francisco, California 94141; and 4 Dana Farber Cancer Institute, Boston, Massachusetts 02115 Submitted 14 May 2003 ; accepted in final form 30 September 2003 Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality post-bone marrow transplant (BMT) in humans. In our murine model, lethal pre-BMT conditioning and allogeneic T cells result in the recruitment of host antigen-presenting cells (APC) and donor T cells into the lung post-BMT concomitant with development of severe lung dysfunction. CCL2 induction is found in bronchoalveolar lavage fluid (BALF) before host monocyte influx. The major receptor for CCL2 is CCR2 present on monocytes; this interaction can play a crucial role in monocyte recruitment in inflammation. To determine whether blockade of the CCL2/CCR2 pathway could hinder host monocyte influx, lethally conditioned wild-type (WT), CCL2 -/- , or CCR2 -/- mice were transplanted with allogeneic marrow and spleen cells. WT and -/- recipients exhibited equivalent lung dysfunction post-BMT. The frequencies of host macrophages as well as donor CD4 + and CD8 + T cells in lungs post-BMT did not differ between WT and -/- recipients. However, the T cell dependency of the host CD11b + major histocompatibility complex class II + cell influx was lost in CCR2 -/- recipients. In CCR2 -/- mice, this influx was accompanied by elevated levels of CCL20. Post-BMT BALF and sera of -/- mice did not reveal any decrease in cytokines or chemokines compared with WT mice. CCL2 -/- mice had a deficiency of CCL2 in their BALF and sera post-BMT, confirming our hypothesis that CCL2 is predominantly host derived. Therefore, IPS can occur independently of host expression of CCL2 or CCR2, and compensatory mechanisms exist for regulating APC recruitment into the lung during the early post-BMT period. chemokines; mouse models; monocytes; idiopathic pneumonia syndrome; bone marrow transplant Address for reprint requests and other correspondence: A. Panoskaltsis-Mortari, Univ. of Minnesota, Dept. of Pediatrics, Division of Hematology-Oncology, Blood and Marrow Transplant Program, Mayo Mail Code 366, 420 Delaware St. SE, Minneapolis, MN 55455 (E-mail: panos001{at}umn.edu ).